Trajectories of body mass index from early adulthood to late midlife and incidence of total knee arthroplasty for osteoarthritis: findings from a prospective cohort study.

OBJECTIVE: To examine the association between body mass index (BMI) trajectories from early adulthood to late midlife and risk of total knee arthroplasty (TKA) for osteoarthritis. METHODS: 24,368 participants from the Melbourne Collaborative Cohort Study with weight collected during 1990-1994, 1995-1998, and 2003-2007, recalled weight at age 18-21 years, and height measured during 1990-1994 were included. Incident TKA from 2003 to 2007 to December 2018 was determined by linking cohort records to the National Joint Replacement Registry. RESULTS: Using group-based trajectory modelling, six distinct trajectories (TR) of BMI from early adulthood (age 18-21 years) to late midlife (approximately 62 years) were identified: lower normal to normal BMI (TR1; 19.7% population), normal BMI to borderline overweight (TR2; 36.7%), normal BMI to overweight (TR3; 26.8%), overweight to borderline obese (TR4; 3.5%), normal BMI to class 1 obesity (TR5; 10.1%), overweight to class 2 obesity (TR6; 3.2%). Over 12.4 years, 1,328 (5.4%) had TKA. The hazard ratios for TKA increased in all TR compared to TR1 [from TR2: 2.03 (95% CI 1.64-2.52) to TR6: 8.59 (6.44-11.46)]. 28.4% of TKA could be prevented if individuals followed the trajectory one lower, an average weight reduction of 8-12 kg from early adulthood to late midlife, saving $AUS 373 million/year. Most reduction would occur in TR2 (population attributable fraction 37.9%, 95% CI 26.7-47.3%) and TR3 (26.8%, 20.0-31.2%). CONCLUSIONS: Prevention of weight gain from young adulthood to late midlife in order to reduce overweight/obesity has the potential to significantly reduce the cost and burden of TKA.

Coffee, tea, and caffeine intake and amyotrophic lateral sclerosis mortality in a pooled analysis of eight prospective cohort studies.

BACKGROUND AND PURPOSE: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea and caffeine intake, and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351 565 individuals (120 688 men and 230 877 women). We assessed coffee, tea and caffeine intake using validated food-frequency questionnaires administered at baseline. We used Cox regression to estimate study- and sex-specific risk ratios and 95% confidence intervals (CI) for ALS mortality, which were then pooled using a random-effects model. We conducted analyses using cohort-specific tertiles, absolute common cut-points and continuous measures of all exposures. RESULTS: During follow-up, 545 ALS deaths were documented. We did not observe statistically significant associations between coffee, tea or caffeine intake and risk of ALS mortality. The pooled multivariable risk ratio (MVRR) for ≥3 cups per day vs. >0 to <1 cup per day was 1.04 (95% CI, 0.74-1.47) for coffee and 1.17 (95% CI, 0.77-1.79) for tea. The pooled MVRR comparing the highest with the lowest tertile of caffeine intake (mg/day) was 0.99 (95% CI, 0.80-1.23). No statistically significant results were observed when exposures were modeled as tertiles or continuously. CONCLUSIONS: Our results do not support associations between coffee, tea or total caffeine intake and risk of ALS mortality.

Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

Dietary inflammatory index or Mediterranean diet score as risk factors for total and cardiovascular mortality.

BACKGROUND AND AIMS: Dietary patterns are associated with risk of cardiovascular disease (CVD). We aimed to examine associations of the Dietary Inflammatory Index (DII) and the Mediterranean Diet Score (MDS) with total, cardiovascular disease (CVD) and coronary heart disease (CHD) mortality in the Melbourne Collaborative Cohort Study; and compare the strengths of the associations. METHODS AND RESULTS: In our prospective cohort study of 41,513 men and women aged 40-69 years, a food frequency questionnaire was completed at baseline and mortality data were obtained via linkage with local and national registries over an average of 19 years follow up. At baseline, questionnaires were completed and physical measures and blood samples taken. Cox proportional hazards models, adjusting for age, alcohol consumption, sex, region of origin, personal history of CVD or diabetes and family history of CVD, were used to assess associations between dietary scores and mortality. More Mediterranean or less inflammatory diets were associated with lower total, CVD and CHD mortality. The hazard ratio for total mortality comparing the highest and lowest quintiles was 1.16 (95%CI: 1.08-1.24) for DII; and 0.86 (95%CI: 0.80-0.93) comparing the highest and lowest three categories of MDS. Using the Bayesian information criterion, there was no evidence that the DII score was more strongly associated with total and CVD mortality than was the MDS. CONCLUSIONS: The MDI and the DII show similar associations with total and cardiovascular mortality, consistent with the consensus that plant-based diets are beneficial for health.

Associations between hip bone mineral density, aortic calcification and cardiac workload in community-dwelling older Australians.

In older adults, lower bone density in the proximal femur was associated with increased heart burden, and this association was linked to calcification in the aorta. These results were seen in women but not in men. PURPOSE: To determine whether there is an association between lower bone mineral density (BMD) and increased cardiac workload in older adults, and if this association was independent of abdominal aortic calcification (AAC). METHODS: Three hundred thirty-seven participants [mean ± SD age = 70 ± 5 years and BMI = 28 ± 5 kg/m2, 61% females] had BMD determined by dual-energy X-ray absorptiometry and AAC determined by radiography. Aortic calcification score (ACS) was determined visually in the L1-L4 vertebrae (range 0-24). Systolic blood pressure (BP) and heart rate (HR) were measured. The rate pressure product (RPP), a measure of cardiac workload, was determined by multiplying BP and HR. RESULTS: AAC was present in 205 (61%) participants. Mean ± SD RPP was 9120 ± 1823; range was 5424-18,537. In all participants, ACS was positively associated with log-transformed RPP [LnRPP] (ß = 0.011, p < 0.001), and severe calcification was positively associated with LnRPP (ß = 0.083, p = 0.004 relative to no calcification). In sex-stratified analyses, these associations were significant only in females. Lower odds of any AAC were observed per 1 g/cm2 increment in femoral neck BMD (OR = 0.08, 95% CI 0.01-0.95). A similar trend was evident in women separately (OR = 0.05, 95% CI 0-1.17) but not men. In all participants, femoral neck (ß = -0.20, p = 0.04) and total hip BMD (ß = -0.17, p = 0.04) were inversely associated with LnRPP after multivariate adjustment. Adjusting additionally for AAC reduced the strength of the association in femoral neck (ß = -0.19, p = 0.05) but not total hip BMD (ß = -0.17, p = 0.04). CONCLUSION: Lower BMD was marginally, but significantly with increased LnRPP, and this relationship was partially mediated by AAC suggesting that older adults, particularly females, with osteoporosis may have an increased cardiovascular risk.

Dietary inflammatory index, Mediterranean diet score, and lung cancer: a prospective study.

PURPOSE: To investigate prospectively the associations of Dietary Inflammatory Index (DII) and Mediterranean Diet Score (MDS) with lung cancer. METHODS: We used data from men and women aged 40-69 years at recruitment in 1990-1994, who were participants in the Melbourne Collaborative Cohort Study (n = 35,303). A total of 403 incident lung cancer cases were identified over an average 18-year follow-up. Hazard ratios (HR) were estimated using Cox regression, adjusting for smoking status and other risk factors, with age as the time metric. RESULTS: An inverse correlation was observed between the DII and MDS (ρ = -0.45), consistent with a higher DII being pro-inflammatory and less 'healthy,' while a high MDS reflects a 'healthier' diet. The DII was positively associated with risk of lung cancer in current smokers [HRQ4 vs Q1 = 1.70 (1.02, 2.82); Ptrend = 0.008] (p interaction between DII quartiles and smoking status = 0.03). The MDS was inversely associated with lung cancer risk overall [HR7-9 vs 0-3 = 0.64 (0.45, 0.90); Ptrend = 0.005] and for current smokers (HR7-9 vs 0-3 = 0.38 (0.19, 0.75); Ptrend = 0.005) (p interaction between MDS categories and smoking status = 0.31). CONCLUSIONS: The MDS showed an inverse association with lung cancer risk, especially for current smokers. A high DII, indicating a more pro-inflammatory diet, was associated with risk of lung cancer only for current smokers. A healthy diet may reduce the risk of lung cancer, especially in smokers.

Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies.

Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82-1.18 comparing ≥500 with 1-69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and ice-cream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77-1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71-1.12) intake and pancreatic cancer risk overall when comparing intakes ≥1300 with <500 mg/day. In addition, null associations were observed for dietary and total vitamin D intake and pancreatic cancer risk. Findings were consistent within sex, smoking status, and BMI strata or when the case definition was limited to pancreatic adenocarcinoma. Overall, these findings do not support the hypothesis that consumption of dairy foods, calcium, or vitamin D during adulthood is associated with pancreatic cancer risk.

