Busseltonhealthstudy

 

Recent Publications

        
There are over 300 research articles published in medical journals using the Busselton data. Many of these can be accessed through PubMed using "Busselton" as a key word. A comprehensive list of research publications are also listed here.

Below are brief descriptions and summaries of recent scientific papers that have been published in medical journals and highlight the important discoveries being made using the Busselton data. 





Eur J Endocrinol. 2011 Feb 11. [Epub ahead of print]

A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters; including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement.

Taylor P, Panicker V, Sayers A, Shields B, Iqbal A, Bremner A, Beilby J, Leedman P, Hattersley A, Vaidya B, Frayling T, Evans J, Tobias JH, Timpson NJ, Walsh JP, Dayan CM.

P Taylor, Henry Wellcome Labarotories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom.

Objective Common variants in PDE8B are associated with TSH, but apparently without any effect on thyroid hormone levels which is difficult to explain. Furthermore the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine. Design Four cohorts were used (N=2,557) the Busselton Health Study (thyroid function measured on 2 occasions), DEPTH, EFSOCH (selective cohorts) and WATTS (individuals on levothyroxine). Methods Meta-analysis to clarify associations between the rs4704397 SNP in PDE8B on TSH, T3 and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (p=1.64x10-10 0.20 SD/allele, 95%CI 0.142, 0.267) and identified a possible new association with free T4 (p=0.023, -0.07 SD/allele, 95% CI -0.137, -0.01) no association was seen with free T3 (p=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 SD/allele, 95%CI 0.04, 0.238) and 1994 (0.20 SD/allele, 95%CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (-0.068 SD/allele, 95% CI: -0.167, 0.031) and 1994 (-0.07 SD/allele, 95%CI: -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on levothyroxine. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on levothyroxine. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.






Respirology. 2011 Feb;16(2):359-66

Functional haplotypes in the PTGDR gene fail to associate with asthma in two Australian populations.

Jamrozik EF, Warrington N, McClenaghan J, Hui J, Musk AW, James A, Beilby JP, Hansen J, DE Klerk NH, Palmer LJ.

Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, West Perth, Western Australia, Australia. 


BACKGROUND AND OBJECTIVE: Haplotypes in the promoter region of the prostanoid DP receptor (PTGDR) gene have been shown to functionally influence gene transcription and to be associated with asthma in two previous case-control studies in Caucasians. This study tested the association of PTGDR haplotypes with asthma phenotypes in two large Caucasian-Australian populations. These results were incorporated in a meta-analysis with previously published data to determine the overall role for these haplotypes in the risk of asthma. METHODS: Three PTGDR promoter-region single nucleotide polymorphisms (SNP) were genotyped in 368 individuals from the Western Australian Twin Child Health study and 2988 individuals from the Busselton Health Study. Logistic regression and transition disequilibrium tests were used to assess whether SNP genotypes and three SNP haplotypes were associated with doctor-diagnosed asthma or intermediate quantitative traits. Longitudinal data from the Busselton Health Study were used to examine whether PTGDR influences changes in lung function over time. Meta-analysis incorporated the findings of this study with those of two previous studies in Caucasian populations. RESULTS: Cross-sectional associations between PTGDR haplotypes and asthma phenotypes were non-significant (P > 0.05) in both populations. Longitudinal analyses of PTGDR and lung function were also non-significant. Meta-analysis, however, suggested that haplotype TCT was significantly associated with decreased risk of asthma (OR = 0.76; P = 0.02) while haplotype CCC was not significantly associated with asthma (OR = 1.30; P = 0.07). CONCLUSIONS: These results suggest that despite the non-significant findings in the present study populations, PTGDR promoter haplotypes may account for a small but significant proportion of the risk of asthma in Caucasian populations.





Genet. 2010 Oct 8;11:140.

The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI.

Webster RJ, Warrington NM, Beilby JP, Frayling TM, Palmer LJ.

Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, WA, Australia.


BACKGROUND: Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI). METHODS: The study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. RESULTS: In cross-sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the A allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood. CONCLUSIONS: There was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time.



Am J Hum Genet. 2010 Sep 10;87(3):430-5.

A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study.

Panicker V, Wilson SG, Walsh JP, Richards JB, Brown SJ, Beilby JP, Bremner AP, Surdulescu GL, Qweitin E, Gillham-Nasenya I, Soranzo N, Lim EM, Fletcher SJ, Spector TD.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia.


Thyroid hormones are key regulators of cellular growth, development, and metabolism, and thyroid disorders are a common cause of ill health in the community. Circulating concentrations of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) have a strong heritable component and are thought to be under polygenic control, but the genes responsible are mostly unknown. In order to identify genetic loci associated with these metabolic phenotypes, we performed a genome-wide association study of 2,120,505 SNPs in 2014 female twins from the TwinsUK study and found a significant association between rs10917469 on chromosome 1p36.13 and serum TSH (p = 3.2 × 10(-8)). The association of rs10917469 with serum TSH was replicated (p = 2.0 × 10(-4)) in an independent community-based sample of 1154 participants in the Busselton Health Study. This SNP is located near CAPZB, which might be a regulator of TSH secretion and thus of pituitary-thyroid axis function. Twenty-nine percent of white individuals carry the variant, and the difference in mean TSH concentrations between wild-type individuals and those homozygous for the minor G allele was 0.5 mU/l, which is likely to be clinically relevant. We also provide evidence of suggestive association (p < 5.0 × 10(-6)) of other SNPs with serum TSH, free T4, and free T3 concentrations, and these SNPs might be good targets for further studies. These results advance understanding of the genetic basis of pituitary-thyroid axis function and metabolic regulation.


 

Cancer Epidemiol Biomarkers Prev. 2010 Sep;19(9):2238-46

SERUM MESOTHELIN FOR EARLY DETECTION OF THE ASBESTOS-INDUCED CANCER MALIGANT MESOTHELIOMA.

Creaney J, Olsen NJ, Brims F, Dick IM, Musk AW, de Klerk NH, Skates SJ, Robinson BW.

School of Medicine and Pharmacology, University of Western Australia.

 

BACKGROUND: Malignant mesothelioma is an aggressive, almost uniformly fatal tumour, primarily caused by exposure to asbestos. Since the recent discovery that serum mesothelin is a sensitive and highly specific biomarker for mesothelioma one of the key issues raised is whether mesothelin levels represent a useful screening test for asbestos-exposed at-risk individuals. In this study soluble mesothelin was determined in sequential serum samples collected from asbestos-exposed individuals prior to the development of mesothelioma.

METHODS: Archival serum samples from 106 individuals who developed mesothelioma and 99 asbestos exposed individuals from the Wittenoom Cancer Surveillance Program and from 109 non-asbestos exposed individuals from the Busselton Health Survey were identified and serum mesothelin concentrations were determined using the MESOMARK assay.

RESULTS: Longitudinal mesothelin levels determined in healthy asbestos exposed individuals over a period of 4 years were stable (Pearson's r=0.96; p<0.0001). There was no correlation between mesothelin concentration and cumulative asbestos exposure. Mesothelin concentrations were greater than a threshold of 2.5nM in the penultimate serum sample before the diagnosis of mesothelioma in 17 of 106 people. Using an increase above the 95% confidence interval of the mean of a given individual's longitudinal mesothelin results, 33 out of 82 individuals had increasing mesothelin levels before diagnosis.

CONCLUSION: In a population with a high pre-test probability of developing mesothelioma the serum biomarker mesothelin is elevated in absolute terms in 15% and in relative terms in 40% of the group.Impact: Future studies examining a combination of biomarkers could improve sensitivity of screening.

 


J Sleep Res. 2011 Mar;20(1pt2):241-249

Gastro-oesophageal reflux symptoms are related to the presence and severity of obstructive sleep apnoea.

Shepherd KL, James AL, Musk AW, Hunter ML, Hillman DR, Eastwood PR.

Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Nedlands, Australia.

 

Summary: Repetitive airway occlusion during sleep in patients with obstructive sleep apnoea (OSA) results in the generation of negative intrathoracic pressures and ends in arousal, both of which may predispose to reflux during sleep (nocturnal reflux). We aimed to determine and compare the prevalence of nocturnal reflux symptoms and their sleep-associated risk factors in untreated OSA patients, OSA patients using continuous positive airway pressure (CPAP) therapy, and the general population. Gastro-oesophageal reflux and sleep questionnaires were completed by 1116 patients with polysomnography diagnosed OSA and by 1999 participants of the 2007 Busselton population health survey. Of the OSA patients, 137 completed the reflux questionnaire before and after treatment. Risk of OSA in the general population was assessed using the Berlin score. The prevalence of frequent (>weekly) nocturnal reflux symptoms was increased (P < 0.001) in OSA patients (10.2%) versus the general population (5.5%), in individuals from the general population at high (8.7%) versus low risk (4.3%) of OSA and in patients with severe (13.9%) versus mild OSA (5.1%). Frequent nocturnal reflux symptoms were associated with high risk (general population) (OR 1.9, P < 0.01) and severity of OSA (OSA population) OR 3.0, severe versus mild OSA, P < 0.001) after correcting for age, gender and body mass index. Treatment with CPAP decreased the prevalence of reflux symptoms significantly. In conclusion, the prevalence of nocturnal reflux symptoms is increased in those with or suspected of having OSA. This association is independent of other risk factors including age, gender and body mass index, suggesting a causal relationship between OSA and nocturnal reflux.

 


Respir Physiol Neurobiol. 2010 Jul 31;172(3):162-8..

Reference equations for respiratory system resistance and reactance in adults.

Brown NJ, Xuan W, Salome CM, Berend N, Hunter ML, Musk AW, James AL, King GG.

The Woolcock Institute of Medical Research, Glebe, NSW, Australia. njb@woolcock.org.au

 

AIM: To determine reference equations for respiratory system resistance and reactance in a large randomly selected sample from a general, predominantly Caucasian population.

METHODS: A prospective respiratory health survey of the general population in Busselton, Western Australia, was conducted between 2005 and 2007. Subjects had measures of spirometry, and resistance and reactance at 6, 11, 19 Hz. Eligible subjects were never smokers, with no history of respiratory disease, no symptoms of cough, shortness of breath or chest tightness in the previous 12 months, and no respiratory tract infections in the previous 4 weeks.

RESULTS: 904 Eligible subjects (341 male) aged 18-92 years had technically satisfactory measurements. Reference equations were established for males and females separately. Both resistance and reactance were predicted by height and weight. Age was a predictor of reactance only.

CONCLUSIONS: These data provide reference equations for forced oscillatory parameters, in well-characterized Caucasian subjects, with no respiratory symptoms, from a large general population.

 


Mult Scler. 2010 May;16(5):526-32.

