Melbourne School of Population and Global Health - Research Publications
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ItemNo Preview AvailableHeterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics(PUBLIC LIBRARY SCIENCE, 2008-04)A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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ItemReduced rates of primary joint replacement for osteoarthritis in Italian and Greek migrants to Australia: the Melbourne Collaborative Cohort Study(BMC, 2009)INTRODUCTION: Racial and ethnic disparities in rates of total joint replacement have been described, but little work has been done in well-established migrant groups. The aim of this study was to compare the rates of primary joint replacement for osteoarthritis for Italian and Greek migrants to Australia and Australian-born individuals. METHODS: Eligible participants (n = 39,023) aged 27 to 75 years, born in Italy, Greece, Australia and the United Kingdom, were recruited for the Melbourne Collaborative Cohort Study between 1990 and 1994. Primary hip and knee replacement for osteoarthritis between 2001 and 2005 was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. RESULTS: Participants born in Italy and Greece had a lower rate of primary joint replacement compared with those born in Australia (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.26 to 0.39, P < 0.001), independent of age, gender, body mass index, education level, and physical functioning. This lower rate was observed for joint replacements performed in private hospitals (HR 0.17, 95% CI 0.13 to 0.23), but not for joint replacements performed in public hospitals (HR 0.96, 95% CI 0.72 to 1.29). CONCLUSIONS: People born in Italy and Greece had a lower rate of primary joint replacement for osteoarthritis in this cohort study compared with Australian-born people, which could not simply be explained by factors such as education level, physical functioning, and weight. Although differential access to health care found in the population may explain the different rates of joint replacement, it may be that social factors and preferences regarding treatment or different rates of progression to end-stage osteoarthritis in this population are important to ethnic disparity.
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ItemRelationship between body adiposity measures and risk of primary knee and hip replacement for osteoarthritis: a prospective cohort study(BMC, 2009)INTRODUCTION: Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. It is unknown whether the adipose mass and the distribution of adipose mass are associated with the risk of primary knee and hip replacement for osteoarthritis. The aim of the present investigation was to examine this in a cohort study. METHODS: A total of 39,023 healthy volunteers from Melbourne, Australia were recruited for a prospective cohort study during 1990 to 1994. Their body mass index, waist circumference, and waist-to-hip ratio were obtained from direct anthropometric measurements. The fat mass and percentage fat were estimated from bioelectrical impedance analysis. Primary knee and hip replacements for osteoarthritis between 1 January 2001 and 31 December 2005 were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) for primary joint replacement associated with each adiposity measure. RESULTS: Comparing the fourth quartile with the first, there was a threefold to fourfold increased risk of primary joint replacement associated with body weight (HR = 3.44, 95% confidence interval (CI) = 2.83 to 4.18), body mass index (HR = 3.44, 95% CI = 2.80 to 4.22), fat mass (HR = 3.51, 95% CI = 2.87 to 4.30), and percentage fat (HR = 2.99, 95% CI = 2.46 to 3.63). The waist circumference (HR = 2.77, 95% CI = 2.26 to 3.39) and waist-to-hip ratio (HR = 1.46, 95% CI = 1.21 to 1.76) were less strongly associated with the risk. Except for the waist-to-hip ratio, which was not significantly associated with hip replacement risk, all adiposity measures were associated with the risk of both knee and hip joint replacement, and were significantly stronger risk factors for knee. CONCLUSIONS: Risk of primary knee and hip joint replacement for osteoarthritis relates to both adipose mass and central adiposity. This relationship suggests both biomechanical and metabolic mechanisms associated with adiposity contribute to the risk of joint replacement, with stronger evidence at the knee rather than the hip.
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ItemVastus medialis cross-sectional area is positively associated with patella cartilage and bone volumes in a pain-free community-based population(BMC, 2008)INTRODUCTION: Although vastus medialis and lateralis are important determinants of patellofemoral joint function, their relationship with patellofemoral joint structure is unknown. The aim of this study was to examine potential determinants of vastus medialis and lateralis cross-sectional areas and the relationship between the cross-sectional area and patella cartilage and bone volumes. METHODS: Two hundred ninety-seven healthy adult subjects had magnetic resonance imaging of their dominant knee. Vastus medialis and lateralis cross-sectional areas were measured 37.5 mm superior to the quadriceps tendon insertion at the proximal pole of the patella. Patella cartilage and bone volumes were measured from these images. Demographic data and participation in vigorous physical activity were assessed by questionnaire. RESULTS: The determinants of increased vastus medialis and lateralis cross-sectional areas were older age (P
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ItemDietary fatty acid intake affects the risk of developing bone marrow lesions in healthy middle-aged adults without clinical knee osteoarthritis: a prospective cohort study(BMC, 2009)INTRODUCTION: Fatty acids have been implicated in osteoarthritis (OA), yet the mechanism by which fatty acids affect knee structure and consequently the risk of knee OA has not been fully elucidated. Higher intakes of fatty acids have been shown to be associated with the risk of bone marrow lesions (BMLs) in a healthy population. The aim of this study was to examine the association between fatty acid consumption and the incidence of BMLs in healthy middle-aged adults without clinical knee OA. METHODS: Two hundred ninety-seven middle-aged adults without clinical knee OA underwent magnetic resonance imaging (MRI) of their dominant knee at baseline. BMLs were assessed. Of the 251 participants with no BMLs in their knee at baseline, 230 underwent MRI of the same knee approximately 2 years later. Intakes of fatty acids were estimated from a food frequency questionnaire. RESULTS: Increased consumption of saturated fatty acids was associated with an increased incidence of BMLs over 2 years after adjusting for energy intake, age, gender, and body mass index (odds ratio of 2.56 for each standard deviation increase in dietary intake, 95% confidence interval 1.03 to 6.37, P = 0.04). Intake of monounsaturated or polyunsaturated fatty acids was not significantly associated with the incidence of BMLs. CONCLUSIONS: Increased fatty acid consumption may increase the risk of developing BMLs. As subchondral bone is important in maintaining joint integrity and the development of OA, this study suggests that dietary modification of fatty acid intake may be one strategy in the prevention of knee OA which warrants further investigation.