Effects of Vitamin D Supplementation on Telomere Length: An Analysis of Data from the Randomised Controlled D-Health Trial.

OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation. RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration. CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.

Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study.

BACKGROUND: We aimed to assess whether 2D:4D measures are associated with breast cancer risk. METHODS: We derived the ratio of the lengths of the index and ring fingers (2D:4D), and right minus left 2D:4D (Δ(r-l)) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D:4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D:4D measures and age at menarche and menopause. RESULTS: We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk. Among breast cancer cases, both right 2D:4D and Δ(r-l) were inversely associated with age at diagnosis. We also observed associations between both right 2D:4D and Δ(r-l) and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause. CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.

Second to fourth digit ratio (2D:4D) and prostate cancer risk in the Melbourne Collaborative Cohort Study.

BACKGROUND: The ratio of the lengths of index and ring fingers (2D:4D) is a marker of prenatal exposure to sex hormones, with low 2D:4D being indicative of high prenatal androgen action. Recent studies have reported a strong association between 2D:4D and risk of prostate cancer. METHODS: A total of 6258 men participating in the Melbourne Collaborative Cohort Study had 2D:4D assessed. Of these men, we identified 686 incident prostate cancer cases. Hazard ratios (HRs) and confidence intervals (CIs) were estimated for a standard deviation increase in 2D:4D. RESULTS: No association was observed between 2D:4D and prostate cancer risk overall (HRs 1.00; 95% CIs, 0.92-1.08 for right, 0.93-1.08 for left). We observed a weak inverse association between 2D:4D and risk of prostate cancer for age <60, however 95% CIs included unity for all observed ages. CONCLUSION: Our results are not consistent with an association between 2D:4D and overall prostate cancer risk, but we cannot exclude a weak inverse association between 2D:4D and early onset prostate cancer risk.

Dietary patterns and risk of breast cancer.

BACKGROUND: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. METHODS: Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. RESULTS: During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). CONCLUSION: Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes.

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Does a Mediterranean diet reduce the mortality risk associated with diabetes: evidence from the Melbourne Collaborative Cohort Study.

BACKGROUND AND AIMS: Diabetes is a risk factor for cardiovascular disease (CVD), yet southern European migrants to Australia with high rates of type 2 diabetes have relatively low CVD mortality. Our aim was to determine whether a Mediterranean style diet could reduce mortality in people with diabetes. METHODS AND RESULTS: Participants included 16,610 males and 23,860 females from the Melbourne Collaborative Cohort Study; 25% were born in Greece or Italy, and 2150 had previously been diagnosed with diabetes or had elevated blood glucose at baseline (1990-94). Data on demographic, behavioral and physical risk factors were also collected. A personal Mediterranean Diet Score (MDS) was calculated using data from a validated 121-item food frequency questionnaire. Total and CVD mortality data were available up to 2003. Diabetes (new and known) at baseline, was associated with total mortality (men HR 1.43, 95%CI 1.26-1.62; women HR 1.86 95%CI 1.58-2.18), and CVD mortality (men HR 1.53, 95%CI 1.21-1.94; women HR 2.10 95%CI 1.48-2.97) in multivariate models. There was no evidence that glucose tolerance modified the associations between MDS and total or CVD mortality (p interaction all > 0.16). The HRs for total mortality per unit of MDS were 0.96 (95% CI 0.93-0.99) in men and 0.94 (95% CI 0.92-0.97) in women. The HRs for CVD mortality per unit of MDS were 0.94 (95% CI 0.89-0.99) in men and 0.94 (95% CI 0.87-1.01) in women. CONCLUSION: Our results add to the evidence supporting the benefit of a Mediterranean style diet for people with type 2 diabetes.

NMR-determined lipoprotein subclass profile is associated with dietary composition and body size.

BACKGROUND AND AIMS: Dyslipidemia is influenced by diet and body habitus. The Nuclear Magnetic Resonance spectroscopy lipoprotein subclass profile (NMR-LSP) is associated with diabetes and its vascular complications; and an NMR-LSP featuring large VLDL particles and small LDL and HDL particles is linked with cardiovascular disease (CVD). Thus interventions which favourably modify NMR-LSP may reduce risk for diabetes, its complications and CVD. The study aim was to investigate the associations between NMR-LSP, dietary composition and body size measures using data from the Melbourne Collaborative Cohort Study (MCCS). METHODS AND RESULTS: NMR-LSP was assessed in 313 men and 403 women (median age 54 years) randomly selected from a community-based cohort study. Diet was assessed using a specifically developed food frequency questionnaire (FFQ), and body size was assessed by body mass index (BMI) or waist:hips ratio (WHR). To simplify the 15 NMR-LSP variables, factor analysis was used to derive a single factor. Multivariate linear regression with this factor score as the dependent variable demonstrated that in men, total PUFA and n-6 dietary fat intake and BMI were associated with a more atherogenic NMR-LSP pattern; while in women dietary glycemic index and WHR demonstrated positive associations, and n-3 fat intake an inverse association. CONCLUSIONS: We developed a single factor score to summarize the NMR-LSP that has the benefit of combining all aspects of the NMR-LSP and accounting for correlations between them. We have shown correlations between the NMR-LSP and body size and dietary composition.

Analgesic use and the risk of renal cell carcinoma - Findings from the Consortium for the Investigation of Renal Malignancies (CONFIRM) study.

PURPOSE: The incidence of renal cell carcinoma (RCC) is rising. Use of analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol may affect renal function. The aim of this study was to assess associations between analgesic use and risk of RCC. METHODS: A population-based case-control family design was used. Cases were recruited via two Australian state cancer registries. Controls were siblings or partners of cases. Analgesic use was captured by self-completed questionnaire. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for RCC risk associated with regular analgesic use (at least 5 times per month for 6 months or more) and duration and frequency of use. RESULTS: The analysis included 1064 cases and 724 controls. Regular use of paracetamol was associated with an increased risk of RCC (OR 1.41, 95%CI 1.13-1.77). Regular use of NSAIDs was associated with increased risk of RCC for women (OR 1.71, 95% CI 1.23-2.39) but not men (OR 0.83, 95% CI 0.58-1.18; p-interaction=0.003). There was no evidence of a dose-response for duration of use of paracetamol (linear trend p = 0.77) and weak evidence for non- aspirin NSAID use by women (linear trend p = 0.054). CONCLUSION: This study found that regular use of paracetamol was associated with increased risk of RCC. NSAID use was associated with increased risk only for women.

Comprehensive analysis of the cytokine-rich chromosome 5q31.1 region suggests a role for IL-4 gene variants in prostate cancer risk.

Although inflammation is emerging as a candidate prostate cancer risk factor, the T-helper cytokine-rich [interleukins (IL)-5, 13 and 4] chromosomal region at 5q31.1 has been implicated in prostate cancer pathogenesis. In particular, IL-4 has been associated with prostate cancer progression, whereas the IL-4 -589C>T (rs2243250) promoter variant has been associated with differential gene expression. We genotyped rs2243250 and 11 tag single-nucleotide polymorphisms (SNPs) spanning 200 kb across the 5q31.1 region on 825 cases and 732 controls from the Risk Factors for Prostate Cancer Study. The minor alleles of rs2243250 and an IL-4 tagSNP rs2227284 were associated with a small increase in prostate cancer risk. Per allele odds ratios (ORs) are 1.32 [95% confidence interval (CI) 1.08-1.61, P = 0.006] and 1.26 (95% CI 1.07-1.48, P = 0.005), respectively. Although these associations were not replicated in an analysis of the Melbourne Collaborative Cohort Study, including 810 cases and 1733 controls, no clinicopathological characteristic was implicated for this divergence. Correlating rs2243250 genotypes to IL-4 gene transcript levels and circulating IL-4 plasma levels, we observe in contrast to previous reports, a non-significant trend toward the minor T-allele decreasing the likelihood of IL-4 activity. From our observed association between a low IL-4 producing promoter T-allele and prostate cancer risk, our study suggests an antitumor role for IL-4 in prostate cancer. Although we saw no association for IL-5 or IL-13 gene variants and prostate cancer risk, our findings call for further evaluation of IL-4 as a contributor to prostate cancer susceptibility.

Plasma concentration of Propionibacterium acnes antibodies and prostate cancer risk: results from an Australian population-based case-control study.

BACKGROUND: Recent studies in prostatic tissue suggest that Propionibacterium acnes (P. acnes), a bacterium associated with acne that normally lives on the skin, is the most prevalent bacterium in the prostate and in men with benign prostatic hyperplasia. Its prevalence is higher in samples from patients subsequently diagnosed with prostate cancer. The aim of our study was to test whether circulating levels of P. acnes antibodies are associated with prostate cancer risk and tumour characteristics using plasma samples from a population-based case-control study. METHODS: We measured plasma concentration of P. acnes antibodies for 809 cases and 584 controls using a recently developed ELISA assay. We compared antibody titres between cases and controls using unconditional logistic regression adjusted for batch and variables associated with the study design (i.e., age, year of selection and centre). The primary analysis included P. acnes titres in the model as a dichotomous variable using the median value for controls as the cut-off value. RESULTS: P. acnes antibody titres for both cases and controls ranged from 1 : 16 (i.e., low concentration) to 1 : 65,536 (i.e., high concentration; median value=1 : 1024). The odds ratio for prostate cancer associated with titres at or above the median value was 0.73 (95% CI 0.58-0.91, P=0.005). The association appeared to be particularly strong for advanced prostate cancer (AJCC Stage grouping III-IV) for which the odds ratio was 0.59 (95% CI 0.43-0.81, P=0.001) but there was insufficient evidence that the association differed by tumour stage (p heterogeneity=0.07). CONCLUSION: These results need to be confirmed in prospective studies but they are consistent with the hypothesis that P. acnes has a role in prostate cancer.

Obesity and adiposity are associated with the rate of patella cartilage volume loss over 2 years in adults without knee osteoarthritis.

OBJECTIVES: The aim of this study was to determine whether measures of obesity and adiposity are associated with the rate of patella cartilage volume loss in healthy adults. METHODS: 297 community-based adults aged 50-79 years with no clinical knee osteoarthritis were recruited at baseline (2003-4). 271 (62% female) subjects were re-examined at follow-up (2006-7). Measures of obesity (body mass index (BMI) and weight) and adiposity (fat mass and percentage fat mass), as well as patella cartilage volume, were determined by established protocols. RESULTS: Patella cartilage volume was lost at an annual rate of 1.8% (95% CI 1.4% to 2.1%). Increased baseline BMI, weight, fat mass and percentage fat mass were all associated with an increased rate of patella cartilage volume loss after adjustment for confounders (all p< or =0.04). The direction and magnitude of the effects were similar for both sexes but the number of men examined was considerably smaller and the associations were not statistically significant. There were no significant associations observed between change in any of the obesity and adiposity measures and the rate of patella cartilage volume loss. CONCLUSION: This study demonstrated that increased levels of obesity and adiposity are associated with an increased annual rate of patella cartilage volume loss in healthy adults. Weight-loss interventions that reduce body mass, or specifically target a reduction in fat mass, may help to reduce the rate at which patella cartilage volume is lost, and subsequently the risk of patellofemoral osteoarthritis.

The natural history of bone marrow lesions in community-based adults with no clinical knee osteoarthritis.

OBJECTIVE: Although bone marrow lesions (BML) have been implicated in the pathogenesis of osteoarthritis, their natural history in a healthy population is unknown. This study in a healthy, pain-free population aimed to examine the natural history of BML; factors associated with incidence and progression of BML over 2 years and whether incident BML are associated with the development of pain. METHODS: 271 subjects with no clinical knee osteoarthritis, being pain free at baseline, underwent magnetic resonance imaging of their dominant knee at baseline and 2 years later. The presence of BML was assessed. RESULTS: In knees initially free of BML, incident BML developed in 14% of people over the study period. Increased body mass index (BMI; odds ratio (OR) 1.15, 95% CI 1.06 to 1.2, p = 0.001) was associated with incident BML. Those who developed a BML were more likely to develop knee pain compared with those in whom no BML developed (OR 4.2, 95% CI 1.2 to 15.1, p = 0.03). Among those in whom BML were present at baseline, 46% completely resolved. There was no association between age, gender and BMI and persistence of BML over 2 years. CONCLUSION: In this healthy population, the rate of incident BML is lower than previously described in a population with osteoarthritis. Incident BML are associated with increased BMI and the development of pain. Approximately half the BML present at baseline resolved. These data suggest that in pain-free people with no clinical knee osteoarthritis, BML are reversible and may provide a target for interventions aimed at the prevention of knee osteoarthritis.