Influence of HLA-DRB1 allele heterogeneity on disease risk and clinical course in a West Australian MS cohort: a high-resolution genotyping study.

Wu JS, James I, Wei Qiu, Castley A, Christiansen FT, Carroll WM, Mastaglia FL, Kermode AG.

Centre of Neuromuscular and Neurological Disorders, University of Western Australia, and Department of Neurology, Sir Charles Gairdner Hospital, Queen Elizabeth Medical Centre, Perth, Western Australia, Australia.

 

BACKGROUND: Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method.

OBJECTIVE: To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping.

METHODS: Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study.

RESULTS: In addition to the known risk allele HLA-DRB1*1501, evidence of increased susceptibility to MS was found for three additional alleles, DRB1*0405, DRB1*1104 and DRB1*1303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB1*0701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB1*04 sub-allele HLA-DRB1*0407 and HLA-DRB1*0901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB1*1501/*0801 heterozygotes and DRB1*1501 homozygotes and the lowest in HLA-DRB1*0701/*0101 heterozygotes. There was no significant gender association with HLA-DRB1*1501 overall, but the HLA-DRB1*1501/*1104 risk genotype was significantly associated with female gender. HLA-DRB1*1501 was the strongest risk allele in both primary progressive MS and relapsing-remitting MS.

CONCLUSION: Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB1*04 and DRB1*11 sub-alleles.

 


Clin Chem. 2010 May;56(5):799-804. 

Comparison of cystatin C and creatinine as predictors of cardiovascular events in a community-based elderly population.

Beilby J, Divitini ML, Knuiman MW, Rossi E, Hung J.

Biochemistry Section, PathWest, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia.

 

BACKGROUND: Reduced renal function is an established risk factor for cardiovascular events. We compared 3 measures of renal function--serum cystatin C, serum creatinine, and calculated creatinine clearance--as predictors of subsequent cardiovascular events in a community-based population of elderly individuals.

METHODS: Comprehensive cardiovascular risk factor data were available for 1410 surviving participants of previous Busselton health surveys who were >or=60 years old. Hazard ratios for risk of incident coronary heart disease and cardiovascular disease over 10 years of follow-up were derived for each baseline measure of renal function by use of Cox regression.

RESULTS: All measures of renal function were significantly related to risks of morbidity and mortality from coronary heart disease and cardiovascular disease. There were 453 incident cardiovascular disease events; and the age- and sex-adjusted hazard ratios (95% CIs) were 1.34 (1.23-1.46), 1.32 (1.20-1.45), and 1.22 (1.06-1.41) per 1-SD deterioration in cystatin C, creatinine, and creatinine clearance, respectively. All 3 measures gave approximately the same age-adjusted relative risk estimates. After further adjustment for established cardiovascular risk factors, the relative risk estimates were all reduced but remained statistically significant (P < 0.05). Cystatin C was not a significant predictor for cardiovascular disease after adjustment for creatinine clearance.

CONCLUSIONS: In relation to predicting risk for coronary heart disease or cardiovascular disease over a 10-year follow-up in a community-based population of elderly subjects, there was no evidence that cystatin C was a better risk predictor than creatinine or creatinine clearance.

 


J Alzheimers Dis. 2010;20(2):617-23.

A cross-sectional community study of serum iron measures and cognitive status in older adults.

Milward EA, Bruce DG, Knuiman MW, Divitini ML, Cole M, Inderjeeth CA, Clarnette RM, Maier G, Jablensky A, Olynyk JK.

The School of Biomedical Sciences, University of Newcastle, Callaghan, Australia. Liz.Milward@newcastle.edu.au

 

The relationship of iron status with cognition and dementia risk in older people is contentious. We have examined the longitudinal relationship between serum ferritin and cognition in 800 community-dwelling Australians 60 years or older. Iron studies (serum iron, transferrin saturation, serum ferritin) were performed in 1994/5 and 2003/4 and clinical and cognitive assessments were conducted in 2003/4 for 800 participants of the Busselton Health Study. All participants completed the Cambridge Cognitive test (CAMCOG). Those with CAMCOG scores <84 underwent expert clinical review for cognitive disorders, including the Clinical Dementia Rating scale. Mean serum iron (18.3 micromol/l) and transferrin saturation (28.5%) in 2003/4 did not differ significantly from 1994/5 whereas mean serum ferritin decreased from 162 microg/l in 1994/5 to 123 microg/l in 2003/4, possibly reflecting aging or dietary changes. No relationships were observed between serum iron or transferrin saturation and presence or absence of dementia (p> 0.05). In participants without dementia (n=749), neither serum ferritin in 1994/5 or 2003/4 nor change in serum ferritin between these times was related to total CAMCOG or executive function scores, with or without adjustment for gender, age, National Adult reading test, or stroke history (all p> 0.05). No relationships were observed between ferritin and cognition for participants with possible or probable dementia (n=51). All participants identified as HFE C282Y homozygous or with serum ferritin >1,000 ng/ml had normal CAMCOG scores. We conclude abnormal body iron stores (low or high) are unlikely to have clinically significant effects on cognition or dementia risk in community-dwelling older people.

 


J Clin Endocrinol Metab. 2010 Mar;95(3):1095-104. Epub 2010 Jan 22.

Thyrotropin and thyroid antibodies as predictors of hypothyroidism: a 13-year, longitudinal study of a community-based cohort using current immunoassay techniques.

Walsh JP, Bremner AP, Feddema P, Leedman PJ, Brown SJ, O'Leary P.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009. john.walsh@health.wa.gov.au

 

Context: Longitudinal studies of risk factors for hypothyroidism are required to inform debate regarding the TSH reference range. There are limited longitudinal data on the predictive value of thyroid antibodies measured by automated immunoassay (as opposed to semiquantitative methods). Methods: We measured TSH, free T(4), thyroid peroxidase antibodies (TPOAbs), and thyroglobulin antibodies (TgAbs) using the Immulite platform on sera from 1184 participants in the 1981 and 1994 Busselton Health Surveys. Outcome measures at follow-up were hypothyroidism, defined as TSH greater than 4.0 mU/liter or on thyroxine treatment; and overt hypothyroidism, defined as TSH above 10.0 mU/liter or on thyroxine treatment. Receiver-operator characteristic analysis was used to determine optimal cutoffs for baseline TSH, TPOAbs, and TgAbs as predictors of hypothyroidism. Results: At 13 yr follow-up, 110 subjects (84 women) had hypothyroidism, of whom 42 (38 women) had overt hypothyroidism. Optimal cutoffs for predicting hypothyroidism were baseline TSH above 2.5 mU/liter, TPOAbs above 29 kIU/liter, and TgAbs above 22 kIU/liter, compared with reference range upper limits of 4.0 mU/liter, 35 kIU/liter, and 55 kIU/liter, respectively. In women with positive thyroid antibodies (TPOAbs or TgAbs), the prevalence of hypothyroidism at follow-up (with 95% confidence intervals) was 12.0% (3.0-21.0%) when baseline TSH was 2.5 mU/liter or less, 55.2% (37.1-73.3%) for TSH between 2.5 and 4.0 mU/liter, and 85.7% (74.1-97.3%) for TSH above 4.0 mU/liter. Conclusions: The use of TSH cutoffs of 2.5 and 4.0 mU/liter, combined with thyroid antibodies, provides a clinically useful estimate of the long-term risk of hypothyroidism.

 


Respirology. 2009 Aug;14(6):814-21.

Risk factors for adult-onset asthma: a 14-year longitudinal study.

Jamrozik E, Knuiman MW, James A, Divitini M, Musk AW.

Busselton Health Study, University of Western Australia, Nedlands, WA, Australia. zeb.jamrozik@gmail.com

 

BACKGROUND AND OBJECTIVES: Few longitudinal studies have examined the risk factors and natural history of adult-onset asthma. This study assessed the subject characteristics and lifestyle factors that predicted the new diagnosis of asthma in adulthood and how these factors changed over time in those who developed asthma compared with those who do not.

METHODS: The study enrolled 1554 adults from the Busselton Health Study seen in 1981 and again in 1994-1995 who initially reported never having had doctor-diagnosed asthma. Questionnaire measures were used to assess doctor-diagnosed asthma, respiratory history and tobacco smoking. Height, weight and spirometric measures of lung function were measured. Atopy was assessed by skin prick tests. Logistic regression analysis was used to identify risk factors for adult-onset asthma and changes over time.

RESULTS: Reported wheeze, rhinitis, chronic cough, smoking and lower levels of lung function in 1981 each predicted asthma diagnosis by 1994-1995. Neither initial skin-prick reactivity nor newly positive skin-prick tests at follow up were associated with adult-onset asthma. Those diagnosed with asthma were more likely to have new wheeze, new rhinitis, new habitual snoring, weight gain and excess decline in lung function.

CONCLUSIONS: Adult-onset asthma has risk factors that are distinct from those observed in childhood asthma. The presence of upper airway symptoms including rhinitis, as well as lifestyle factors, such as smoking, predicts those at greatest risk. However, neither pre-existing atopy nor new atopy as measured by skin prick tests was associated with adult-onset asthma.

 


Eur Respir J. 2010 Feb;35(2):273-8. Epub 2009 Jul 30.

Changes in the prevalence of asthma in adults since 1966: the Busselton health study.

James AL, Knuiman MW, Divitini ML, Hui J, Hunter M, Palmer LJ, Maier G, Musk AW.

Dept of Pulmonary Physiology/West Australian Sleep Disorders Research Institute, Level 5, G Block, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009, Australia. Alan.James.SCGH@health.wa.gov.au

 
Asthma prevalence has increased worldwide; although less so in developed countries recently. This study assessed changes in the prevalence of asthma and related symptoms in the Busselton community since 1966. Cross-sectional respiratory health surveys of Busselton adults were conducted in 1966, 1969, 1972, 1975, 1981, 1990 and 2005-2007. Logistic regression models were used to estimate prevalence rates of asthma, respiratory symptoms, smoking, airway hyperresponsiveness (AHR) and atopy and to make comparisons in 2005-2007 and previous survey years. Asthma was defined as ever having doctor-diagnosed asthma (DDA). The prevalence of DDA was around 6% from 1966 to 1975, 8% in 1981 and rose to 19% in 2005-2007. From 1981 to 2005-2007, smoking prevalence declined and obesity and atopy increased but changes in these variables explained only a small part of the increase in DDA. Wheeze and cough/phlegm increased but AHR, breathlessness and doctor-diagnosed bronchitis remained relatively stable over the same period. These observations indicate that the increase in DDA is partly explained by increased symptoms and atopy. The lack of changes in AHR and doctor-diagnosed bronchitis suggests that factors such as diagnostic transfer and increased awareness of asthma have also contributed to the rise in prevalence of DDA.

 


Am J Gastroenterol. 2009 Jul;104(7):1715-22. Epub 2009 Jun 2.

Serum alanine aminotransferase, metabolic syndrome, and cardiovascular disease in an Australian population.

Olynyk JK, Knuiman MW, Divitini ML, Davis TM, Beilby J, Hung J.

School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia. john.olynyk@uwa.edu.au

 

OBJECTIVES: Elevations of serum alanine aminotransferase (ALT) are common and have been associated with metabolic syndrome (Met S) and cardiovascular risk. The aim of this study was to determine whether elevated ALT concentrations are predictive of Met S or cardiovascular events.

METHODS: In 1994/95, surviving participants of the previously conducted Busselton health population surveys completed a series of clinical and biochemical assessments. Using the Western Australian Health Department data linkage system, admissions for cardiovascular disease (CVD) were determined for 15 years before the survey (from 1980 to 1994). Incident CVD events during the 10-year follow-up period to the end of 2004 were also ascertained. Met S was defined using NCEP ATP III (2005) criteria.

RESULTS: 3,719 Subjects (1,544 men and 2,175 women), aged 25-84 years who did not have serologically diagnosable chronic liver diseases or excessive consumption of alcohol, had their levels of ALT measured. The prevalence of Met S was 17% in men and 15% in women. In age-adjusted analyses, ALT was significantly associated with Met S and each of its five components and the association with Met S remained significant after adjustment for insulin resistance. There was no positive association between ALT and incident CVD events over the 10-year follow-up period in age-adjusted or multivariate-adjusted analyses.

CONCLUSIONS: The findings from this Australian population-based cohort study support a strong association between ALT concentration and Met S independent of insulin resistance. Serum ALT level does not appear to contribute significantly to cardiovascular risk assessment.

 


Med J Aust. 2009 Apr 20;190(8):429-32.

Screening for coeliac disease using anti-tissue transglutaminase antibody assays, and prevalence of the disease in an Australian community.

Chin MW, Mallon DF, Cullen DJ, Olynyk JK, Mollison LC, Pearce CB.

Department of Hepatology, Sir Charles Gairdner Hospital, Perth, WA. marcus.chin@health.wa.gov.au

 

OBJECTIVES: To determine (i) the prevalence of positive results of anti-tissue transglutaminase (anti-tTG) antibody assays and coeliac disease (CD) in a rural Australian community; and (ii) whether confirmatory testing of a positive assay result with an alternative anti-tTG assay improved the positive predictive value of the test in population screening for CD.

DESIGN: Retrospective analysis in December 2004 of stored serum samples taken in 1994-1995 from 3011 subjects in the Busselton Health Study follow-up. Assays for IgA and IgG anti-tTG antibodies were performed, and positive or equivocal samples were retested with a different commercial anti-tTG assay. Available subjects with one or more positive assay results were interviewed, had serum collected for repeat anti-tTG assays and for HLA-DQ2 and HLA-DQ8 haplotyping and, if appropriate, gastroscopy and duodenal biopsy were performed. In unavailable subjects, HLA-DQ2 and -DQ8 haplotyping was performed on stored sera. Total serum IgA levels were assessed in subjects with initially negative assay results.

MAIN OUTCOME MEASURE: Prevalence of anti-tTG positivity and biopsy-proven CD.

RESULTS: In 47 of 3011 serum samples (1.56%), at least one anti-tTG assay gave positive results: 31 of the subjects who provided these sera were available for clinical review, and 21 were able to have a gastroscopy. Seventeen subjects (0.56%) were diagnosed with definite CD (14 were confirmed at gastroscopy, and three unavailable subjects had three positive results of anti-tTG assays and an HLA haplotype consistent with CD); in a further 12 unavailable subjects, CD status was considered equivocal, with one or more positive anti-tTG assay results and an HLA haplotype consistent with CD. If these subjects were regarded as having CD, the prevalence of CD would be 0.96%. The positive predictive value when all three anti-tTG assays gave positive results was 94%, but fell to 45.2% with only one positive result.

CONCLUSIONS: The prevalence of anti-tTG antibodies in this population is 1.56%; the prevalence of CD is at least 0.56%. The utility of a single, positive result of an anti-tTG assay in screening for CD in the community is poor, and repeat and/or collateral assessment with different assays may decrease the need for gastroscopy and distal duodenal biopsy.

 


Intern Med J. 2010 Apr;40(4):286-92. Epub 2009 Mar 23.

An Australian cardiovascular risk equation for type 2 diabetes: the Fremantle Diabetes Study.

Davis WA, Knuiman MW, Davis TM.

University of Western Australia, School of Medicine and Pharmacology, Fremantle Hospital, Fremantle, Australia. wdavis@meddent.uwa.edu.au

 

BACKGROUND: There is no valid cardiovascular disease (CVD) risk prediction equation for Australians with diabetes. The aim of this study is to develop and validate a multivariate risk function for 5-year cardiovascular risk prediction in Australian type 2 diabetes patients.

METHODS: The Fremantle Diabetes Study is a community-based longitudinal observational study. A total of 1240 type 2 diabetic patients (95.8% of the baseline cohort) with all required risk factor data were followed from baseline (1993-1996) for 5 years or until they experienced a cardiovascular event or died, whichever came first. CVD during follow up was defined as hospitalization for/with myocardial infarction or stroke, and death from cardiac or cerebrovascular causes or sudden death. Validation of the algorithm was performed on an independent diabetic cohort from the Busselton Health Study.

RESULTS: During 5570 patient-years of follow up, 185 (14.9%) had at least one CVD event and 175 (14.1%) died (57.7% from CVD). Variables in the final model comprised age, sex, prior CVD, ln(urinary albumin : creatinine ratio), lnHbA(1c), ln(high density lipoprotein-cholesterol), Southern European ethnic background and Aboriginality. The mean 5-year predicted risk of a CVD event was 15.5%. Applied to the Busselton cohort, discrimination of the model was good (AUC = 0.84, P < 0.001) as was the goodness-of-fit (Hosmer-Lemeshow C-test, P= 0.85) and accuracy (mean squared error (95% confidence interval) = 0.09 (0-0.76)). The positive and negative predictive values for a 10% 5-year CVD risk cut-off were 23.4% and 97.7% respectively.

CONCLUSION: This simple diabetes-specific 5-year CVD risk equation is the first validated, population-based Australian model. It should have a role in diabetes management in primary and specialist care.

 


J Clin Sleep Med. 2009 Feb 15;5(1):15-20.

Is sleep apnea an independent risk factor for prevalent and incident diabetes in the Busselton Health Study?

Marshall NS, Wong KK, Phillips CL, Liu PY, Knuiman MW, Grunstein RR.

Woolcock Institute of Medical Research, University of Sydney, Australia. nmarshall@med.usyd.edu.au

 

BACKGROUND: Cross-sectional analyses of North American population-based cohorts and one nonsignificant longitudinal analysis have suggested that obstructive sleep apnea (OSA) is a risk factor for diabetes mellitus. However, this observation has yet to be replicated outside the USA or be observed lonigitudinally.

METHODS: Residents of the Western Australian town of Busselton had their OSA quantified by the respiratory disturbance index (RDI) overnight in their own homes (MESAM IV device). Diabetes was defined as either a fasting blood glucose > or = 7 mmol/L or physician diagnosed diabetes.

RESULTS: Of 399 participants at baseline, 295 had complete data and did not have diabetes at baseline; 9 incident cases were observed within 4 years. At baseline moderate-severe OSA was associated with a univariate, but not multivariate, increased risk of diabetes (odds ratio = 4.37, 95% CL = 1.12, 17.12). Longitudinally, moderate-severe OSA was a significant univariate and independent risk factor for incident diabetes (fully adjusted OR = 13.45, 95% CL = 1.59, 114.11).

CONCLUSIONS: Moderate-severe sleep apnea was a significant risk factor for incident diabetes in this Australian population-based cohort. However, the confidence intervals were wide and meta-analyses or studies with greater power will be required to verify the relationship between sleep apnea and the incidence of diabetes in community-based populations.

 


Am J Gastroenterol. 2009 Apr;104(4):861-7. Epub 2009 Mar 17.

NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study.

Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK.

School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, Australia. leon.adams@uwa.edu.au

 

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) uncommonly results in cirrhosis and liver-related death; however, its impact on the development of metabolic complications remains unclear. We sought to determine whether NAFLD with elevated aminotransaminase (ALT) levels was a risk factor for incident diabetes or the metabolic syndrome (MS) over an 11-year period.

METHODS: Adult residents of Busselton, Western Australia underwent assessment in 1994-1995 as part of the Busselton Health Survey. NAFLD was diagnosed on the basis of a raised ALT (>40 IU/l) after the exclusion of alcohol, viral, metabolic, and autoimmune liver disease. NAFLD and non-NAFLD subjects were reassessed in 2005 for liver complications, diabetes, and the MS.

RESULTS: A total of 358 subjects, 68% male (109 NAFLD, 249 non-NAFLD), mean age (s.d.) 59.9 (11.6) years, attended follow-up 11.1 years after the initial assessment. After excluding subjects with diabetes at baseline, those with NAFLD were more likely to have developed diabetes on follow-up (20/106, 18.9% vs. 15/246, 6.1%; P<0.001). After excluding subjects with MS at baseline, those with NAFLD were more likely to have developed MS at follow-up (27/81, 33.3% vs. 51/226, 22.6%; P=0.056). However, in multivariate logistic regression models, NAFLD was no longer a significant independent predictor of the development of diabetes or MS after adjusting for baseline waist circumference, hypertension, and insulin resistance. None of the subjects developed liver complications.

CONCLUSIONS: Subjects with NAFLD and elevated ALT levels are at an increased risk of developing diabetes and the MS. This may be because of the presence of associated metabolic risk factors.

 


Eur J Cardiovasc Prev Rehabil. 2009 Apr;16(2):235-41.

Utility of the metabolic syndrome and its components in the prediction of incident cardiovascular disease: a prospective cohort study.

Knuiman MW, Hung J, Divitini ML, Davis TM, Beilby JP.

School of Population Health, University of Western Australia, Nedlands, Western Australia, Australia. Matthew.Knuiman@uwa.edu.au

 

BACKGROUND: To investigate the prognostic importance of the metabolic syndrome (MetS) on incident cardiovascular disease (CVD).

DESIGN: Prospective cohort study.

METHODS: The study was based on 10-year follow-up of 3041 men and women aged 25-84 years without CVD or diabetes who participated in the 1994/1995 Busselton Health Survey. Hazards ratio (HRs) from Cox regression models were used to describe the effect of the MetS as a dichotomous classification and as the number of risk components on incident coronary heart disease (CHD), stroke and all CVD events.

RESULTS: All cardiovascular and metabolic risk factors studied showed a strong association with the number of MetS risk components. The age-adjusted and sex-adjusted HR for the MetS was 1.70 (95% confidence interval: 1.15-2.51) for incident CHD but this was reduced to almost unity after adjustment for cardiovascular risk factors or the homoeostasis model assessment measure of insulin resistance. However, the number of MetS risk components remained significant (P<0.01) with those having 3+ risk components with a three-fold increase in risk compared with those with no risk components (adjusted HR: 3.59, 95% confidence interval: 1.43-8.99).

CONCLUSION: Consideration of the number of MetS risk components seems to be more informative than the (dichotomous) MetS classification when determining risk in clinical practice. Identification of people without any MetS risk components is clinically valuable, as these people seem to have a substantially reduced risk of developing CHD.

 


Intern Med J. 2009 Aug;39(8):532-8. Epub 2008 Aug 16.

Serum testosterone levels correlate with haemoglobin in middle-aged and older men.

Yeap BB, Beilin J, Shi Z, Knuiman MW, Olynyk JK, Bruce DG, Milward EA.

School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.

 

BACKGROUND: Lower testosterone levels are associated with anaemia in older men and women. The relation between testosterone and haemoglobin (Hb) in younger and middle-aged men is less well defined. The aim of the study was to examine the association between testosterone and Hb levels in men spanning middle to older ages.

METHODS: A cross-sectional analysis of 492 men aged 30.7-94.5 years from the Busselton Health Survey, Western Australia, was carried out. Haemoglobin (Hb), early-morning serum total testosterone and sex hormone-binding globulin (SHBG) were measured. Free testosterone was calculated using mass action equations.

RESULTS: Haemoglobin correlated to total and free testosterone concentrations (r= 0.13, P= 0.003 and r= 0.20, P < 0.001, respectively). Hb and SHBG were inversely correlated (r=-0.14, P= 0.001). Hb increased across lowest to highest quartiles of total testosterone (P= 0.02) and free testosterone (P < 0.001), but not SHBG. After adjusting for age, waist circumference, smoking status, alcohol consumption, renal function and ferritin, total testosterone was associated with Hb (beta= 0.037, P= 0.003) as was free testosterone (beta= 2.32, P < 0.001), whereas SHBG was not associated.

CONCLUSION: Testosterone concentration modulates Hb levels in community-dwelling men across a wide age range. Further studies are needed to clarify implications of this association between testosterone and Hb in men.

 


Diabetologia. 2009 Jan;52(1):106-14. Epub 2008 Nov 19.

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits.

Webster RJ, Warrington NM, Weedon MN, Hattersley AT, McCaskie PA, Beilby JP, Palmer LJ, Frayling TM.

Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, B Block, Queen Elizabeth II Medical Centre, Nedlands, WA 6009, Australia. bwebster@meddent.uwa.edu.au

 

AIMS/HYPOTHESIS: Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels.

METHODS: The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.

RESULTS: The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007).

CONCLUSIONS/INTERPRETATION: The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.

 


Sleep. 2008 Aug 1;31(8):1079-85.

Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study.

Marshall NS, Wong KK, Liu PY, Cullen SR, Knuiman MW, Grunstein RR.

Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia. nmarshall@woolcock.org.au

 

BACKGROUND: Previously published cohort studies in clinical populations have suggested that obstructive sleep apnea (OSA) is a risk factor for mortality associated with cardiovascular disease. However, it is unknown whether sleep apnea is an independent risk factor for all-cause mortality in a community-based sample free from clinical referral bias.

METHODS: Residents of the Western Australian town of Busselton underwent investigation with a home sleep apnea monitoring device (MESAM IV). OSA was quantified via the respiratory disturbance index (RDI). Mortality status was determined in 397/400 participants (99.3%) after up to 14 years (mean follow-up 13.4 years) by data matching with the Australian National Death Index and the Western Australian Death Register. Univariate analyses and multivariate Cox proportional hazards modelling were used to ascertain the association between sleep apnea and mortality after adjustment for age, gender, body mass index, mean arterial pressure, total cholesterol, high-density lipoprotein cholesterol, diabetes, and medically diagnosed angina in those free from heart attack or stroke at baseline (n = 380).

RESULTS: Among the 380 participants, 18 had moderate-severe OSA (RDI > or = 15/hr, 6 deaths) and 77 had mild OSA(RDI 5 to < 15/hr, 5 deaths). Moderate-to-severe OSA was independently associated with greater risk of all-cause mortality (fully adjusted hazard ratio [HR] = 6.24, 95% CL 2.01, 19.39) than non-OSA (n = 285, 22 deaths). Mild OSA (RDI 5 to < 15/hr) was not an independent risk factor for higher mortality (HR = 0.47, 95% CL 0.17, 1.29).

CONCLUSIONS: Moderate-to-severe sleep apnea is independently associated with a large increased risk of all-cause mortality in this community-based sample.

 


J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 1):1089-93. Epub 2008 Jun 28.

Body mass index is a stronger predictor of alanine aminotransaminase levels than alcohol consumption.

Adams LA, Knuiman MW, Divitini ML, Olynyk JK.

School of Medicine and Pharmacology, Fremantle Hospital Campus, The University of Western Australia, Fremantle, Australia. leon.adams@uwa.edu.au

 

BACKGROUND AND AIMS: The relative effects of obesity compared to alcohol on liver injury are uncertain. We examined their effects on alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels in a population-based cohort.

METHODS: Adult residents (2610: 1326 males, 1284 females) from Busselton, Australia, participated in a cross-sectional survey determining alcohol intake as determined by a validated questionnaire, anthropometric measurements and serum analysis. Alcohol consumption was classified as never, light (<140 g/week), moderate (140-420 g/week) or heavy (>420 g/week).

RESULTS: The majority of subjects were either overweight (41%) or obese (17%). A minority of subjects were moderate (25%) or heavy drinkers (4%). Body mass index (BMI) and waist circumference were strongly associated with ALT and GGT (P < 0.0001 for all tests). Alcohol consumption was modestly associated with ALT in females (P = 0.01) but not in males (P = 0.9). In contrast, GGT was significantly associated with alcohol in both genders (P < 0.0005). The risk of an elevated ALT was seven-fold higher with obesity but only two-fold higher with moderate or heavy alcohol use. Obesity accounted for half of all elevated ALT levels in the cohort, whereas alcohol excess was responsible for less than 10%. No synergistic effect was observed between BMI or waist circumference and alcohol on ALT or GGT (P > 0.2 for all tests).

CONCLUSIONS: Excess weight is more common than excessive alcohol consumption in the community and confers a greater risk of elevated aminotransaminase levels.

 


Mayo Clin Proc. 2008 May;83(5):543-9.

Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations.

Milward EA, Baines SK, Knuiman MW, Bartholomew HC, Divitini ML, Ravine DG, Bruce DG, Olynyk JK.

School of Biomedical Sciences and Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW, Australia.

 

OBJECTIVE: To investigate whether citrus fruit, noncitrus fruit, and other dietary factors act as environmental modifiers of iron status in the absence or presence of hemochromatotic HFE gene mutations.

PARTICIPANTS AND METHODS: Iron studies, HFE genotypic analyses, and dietary data from a survey conducted from March 21, 1994, through December 15, 1995, were analyzed for a group of 2232 residents (1105 men, 1127 women) aged 20 to 79 years recruited from the community electoral roll of Busselton in Western Australia. Data were analyzed by linear regression analysis and analysis of covariance.

RESULTS: Higher levels of fresh fruit intake (excluding citrus fruits and citrus juices) had a significant protective effect (P=.002) against high body iron status as gauged by ferritin levels in men, irrespective of HFE genotype. Consumption of 2 or more pieces of fruit per day on average reduced mean serum ferritin levels by 20% compared with average consumption of less than 1 piece of fruit per day. This effect was not observed in women. Consumption of citrus fruits and citrus juices had no significant effects in either sex. No protective effects were observed for tea consumption or any other dietary factors studied. Red meat and alcohol consumption correlated with high body iron stores (P<.05), consistent with previous studies, but did not interact with fruit with regard to effects on serum ferritin (P>.05).

CONCLUSION: Noncitrus fruits are environmental modifiers of iron status independent of HFE genotype. This could have important implications for the provision of evidence-based dietary advice to patients with other iron-storage disorders.

 


Clin Endocrinol (Oxf). 2008 Oct;69(4):648-52. Epub 2008 Mar 12.

Significant inverse relationship between serum free T4 concentration and body mass index in euthyroid subjects: differences between smokers and nonsmokers.

Makepeace AE, Bremner AP, O'Leary P, Leedman PJ, Feddema P, Michelangeli V, Walsh JP.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

 

OBJECTIVE: There are conflicting data regarding the relationship between thyroid function and body mass index (BMI) in euthyroid subjects, and it is uncertain whether tobacco smoking modifies this relationship. The objective of this study was to examine the relationships between thyroid function, BMI and smoking in euthyroid subjects.

DESIGN: Linear regression models were used to examine the relationships between serum free T4, serum TSH, BMI and smoking in a cross-sectional, community-based sample of 1853 euthyroid subjects in Busselton, Western Australia.

RESULTS: There was a significant negative relationship between free T4 and BMI: after adjustment for age and sex, each 1 pmol/l increase in free T4 was associated with a decrease in BMI of 0.12 kg/m(2) (95% CI 0.06, 0.18; P < 0.001). The mean BMI +/- SD of subjects in the highest quintile of free T4 concentration was 24.4 +/- 3.5 kg/m(2), compared with 26.1 +/- 3.8 kg/m(2) for the lowest quintile. The relationship between free T4 and BMI was statistically significant (adjusted for age and sex) in subjects who had never smoked (P = 0.001) and former smokers (P = 0.011), but not in current smokers (P = 0.77). There was no significant relationship between TSH and BMI: after adjustment for age and sex, each 1 mU/l increase in TSH was associated with an increase in BMI of 0.08 kg/m(2) (95% CI -0.16, 0.32; P = 0.53).

CONCLUSIONS: In euthyroid subjects, small differences in free T4 are associated with differences in BMI. This relationship is not present in current smokers. We speculate that this may be relevant to weight changes associated with smoking cessation.

 


Prev Med. 2008 Jul;47(1):71-6. Epub 2008 Feb 15.

Are the associations between diet and C-reactive protein independent of obesity?

Hickling S, Hung J, Knuiman M, Divitini M, Beilby J.

School of Population Health, The University of Western Australia, Crawley 6009, Australia. siobhan.hickling@uwa.edu.au

 

OBJECTIVES: To determine the relative magnitude of the effect of dietary factors on circulating C-reactive protein (CRP) levels, controlling for BMI.

METHODS: 1808 men and 2269 women attended the 1994/95 follow-up survey from the Busselton Health Study, Australia. A composite diet score was derived from a short questionnaire. Height and weight were measured.

RESULTS: After controlling for BMI, CRP levels were associated with red meat intake (males only, p=0.001), fruit intake (males p<0.0001, females p=0.029), potato intake (males p=0.008, females p=0.029), using wholemeal bread (males p=0.014, females p=0.018), using polyunsaturated fats as a spread and in cooking (females only, p=0.005), and rarely or never adding salt to food (males p=0.012, females p=0.004). The overall diet score was significantly (negatively) related to CRP in males (p<0.0001) and females (p<0.0001). The relative decrease in CRP from a moderately healthy diet, compared to an unhealthy diet was 37% in men and 24% in women. This was comparable to a difference in BMI of at least 3 kg/m(2) (or a difference in weight of approximately 9 kg for a person of average height).

CONCLUSION: A healthy diet and lower weight have independent beneficial effects of similar magnitude on CRP levels.

 


Hum Genet. 2008 Apr;123(3):297-306. Epub 2008 Feb 6.

A genome-wide association scan for asthma in a general Australian population.

Hui J, Oka A, James A, Palmer LJ, Musk AW, Beilby J, Inoko H.

Western Australian Institute for Medical Research and UWA Centre for Medical Research, B Block, QEII Medical Centre, The University of Western Australia, Nedlands, WA, 6009, Australia. jhui@cyllene.uwa.edu.au

 

To date, almost every chromosome has been implicated in genetic susceptibility to asthma to some degree. When compared with single nucleotide polymorphism, microsatellite markers exhibit high levels of heterozygosity and therefore provide higher statistical power in association. The objective of this study was to perform a genome-wide association study using 23,465 in-house microsatellite markers to detect asthma susceptibility regions in the Busselton population. In this study, three separate pooled DNA screenings yielded 18 markers with significantly different estimated frequencies in the three separate "case and control" pools: each pool consisting of 60 males and 60 females. These markers were evaluated by individual typing in 360 cases and 360 controls. Two markers showed significant differences between cases and controls (P = 0.001 and P = 0.003). Regions surrounding the two markers were subjected to high-density association mapping with a total of 14 additional markers. We were able to confirm and fine map the association in these two regions by typing 14 additional microsatellite markers (1805A09 (D18S0325i), P = 0.002; 1806D05 (D18S0181i), P = 0.001). Each region contains a predicted gene that showed strong associations with asthma. Further studies are underway to characterize the novel candidate asthma susceptibility genes identified in this genome-wide study.

 


Am J Cardiol. 2008 Jan 15;101(2):193-8.

Prevalence and risk factor correlates of elevated C-reactive protein in an adult Australian population.

Hung J, Knuiman MW, Divitini ML, Davis T, Beilby JP.

School of Medicine and Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Perth, Western Australia. jhung@cyllene.uwa.edu.au

 

Measurement of the inflammatory biomarker C-reactive protein (CRP) is advocated for coronary heart disease risk assessment. The distribution and correlates of CRP in the general population should be known before it is used in clinical practice. CRP was measured in 1,761 men and 2,248 women aged 25 to 84 years who attended the 1994/1995 Busselton Health Survey. Prevalences of increased CRP >3 mg/L for age groups 25 to 39, 40 to 59, and 60 to 84 years were 15.7%, 20.6%, and 38.7%, respectively, in men and 21.2%, 22.1%, and 33.7%, respectively, in women not on hormone therapy. Logistic regression analysis identified independent predictors of increased CRP in men as obesity (odds ratio [OR] 3.5, 95% confidence interval [CI] 2.4 to 5.0), smoking (OR 3.1, 95% CI 2.1 to 4.5), hypertension (OR 1.6, 95% CI 1.1 to 2.3), and low high-density lipoprotein cholesterol (OR 1.4, 95% CI 1.0 to 1.8). In women, predictors were obesity (OR 7.8, 95% CI 5.8 to 10.6), hypertension (OR 1.4, 95% CI 1.0 to 1.9), high triglycerides (OR 1.6, 95% CI 1.1 to 2.4), vigorous exercise (OR 0.7, 95% CI 0.5 to 0.9), oral contraceptive use (OR 4.6, 95% CI 3.3 to 6.5), and hormone replacement therapy (OR 2.8, 95% CI 1.9 to 4.0). Overall, risks of increased CRP attributable to the presence of an abnormal or borderline coronary heart disease risk factor were 59% for men and 64% for women. In conclusion, despite gender-related differences in cardiovascular risk, increased CRP occurred commonly in men and women. Because increased CRP was largely attributable to conventional coronary heart disease risk factors, measurement of CRP may have limited utility for risk screening and primary prevention.

 
 


Heart Lung Circ. 2008 Apr;17(2):90-5. Epub 2007 Sep 11.

C-reactive protein and interleukin-18 levels in relation to coronary heart disease: prospective cohort study from Busselton Western Australia.

Hung J, Knuiman MW, Divitini ML, Langton PE, Chapman CL, Beilby JP.

School of Medicine & Pharmacology, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, Western Australia, Australia. jhung@cyllene.uwa.edu.au

 

BACKGROUND: Elevated levels of inflammatory markers are associated with incident coronary heart disease (CHD), but it remains controversial whether these markers provide incremental predictive value to conventional risk factors. We investigated the relationship between C-reactive protein (CRP) and interleukin-18 (IL-18) levels and risk of CHD in men and women without initial cardiovascular disease.

METHODS: A prospective case-cohort design over the period 1981-2001 involving 253 incident CHD cases and a random sub-cohort of 441 subjects was used. Cox proportional hazards regression was used to estimate the relative risks (RRs) of CHD for continuous and tertiles of CRP and IL-18 after controlling for conventional risk factors.

RESULTS: The multivariate-adjusted RR of CHD associated with one unit increase in log CRP in the overall population was 1.29 (1.07, 1.55; trend P=0.008). Men and women in the top compared to bottom third of CRP distribution had an adjusted RR for CHD of 1.65 (1.03-2.65; P=0.036). The multivariate RR for continuous log IL-18 was 1.34 in men, 1.63 in women and 1.36 overall, and none reached statistical significance.

CONCLUSIONS: Baseline CRP but not IL-18 levels are independently predictive of future CHD. However CRP provides only modest additional predictive value over conventional risk factors and the benefit of a prevention strategy based on CRP still needs to be established.

 


Br J Cancer. 2007 Sep 3;97(5):686-7. Epub 2007 Aug 7.

Left-handedness and risk of breast cancer.

Fritschi L, Divitini M, Talbot-Smith A, Knuiman M.

Western Australian Institute for Medical Research, Nedlands, Perth, Western Australia 6009, Australia. fritschi@waimr.uwa.edu.au

 

Left-handedness may be an indicator of intrauterine exposure to oestrogens, which may increase the risk of breast cancer. Women (n=1786) from a 1981 health survey in Busselton were followed up using death and cancer registries. Left-handers had higher risk of breast cancer than right-handers and the effect was greater for post-menopausal breast cancer (hazard ratio=2.59, 95% confidence interval 1.11-6.03).

 


J Clin Endocrinol Metab. 2007 Sep;92(9):3599-603. Epub 2007 Jun 26.

Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts.

Liu PY, Beilin J, Meier C, Nguyen TV, Center JR, Leedman PJ, Seibel MJ, Eisman JA, Handelsman DJ.

Department of Andrology, Concord Hospital and ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.

 

BACKGROUND: Cross-sectional studies from different populations show a variable decline in blood testosterone concentrations as men age. Few population representative cohorts have been followed up over time.

OBJECTIVE: The objective of the study was to quantify longitudinally the change in serum testosterone and SHBG concentrations with age in two well-defined, representative but geographically widely separated regional Australian cohorts.

SUBJECTS AND SETTING: The Busselton cohort comprises individuals aged 18-90 yr residing in Western Australia assessed prospectively since 1981. Sera were assayed from 910 men, from whom further samples were available 14 yr later in 480. The Dubbo cohort involves individuals aged 61-90 yr living in Eastern Australia. Baseline sera were collected from 610 men and additional sera on a second (n = 370) and third (n = 200) occasion from 1989 to 2004. Men from both cohorts are community dwelling and of predominately European origin.

RESULTS: Longitudinal analyses show the following: 1) total testosterone declines comparably (P > 0.9) by 1.3% (Busselton) and 0.9% (Dubbo) per annum with the same rates of decline when analyses were restricted to men older than 60 yr of age; 2) annual changes in SHBG were also very similar in age-restricted analyses (2.3% vs. 2.5%, P = 0.48); and 3) the annual increase in SHBG was steeper in middle-aged and older men (P < 10(-3) vs. young men). These longitudinal changes were all up to 4-fold greater in magnitude, compared with cross-sectional analyses of baseline data.

CONCLUSION: In two separate regional Australian populations, blood testosterone fell and SHBG increased comparably with age. Age-related changes in blood testosterone and SHBG previously described in urban-dwelling men are the same in men who reside in smaller regional cities of another continent.

 


 Chest. 2006 Dec;130(6):1779-83.

Longitudinal study of risk factors for habitual snoring in a general adult population: the Busselton Health Study.

Knuiman M, James A, Divitini M, Bartholomew H.

School of Population Health (M431), The University of Western Australia, Nedlands, 6009 WA, Australia. Matthew.Knuiman@uwa.edu.au

 

BACKGROUND: The aim of this longitudinal study was to identify body size, behavioral, and respiratory risk factors for the development of habitual snoring in a general adult population.

METHODS: The sample for this study comprised 967 adults aged 25 to 74 years who reported not snoring in the 1981 Busselton Health Survey and who also attended the 1994-1995 follow-up survey. Logistic regression was used to identify and quantify the effect of baseline and change risk factors for the development of habitual snoring.

RESULTS: A total of 13% had become habitual snorers by 1994-1995. Male gender (odds ratio [OR], 3.5) and baseline body mass index (OR, 1.4 per 3.4 kg/m(2)) were significant predictors of habitual snoring; after accounting for these variables, no other baseline body size, behavioral, or respiratory/allergy variables were significantly related to the development of habitual snoring. However, change in body mass index over the 14-year follow-up period (OR, 1.55 per 2.3 kg/m(2)), development of asthma (OR, 2.8), and commencement of smoking (OR, 2.2) were additional significant independent risk factors for development of habitual snoring.

CONCLUSIONS: This study has confirmed male gender, obesity, and weight gain as key determinants of habitual snoring, and has indicated that development of asthma and taking up smoking also play a role. Maintaining a healthy weight and not smoking are recommended lifestyle preventive strategies to reduce the risk of sleep-disordered breathing and its sequelae.

 


 Clin Endocrinol (Oxf). 2006 Oct;65(4):486-91.

Subclinical thyroid dysfunction and blood pressure: a community-based study.

Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, Michelangeli V.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. john.walsh@health.wa.gov.au

 

OBJECTIVE: Overt hypothyroidism and hyperthyroidism are associated with hypertension, but it is uncertain whether the same is true of subclinical hypothyroidism and hyperthyroidism. DESIGN,

SUBJECTS AND MEASUREMENTS: Cross-sectional study of 2033 participants (aged 17-89 years) in the Busselton Thyroid Study who did not have a history of thyroid disease. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and the prevalence of hypertension (defined as SBP >or=140 mmHg, DBP >or=90 mmHg or on treatment for hypertension) in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models. Subjects with treated hypertension (N = 299) were excluded from analyses of SBP and DBP but included in analyses of hypertension prevalence.

RESULTS: Mean SBP, DBP and the prevalence of hypertension did not differ significantly between subjects with subclinical hypothyroidism (N = 105) and euthyroid subjects (N = 1859), nor did they differ between subjects with serum TSH concentrations in the upper reference range (2.0-4.0 mU/l; N = 418) and those with TSH concentrations in the lower reference range (0.4-2.0 mU/l; N = 1441). The prevalence of hypertension was higher in subjects with subclinical hyperthyroidism than euthyroid subjects (prevalence odds ratio 2.8, 95% confidence interval 1.3-6.0 adjusted for age, age(2) and sex), but this was based on a small number of subjects with subclinical hyperthyroidism (N = 35).

CONCLUSIONS: Subclinical hypothyroidism is not associated with hypertension. The observed association between subclinical hyperthyroidism and hypertension requires confirmation in a larger sample.

 


Tissue Antigens. 2006 Aug;68(2):127-34.

The association between non-melanoma skin cancer and a young dimorphic Alu element within the major histocompatibility complex class I genomic region.

Dunn DS, Inoko H, Kulski JK.

Centre for Bioinformatics and Biological Computing, School for Information Technology, Murdoch University, Murdoch, Western Australia, Australia.

 

A non-melanoma skin cancer (NMSC) susceptibility locus within the major histocompatibility complex (MHC) class I region was previously identified telomeric of the HLA-C gene using high-density microsatellite markers. Here, we have extended the previous microsatellite study by using the same DNA samples obtained from 154 NMSC patients and 213 normal controls from the town of Busselton in Western Australia and examined the relationship between five polymorphic Alu insertions (POALINs) within the MHC class I region and their association with NMSC. The genotype distribution of the AluyTF insertion that is located within the NMSC susceptibility region telomeric of the HLA-C gene was significantly increased according to the Fisher's exact test in the NMSC patients, and it was not in Hardy-Weinberg equilibrium in the control group. There was no difference between the cancer patients and controls for the genotypes of the AluyMICB locus within intron 1 of the MICB gene and the other three POALINs (AluyHJ, AluyHG and AluyHF) that are located within the genomic region of the HLA-A, -G and -F gene cluster. The test for significant linkage disequilibrium for 10 pairs of POALIN loci and estimations of two locus POALIN haplotype frequencies also revealed AluyTF differences between the cases and controls. In conclusion, the MHC class I POALIN, AluyTF, that is located within the NMSC susceptibility locus and near the HLA-C gene was strongly associated with NMSC. This finding, using five different polymorphic Alu insertion markers, supports the previous microsatellite association study that one or more genes located in close proximity to the AluyTF insertion has a potential role in NMSC.

 

Clin Exp Allergy. 2006 Jun;36(6):728-34.

AluyMICB dimorphism within the class I region of the major histocompatibility complex is associated with asthma and airflow obstruction in the Busselton population.

Hui J, Palmer LJ, James AL, Musk AW, Beilby JP.

UWA Centre for Medical Research, Western Australian Institute for Medical Research, The University of Western Australia, and Western Australian Sleep Disorders Research Institute, Sir Charles Gairdner Hospital, Western Australia. jhui@cyllene.uwa.edu.au

 

AIM: To examine the association between the Alu dimorphism within the first intron of the MICB gene and asthma and airflow obstruction. Background The highly polymorphic non-classical MHC class I polypeptide-related (MIC) genes, MICA and MICB, encode stress inducible glycoproteins, which are expressed on a variety of epithelial cells, including those of the lungs.

METHODS: AluyMICB genotyping was performed on 1109 subjects from the Busselton Health Study. From a standard questionnaire, 359 individuals indicated that they had been diagnosed by a doctor with asthma. Lung function was assessed by the forced expired volume in 1 second (FEV1) and expressed as a percent of the predicted value. Airflow obstruction was defined as FEV1<80% predicted.

RESULTS: In men, a dominant relationship was found between the AluyMICB DD genotype and asthma (P=0.006; chi2(2)=7.65). Furthermore, multivariate analysis adjusted for age, height, weight and body mass index (BMI) showed a relationship between DD genotype and asthma in men in a dominant model (odds ratio (OR)=1.97; 95% confidence interval (CI)=1.11-3.51; P=0.021). In women, an association was found between the AluyMICB II genotype and FEV1 percent predicted as a continuous variable (P=0.001). When adjusted for age and BMI, it showed a significant relationship between AluyMICB and airflow obstruction in a dominant model (OR=14.11%, 95% CI 3.29-60.57, P<0.001). However, no association was found between the AluyMICB II genotypes and airflow obstruction in men.

CONCLUSION: These findings suggest the possible involvement of a MHC class I gene in abnormal airway structure in women and airway function in men.

 


J Clin Rheumatol. 2006 Jun;12(3):109-13.

Primary osteoarthritis in the ankle joint is associated with finger metacarpophalangeal osteoarthritis and the H63D mutation in the HFE gene: evidence for a hemochromatosis-like polyarticular osteoarthritis phenotype.

Carroll GJ.

ArthroCare Pty Ltd., Mount Lawley, Western Australia, Australia. md@arthrocare.com.au

 

BACKGROUND AND AIM: Osteoarthritis (OA) can occur in the ankle joint. It also occurs in an appreciable proportion of subjects with hereditary hemochromatosis (HH). Might these conditions have common genetic characteristics? The aim of this study was to test the hypothesis that HFE gene mutations are associated with primary osteoarthritis in the ankle joint.

METHODS: Consecutive referred patients who had primary or secondary (posttraumatic) OA of the ankle joint were assessed by a single rheumatologist and had a full physical and joint examination. Plain x-rays of the ankle joint, other clinically involved osteoarthritic joints, iron studies, HFE genotyping, and Hb electrophoresis were performed. The significance of differences was evaluated by 2-tailed Fisher exact test.

RESULTS: Fourteen patients met the inclusion criteria for primary ankle OA and 6 met the criteria for secondary ankle OA. One of the 14 had had a previous subtalar joint fusion and was excluded. Among the remaining 13, 7 had OA in the index and/or middle finger metacarpophalangeal joints (MCP2,3 OA) with radiologic features similar to those found in hemochromatotic arthropathy (HA). Furthermore, 11 of the 13 had at least one HFE mutation, one subject in this group was homozygous for H63D, one was compound heterozygous for C282Y and S65C, and one was compound heterozygous for H63D and S65C. Eight were heterozygous for H63D. The 13 subjects were compared with the 6 secondary ankle OA subjects and with a previously studied population cohort (n = 3011) from the town of Busselton in whom HFE genotyping had been performed. A statistically significant increase in the frequency of HFE gene mutations was observed in the group with primary OA of the ankle joint compared with that with secondary ankle joint OA (P = 0.0095) and compared with the Busselton cohort (P = 0.0008). Furthermore, a statistically significant association between finger MCP joint OA and primary ankle joint OA was observed (P = 0.0436). Iron studies were normal in the 13 primary and 6 secondary ankle OA subjects. None of the subjects with ankle OA had clinical signs of hemochromatosis or abnormal liver function tests.

CONCLUSIONS: A strong and statistically significant association was observed between HFE gene mutations and primary OA in the ankle joint. The frequent presence of MCP2,3 OA in these patients suggests the existence of a type 2 polyarticular OA phenotype that closely resembles the arthropathy of HH and which appears to be clinically differentiable from type 1 OA or nodal generalized OA (NGOA). HFE gene mutations may be a marker for the type 2 polyarticular OA phenotype and a clue to OA pathogenesis.

 


J Gastroenterol Hepatol. 2006 Mar;21(3):595-8.

Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritis.

 

Sherrington CA, Knuiman MW, Divitini ML, Bartholomew HC, Cullen DJ, Olynyk JK.

Department of Gastroenterology, Fremantle Hospital, Fremantle, Western Australia, Australia.

 

BACKGROUND AND AIM: Mutations in the hemochromatosis (HFE) gene are carried by one in three individuals of British Isles descent and may result in increased iron stores. These increased iron stores could potentially induce or exacerbate diseases, such as arthritis, in which iron has a role in pathogenesis. Although arthritis is a well-known association of clinically overt hereditary hemochromatosis, controversy surrounds the role of mutations in the HFE gene as risk factors for arthritis. The aim of the present study was to determine whether mutations in the HFE gene are associated with an increased prevalence of arthritis.

METHODS: A population-based study was conducted in Busselton, Western Australia, of the prevalence of arthritis in 1372 individuals of British Isles descent. Participants completed a questionnaire and general physical examination. Analysis for C282Y and H63D HFE mutations was undertaken. Unadjusted and adjusted odds ratios (OR) were calculated for the relationship between HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis.

RESULTS: There was no association between the presence of HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis (C282Y/wild type (WT) adjusted OR = 1.041 (95% confidence interval (CI) 0.68-1.61), H63D/WT OR = 0.76 (95% CI 0.53-1.08), C282Y/C282Y OR = 0.39 (95% CI 0.04-3.63), C282Y/H 63D OR = 0.808 (95% CI 0.27-2.42), H63D/H63D OR = 0.419 (95% CI 0.13-1.36)). Overall adjusted OR for arthritis in participants with one or more HFE mutations was 0.81 (95% CI 0.61-1.09).

CONCLUSIONS: Mutations of the HFE gene are not risk factors for arthritis in populations of British Isles descent.

 


J Rheumatol. 2006 Apr;33(4):741-3.

HFE gene mutations are associated with osteoarthritis in the index or middle finger metacarpophalangeal joints.

Carroll GJ.

University Department of Medicine, University of Western Australia. md@arthrocare.com.au

 

OBJECTIVE: . To test the hypothesis that possession of either C282Y or H63D mutations in the HFE gene is associated with primary osteoarthritis (OA) in joints commonly affected in hemochromatotic arthropathy.

METHODS: HFE genotyping was performed in 87 patients with radiologically proven OA in 3 joint regions: index or middle finger metacarpophalangeal joints (MCP2,3; n = 52), elbow joints (n = 8), ankle, intertarsal or tarsometatarsal joints (ankle/IT/TMT; n = 27); and in 56 patients with radiologically proven OA in finger interphalangeal (IP) joints, but not MCP2,3 joints (IP OA control group). HFE mutation frequencies in these groups were also compared to those in a similar population (Busselton population control group).

 

RESULTS: A statistically significant association between HFE mutations and OA was observed for the MCP2,3 joints (p = 0.0001) and the ankle/IT/TMT joint group (p = 0.002) as well as for the 3 joint regions collectively (p = 0.0001), but not for the elbow joints (p = 0.062). Comparison with the Busselton population controls showed similar statistically significant associations, except for the elbow and ankle/IT/TMT groups, where similar trends were observed.

CONCLUSION: HFE gene mutations are associated with OA in the MCP2,3 joints. These mutations may be markers for a polyarticular OA phenotype.

 


Clin Endocrinol (Oxf). 2006 Jan;64(1):97-104.

Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study.

O'Leary PC, Feddema PH, Michelangeli VP, Leedman PJ, Chew GT, Knuiman M, Kaye J, Walsh JP.

Clinical Biochemistry, Women's and Children's Health Service, Princess Margaret Hospital, Subiaco Western Australia, Australia. peter.oleary@health.wa.gov.au

 

OBJECTIVE: Overt or subclinical thyroid dysfunction is common within the community, yet the significance of subtle anomalies in thyroid function tests remains contentious. The aims of this study were to: (a) establish reference intervals for serum-free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid antibodies (antithyroperoxidase, TPOAb and antithyroglobulin, TgAb) in the Busselton community of south-western Western Australia; and (b) determine the prevalence of thyroid hormone anomalies in this community.

SUBJECTS AND DESIGN: In 1981, 2115 adults residing in Busselton participated in a cross-sectional health survey that involved blood collection and a questionnaire on lifestyle and general health history.

MEASUREMENTS: Serum samples were analysed for FT4, TSH, TPOAb and TgAb by immunochemiluminescent assays.

RESULTS: Based on standard statistical approaches and using guidelines recommended by the National Academy of Clinical Biochemistry (NACB), reference intervals were derived for each analyte: 9-23 pmol/l for FT4, 0.4-4.0 mIU/l (TSH), < 35 KIU/l (TPOAb) and < 55 KIU/l (TgAb). The prevalence of elevated thyroid antibodies was 12.4% among subjects without a history of thyroid disease and is more common in women than in men. Elevated thyroid antibody levels were observed at both extremes of TSH abnormality, but were more commonly increased when TSH levels were above 4.0 mIU/l (63% subjects) than for those with TSH levels 0.4-4.0 mIU/l (7.8% subjects).

CONCLUSIONS: This study establishes the prevalence of antibodies to thyroperoxidase and thyroglobulin in a community-based sample and reference intervals for free T4 and TSH. When the NACB decision limits are applied to older men or women, there is a markedly increased number with 'elevated' autoantibody levels compared to sex- and age-specific reference intervals.

 


Ann Epidemiol. 2006 Mar;16(3):206-12. Epub 2005 Dec 15.

Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia.

Rossi E, Hung J, Beilby JP, Knuiman MW, Divitini ML, Bartholomew H.

Pathcentre, QEII Medical Centre, Nedlands, WA, Australia. ric.rossi@health.wa.gov.au

 

PURPOSE: To test a community population for the hypothesis that carcinogenesis is related to blood folate levels.

METHODS: Prospective analysis of cancer mortality data for a cohort of 964 men (person-time follow up: 20,254 years) and 1024 women (person-time follow up: 24,970 years) and morbidity data for a subcohort, all of whom participated in the 1969 Busselton (Western Australia) Health survey. Outcome measures were adjusted hazard ratios according to baseline folate levels for total cancer mortality and morbidity and site specific mortality and morbidity for colorectal, lung, breast, and prostate cancers.

RESULTS: In total, there were 278 cancer deaths--45 from colorectal cancer, 44 from lung cancer, 15 from breast cancer, and 31 from prostate cancer. Decreased serum folate levels showed an independent association with increased prostate cancer mortality risk, the adjusted hazard ratio per decrease of 2 microg/L was 1.56 (CI: 1.05, 2.38), men whose levels were in the lowest quartile had an adjusted hazard ratio of 4.79 (CI: 1.56, 14.43) for subsequent death from prostate cancer. The morbidity subcohort data showed that decreased red blood-cell folate was significantly associated with increased events due to breast cancer, the adjusted hazard ratio per decrease of 100 mug/L was 1.96 (CI: 1.22, 3.12), women in the lowest quartile of red cell folate levels had an adjusted hazard ratio of 6.46 (CI: 1.19, 35.07) for a subsequent breast cancer event. Mortality and morbidity from colorectal or lung cancers were not associated with folate levels.

CONCLUSIONS: Independent associations, assessed over periods greater than 20 years, were demonstrated between decreased folate levels and increased risks of prostate cancer mortality and breast cancer morbidity.

 


Clin Endocrinol (Oxf). 2005 Dec;63(6):670-5.

Thyroid dysfunction and serum lipids: a community-based study.

Walsh JP, Bremner AP, Bulsara MK, O'leary P, Leedman PJ, Feddema P, Michelangeli V.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. john.walsh@health.wa.gov.au

 

OBJECTIVE: It is uncertain whether subclinical hypothyroidism (SCH) is associated with hypercholesterolaemia, particularly in subjects with SCH and serum TSH < or = 10 mU/l. Design,

PATIENTS AND MEASUREMENTS: Cross-sectional study of 2108 participants in a 1981 community health survey in Busselton, Western Australia. Serum total cholesterol and triglycerides were measured in all subjects and high density lipoprotein cholesterol (HDL-C) measured (and low density lipoprotein cholesterol (LDL-C) calculated) in a subgroup of 631 subjects at the time of the survey. In 2001, TSH and free T4 concentrations were measured on archived sera stored at -70 degrees C. Serum lipid concentrations in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models.

RESULTS: In the group as a whole, serum total cholesterol was higher in subjects with SCH (N = 119) than in euthyroid subjects (N = 1906) (mean +/- SD 6.3 +/- 1.3 mmol/l vs. 5.8 +/- 1.2 mmol/l, P < 0.001 unadjusted, P = 0.061 adjusted for age, age(2) and sex). Serum total cholesterol was similarly elevated in subjects with SCH and TSH < or = 10 mU/l (N = 89) (6.3 +/- 1.3 mmol/l, P < 0.001 unadjusted, P = 0.055 adjusted for age, age(2) and sex). In the subgroup analysis, LDL-C was higher in subjects with SCH (N = 30) than in euthyroid subjects (N = 580) (4.1 +/- 1.2 mmol/l vs. 3.5 +/- 1.0 mmol/l, P < 0.01 unadjusted, P = 0.024 adjusted for age, age(2) and sex). LDL-C was significantly increased in subjects with SCH and TSH < or = 10 mU/l (N = 23) (4.3 +/- 1.3 mmol/l, P < 0.001 unadjusted, P = 0.002 adjusted for age, age(2) and sex).

CONCLUSION: SCH is associated with increased serum LDL-C concentrations, which is significant after adjustment for age, age(2) and sex.

 


Arch Intern Med. 2005 Nov 28;165(21):2467-72.

Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.

Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, Michelangeli V.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. john.walsh@health.wa.gov.au

 

BACKGROUND: There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease.

METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline).

RESULTS: In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes.

 

CONCLUSION: Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.

 


Aust N Z J Public Health. 2005 Oct;29(5):412-5.

Correlates of habitual snoring and witnessed apnoeas in Busselton, Western Australia.

Knuiman MW, James AL, Divitini ML, Bartholomew HC.

School of Population Health (M431), University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009. matthew@sph.uwa.edu.au

 

OBJECTIVE: The aim of this study was to identify potential body size, behavioural and respiratory risk factors for habitual snoring and witnessed apnoeas in a general population.

METHODS: Correlates of these conditions were studied in a sample of 3,577 adults aged 25-74 years who participated in a comprehensive health survey in Busselton, Western Australia, during 1994/95. Logistic regression was used to assess associations after age and gender adjustment and also in multivariate models.

RESULTS: The prevalence of both conditions was higher in men and rose with age. After controlling for age, gender and body mass index no additional body size variable remained significantly associated with witnessed apnoeas, whereas both waist-hip ratio and neck-height ratio remained significantly associated with habitual snoring. Among behavioural variables, smoking showed the strongest association, and among respiratory symptoms, asthma for habitual snoring and bronchitis for witnessed apnoeas had significant independent associations.

CONCLUSIONS AND IMPLICATIONS: This study has confirmed obesity and smoking as key determinants of habitual snoring and witnessed apnoeas. It has also shown that a number of measures of obesity are independently related to habitual snoring and that asthma and bronchitis may also play a role, independently of obesity.

 


J Gastroenterol Hepatol. 2005 Sep;20(9):1435-41.

Effects of HFE gene mutations and alcohol on iron status, liver biochemistry and morbidity.

Olynyk JK, Knuiman MW, Divitini ML, Bartholomew HC, Cullen DJ, Powell LW.

School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia. jolnyk@cyllene.uwa.edu.au

 

BACKGROUND AND AIMS: The aims of the present study were to determine: (i) whether alcohol consumption is greater in individuals with HFE mutations; and (ii) whether common HFE mutations modify the effects of alcohol on serum iron and liver biochemistry or morbidity.

METHODS: The residents of the town of Busselton in Western Australia were subject to cross-sectional health surveys between 1966 and 1983. In 1994/1995 all surviving participants of the earlier surveys were invited to take part in a follow-up survey. Logistic, linear and Poisson log-linear regression analyses were performed in 1490 men and 1452 women from the 1994/1995 survey to assess the relationships between HFE mutations, alcohol, iron levels, liver biochemistry and morbidity.

RESULTS: Heavy or moderate alcohol consumption was present in 7% or 36% of men and 0.5% or 12% of women, respectively. Alcohol consumption strongly influenced levels of serum ferritin and gamma glutamyl transpeptidase (GGT) and mean cell volume (MCV) in men and women but only alanine aminotransferase (ALT) levels in women. These effects were independent of HFE gene mutations. Hospital admission rates for respiratory disorders were higher in men with the C282Y mutation.

CONCLUSIONS: Alcohol consumption strongly influences serum ferritin and GGT levels and MCV in men and women but only ALT levels in women, and these effects are independent of HFE mutations. HFE gene mutations do not predispose to moderate or heavy alcohol consumption. The C282Y mutation is associated with increased respiratory admission rates in men.

 


Acta Paediatr. 2005 Mar;94(3):275-80.

Cholesterol tracking from childhood to adult mid-life in children from the Busselton study.

Adams C, Burke V, Beilin LJ.

School of Medicine and Pharmacology, Royal Perth Hospital, The University of Western Australia, Perth, Australia. claire@buntaize.net

 

AIM: To determine if subjects' cholesterol levels tracked relative to their peers from early childhood to adult mid-life.

METHODS: Longitudinal study using subjects from the Busselton Health Study. Data were available from 1967 on a triennial basis until 1983, and a re-survey held in 1994. The study included 1764 subjects aged 5-18 y at first measurement. Pearson's correlation coefficient, adjusted for age and survey year, was used to examine cholesterol tracking. The proportion of children who persisted with cholesterol measurements in the extreme high quartile was assessed over time before and after adjusting data for regression to the mean. The variability of the children's cholesterol level was examined by track width using the method of Porkka.

RESULTS: The correlation coefficients for tracking were from 0.35 to 0.55. Stronger correlations coincided with shorter time periods between measurements. Before adjustment for regression to the mean, 55-60% of children from the highest quartile at first measurement remained in the same quartile 27 y later. After adjustment for regression to the mean, the number of children with levels in the extreme high quartile decreased, but 80% of these persisted in that quartile.

CONCLUSION: Intra-individual variations in cholesterol levels have an important influence on population tracking levels and need to be considered when interpreting tracking results from early childhood to adult mid-life. However, removing the effect of regression to the mean by taking multiple measurements of cholesterol will probably improve prediction for individuals.

 


Med J Aust. 2005 Jul 4;183(1 Suppl):S17-9.

What can Busselton population health surveys tell us about asthma in older people?

James AL, Knuiman MW, Bartholomew HC, Musk AB.

West Australian Sleep Disorders Research Institute/Department of Pulmonary Physiology, Queen Elizabeth II Medical Centre, Level 5, G Block, Hospital Avenue, Nedlands, WA 6009, Australia.

 

WHAT WE NEED TO KNOW: Do the characteristics of asthma differ in people older than 55 years compared with younger people with respect to risk factors (atopy, airway hyper-responsiveness and genetic variation), smoking, lung function and other illness? How do inflammation and remodelling of airways vary with age and with duration and severity of asthma? WHAT WE NEED TO DO: Continue collecting prevalence data for asthma and its risk factors. Assess (i) period and cohort effects on asthma and its risk factors and (ii) interactions between age, smoking, severity and duration of asthma, lung function and airway responsiveness, and other concurrent disease. Measure airway responsiveness and exhaled nitric oxide to detect airway abnormalities in older people and relate this to the diagnoses of asthma and other diseases.

 


J Clin Endocrinol Metab. 2005 Sep;90(9):5309-12. Epub 2005 Jun 14.

Parity and the risk of autoimmune thyroid disease: a community-based study.

Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, Michelangeli V.

Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia. john.walsh@health.wa.gov.au

 

CONTEXT: Recent studies have suggested that fetal microchimerism (transplacental passage of fetal cells followed by engraftment into maternal tissues) may play a role in the pathogenesis of autoimmune thyroid disease. If that is true, then parity should be a risk factor for autoimmune thyroid disease.

OBJECTIVE: The objective of this study was to examine parity as a risk factor for autoimmune thyroid disease. Design, SETTING, AND

PARTICIPANTS: TSH, thyroid peroxidase antibody, and thyroglobulin antibody concentrations were measured on archived sera from 1045 female participants in a 1981 community health survey in Busselton, Western Australia.

OUTCOME MEASURES: Odds ratios (ORs) for positive thyroid antibodies (increased concentration of either antibody) or thyroid dysfunction (abnormal serum TSH) were used.

RESULTS: After adjustment for age, women who had previously been pregnant did not have a significantly increased risk of positive thyroid antibodies [OR, 1.20; 95% confidence interval (CI), 0.74-1.97; P = 0.46], raised TSH (OR, 0.93; 95% CI, 0.46-1.87; P = 0.84), or reduced TSH (OR, 0.87; 95% CI, 0.33-2.30; P = 0.79) compared with women who had never been pregnant. For each additional pregnancy, the OR was 1.02 (95% CI, 0.94-1.11; P = 0.57) for positive antibodies, 1.02 (95% CI, 0.91-1.14; P = 0.67) for raised TSH, and 1.03 (95% CI, 0.87-1.22; P = 0.73) for reduced TSH. Analysis using number of live births gave similar results. The results were similar in younger and older women.

 

CONCLUSIONS: Parity is not a risk factor for thyroid autoimmunity or thyroid dysfunction. These data do not support a key pathogenic role for fetal microchimerism in chronic autoimmune thyroid disease.

 


Aust N Z J Public Health. 2004 Jun;28(3):267-72.

Evaluating the impact of repeated community-wide health surveys on cardiovascular morbidity and mortality in the Busselton population.

Knuiman MW, Clarkson JP, Bulsara M, Bartholomew HC.

School of Population Health, University of Western Australia. matthew@sph.uwa.edu.au

 

OBJECTIVE: To evaluate the impact of repeated community-wide mass health examinations on cardiovascular mortality and hospital morbidity trends in Busselton.

METHOD: Population census, hospital admission and death data were used to calculate and compare cardiovascular mortality rates from 1965 to 1998 and hospital morbidity rates from 1971 to 1998 in Busselton residents aged 40 to 84 years with the remainder of the south-west region of Western Australia.

RESULTS: Among men aged 40-69 years, the calendar year trends in standardised cardiovascular mortality and morbidity ratios were relatively flat and non-significant. Among women aged 40-69 years, the mortality ratio declined significantly up to 1989 (p = 0.03) but not over the whole period (p = 0.12), and the downward trend in the morbidity ratio did not reach statistical significance (p = 0.21). Among men aged 70-84 years, both the mortality and morbidity ratios rose significantly over time, whereas among women aged 70-84 years the mortality ratios showed a flat trend and the morbidity ratios a rising trend. These increasing trends were opposite to what was expected if the surveys had a beneficial impact.

CONCLUSION: This analysis of trends, while failing to demonstrate a clear benefit of repeated mass health screenings on cardiovascular event rates, also highlights the difficulties in evaluating the longer-term impact on event rates of such programs and suggests that negative conclusions should be made with caution.

 


Ann Epidemiol. 2005 Jan;15(1):39-43.

Spouse selection and environmental effects on spouse correlation in lung function measures.

Knuiman MW, Divitini ML, Bartholomew HC.

School of Population Health, University of Western Australia, Perth, Western Australia. matthew@sph.uwa.edu.au

 

PURPOSE: Concordance between spouses may be due to partner selection factors and/or the effects of marriage/environment. The extent to which partner selection factors contribute to spouse concordance has important implications for heritability studies. The aim of this study was to examine the magnitude of spouse correlation in lung function measures and its relationship to duration of marriage.

 

METHODS: Cross-sectional and longitudinal data collected over the period 1969 to 1995 for 2615 couples from the Busselton Health Study have been analyzed using the program FISHER.

RESULTS: Unadjusted correlations were around 0.45 for forced expiratory volume in 1 second (FEV1) and 0.25 for FEV1/FVC (forced vital capacity) and were reduced to 0.05 and 0.10, respectively, after adjustment for age, height, and smoking. No trend with marriage duration was apparent in both cross-sectional and longitudinal analyses but there was a significant downward trend in the correlations with age at marriage.

CONCLUSIONS: The findings indicate that observed correlations in lung function measures are mostly due to partner selection factors and that partner selection factors have greater influence for couples that marry at younger ages. Family studies that aim to identify and separate genetic from other influences on lung function measures should not regard the mother-father correlation as due to common environment effects.

 


Am J Respir Crit Care Med. 2005 Jan 15;171(2):109-14. .

Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking.

James AL, Palmer LJ, Kicic E, Maxwell PS, Lagan SE, Ryan GF, Musk AW.

West Australian Sleep Disorders Research Institute, Queen Elizabeth II Medical Centre, Nedlands, Australia

 

Asthma in adults may be associated with chronic airflow obstruction, possibly resulting from airway disease in early life and/or a greater rate of decline in lung function in adult life compared with those with asthma. Treatment and cigarette smoking may also influence the rate of decline of lung function. The aim of this analysis was to examine the level and rate of decline in lung function in relationship to asthma and cigarette smoking in adults. Subjects (n = 9,317) had participated as adults (> 18 years) in one or more of the cross-sectional Busselton Health Surveys between 1966 and 1981 or in the follow-up study of 1994/1995. The effects of sex, doctor-diagnosed asthma, smoking status, and anthropometric data on the level and rate of decline in FEV1 were examined in a linear mixed effects model. At the age of 19 years, FEV1 was reduced in subjects with asthma but was similar in smokers and nonsmokers. Males, taller subjects, smokers, and subjects with asthma had greater declines in FEV1 with age. Smoking and asthma had additive but not multiplicative effects on decline. Thus, asthma is associated with reduced lung function at the beginning of adult life as well as an increased rate of decline during adult life.

 


Ann Epidemiol. 2004 Oct;14(9):627-32.

Is sialic acid an independent risk factor for cardiovascular disease? A 17-year follow-up study in Busselton, Western Australia.

Knuiman MW, Watts GF, Divitini ML.

School of Population Health, University of Western Australia, Crawley, Western Australia. mathew@sph.uwa.edu.au

  
PURPOSE: To investigate the relationship between serum sialic acid level and risk of coronary heart disease (CHD) and stroke in men and women without diagnosed cardiovascular disease.

METHODS: A prospective case-cohort study over the period 1981 to 1998 involving 151 CHD cases, 87 stroke cases, and a random sub-cohort of 340 was used. Sialic acid levels were determined by enzymatic method from frozen serum. Cox proportional hazards regression was used to estimate the relative risks of CHD and stroke for sialic acid tertiles and for continuous sialic acid level after adjustment for age, blood pressure, body mass index, cholesterol, triglycerides, diabetes, and smoking.

RESULTS: The multivariate-adjusted relative risk of CHD associated with a 25 mg/dl increase in sialic acid was 1.22 (95% CI: 1.02-1.45) overall, 1.40 (95% CI: 1.11-1.76) in women, and 1.06 (95% CI: 0.82-1.37) in men. The overall relative risk for stroke was 1.13 (95% CI: 0.87-1.46) and for CHD and stroke combined it was 1.17 (95% CI: 0.99-1.37)

CONCLUSIONS: Serum sialic acid may be a long-term predictor of CHD events in adults (especially women) who are currently clinically free of cardiovascular disease. Further studies are needed to determine whether this association can be explained by sialic acid being a marker of accelerated atherosclerosis or inflammation.






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