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ItemEffect of antioxidants on knee cartilage and bone in healthy, middle-aged subjects: a cross-sectional study(BMC, 2007)The aim of the present study is to examine the effect of dietary antioxidants on knee structure in a cohort of healthy, middle-aged subjects with no clinical knee osteoarthritis. Two hundred and ninety-three healthy adults (mean age = 58.0 years, standard deviation = 5.5) without knee pain or knee injury were selected from an existing community-based cohort. The intake of antioxidant vitamins and food sources by these individuals was estimated from a food frequency questionnaire at baseline. The cartilage volume, bone area, cartilage defects and bone marrow lesions were assessed approximately 10 years later using magnetic resonance imaging. In multivariate analyses, higher vitamin C intake was associated with a reduced risk of bone marrow lesions (odds ratio = 0.50, 95% confidence interval (CI) = 0.29-0.87, P = 0.01) and with a reduction in the tibial plateau bone area (beta = -35.5, 95% CI = -68.8 to -2.3, P = 0.04). There was an inverse association between fruit intake and the tibial plateau bone area (beta = -27.8, 95% CI = -54.9 to -0.7, P = 0.04) and between fruit intake and the risk of bone marrow lesions (odds ratio = 0.72, 95% CI = 0.52-0.99, P = 0.05). Neither fruit intake nor vitamin C intake was significantly associated with the cartilage volume or cartilage defects. Lutein and zeaxanthin intake was associated with a decreased risk of cartilage defects (odds ratio = 0.71, 95% CI = 0.51-0.99, P = 0.04), and vitamin E intake tended to be positively associated with the tibial plateau bone area (beta = 33.7, 95% CI = -3.1 to 70.4, P = 0.07) only after adjusting for vitamin C intake. The beta-cryptoxanthin intake was inversely associated with the tibial plateau bone area after adjusting for vitamin E intake (beta = -33.2, 95% CI = -63.1 to -3.4, P = 0.03). Intake of vegetables and other carotenoids was not significantly associated with cartilage or bone measures. The present study suggests a beneficial effect of fruit consumption and vitamin C intake as they are associated with a reduction in bone size and the number of bone marrow lesions, both of which are important in the pathogenesis of knee osteoarthritis. While our findings need to be confirmed by longitudinal studies, they highlight the potential of the diet to modify the risk of osteoarthritis.
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ItemThe AIB1 glutamine repeat polymorphism is not associated with risk of breast cancer before age 40 years in Australian women(BMC, 2005)INTRODUCTION: AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormones. METHODS: We evaluated this repeat polymorphism in the context of early-onset disease by conducting a case-control study of 432 Australian women diagnosed with breast cancer before the age of 40 years and 393 population-based control individuals who were frequency matched for age. Genotyping was performed using a scanning laser fluorescence imager. RESULTS: There were no differences in genotype frequencies between cases and control individuals, or between cases categorized by family history or by BRCA1 and BRCA2 germline mutation status. There was no evidence that the presence of one or two alleles of 26 glutamine repeats or fewer was associated with breast cancer (odds ratio = 1.03, 95% confidence interval = 0.73-1.44), or that women with alleles greater than 29 repeats were at increased risk of breast cancer. Exclusion of women who carried a BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter the risk estimates or inferences. We present raw data, including that on mutation carriers, to allow pooling with other studies. CONCLUSION: There was no evidence that risk of breast cancer depends on AIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2.
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ItemCYP17 genetic polymorphism, breast cancer, and breast cancer risk factors:: Australian Breast Cancer Family Study(BMC, 2005)INTRODUCTION: Because CYP17 can influence the degree of exposure of breast tissues to oestrogen, the interaction between polymorphisms in this gene and hormonal risk factors is of particular interest. We attempted to replicate the findings of studies assessing such interactions with the -34T-->C polymorphism. METHODS: Risk factor and CYP17 genotyping data were derived from a large Australian population-based case-control-family study of 1,284 breast cancer cases and 679 controls. Crude and adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses. RESULTS: We found no associations between the CYP17 genotype and breast cancer overall. Premenopausal controls with A2/A2 genotype had a later age at menarche (P < 0.01). The only associations near statistical significance were that postmenopausal women with A1/A1 (wild-type) genotype had an increased risk of breast cancer if they had ever used hormone replacement therapy (OR 2.40, 95% CI 1.0 to 5.7; P = 0.05) and if they had menopause after age 47 years (OR 2.59, 95% CI 1.0 to 7.0; P = 0.06). We found no associations in common with any other studies, and no evidence for interactions. CONCLUSION: We observed no evidence of effect modification of reproductive risk factors by CYP17 genotype, although the experiment did not have sufficient statistical power to detect small main effects and modest effects in subgroups. Associations found only in subgroup analyses based on relatively small numbers require cautious interpretation without confirmation by other studies. This emphasizes the need for replication in multiple and large population-based studies to provide convincing evidence for gene-environment interactions.
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ItemThe androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers(BMC, 2005)INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers.