Pierre-Antoine Dugué

Association between selected dietary scores and the risk of urothelial cell carcinoma: A prospective cohort study

Studies investigating the association of food and nutrient consumption with the risk of urothelial cell carcinoma (UCC) have produced mixed results. We used three common dietary scores, the Mediterranean Diet Score (MDS), the Alternate Healthy Eating Index 2010 (AHEI‐2010) and the Dietary Inflammatory Index (DII) to assess the evidence of an association between diet and the risk of UCC. Over a median follow‐up time of 21.3 years, 379 incident UCC cases were diagnosed. Dietary scores were calculated using data from a 121‐item food frequency questionnaire administered at baseline. We used Cox models to compute hazard ratios (HR) for the association between dietary scores (per one standard deviation) and UCC risk. In order to reflect overall adherence to a healthy diet, a metascore was constructed by summing the quintiles of each of the three scores. None of the dietary scores was associated with the risk of UCC overall. A healthier diet was found to be inversely associated with the risk of invasive (MDS: HR = 0.86, 95% CI: 0.74–1.00, metascore: HR = 0.84, 95% CI: 0.71–0.98), but not superficial disease (heterogeneity between subtypes p = 0.04 and p = 0.03, respectively). Results were consistent but weaker for the DII and the AHEI‐2010. We found some evidence of effect modification by smoking, in particular for the metascore (Current: HR = 0.77, 95% CI: 0.58–1.01, Former: HR = 0.77, 95% CI: 0.64–0.92, Never: HR = 1.01, 95% CI: 0.81–1.26, p for heterogeneity = 0.05). A healthy diet may be protective against the risk of invasive, but not superficial, UCC. Promoting healthy dietary habits may help lower the risk of invasive UCC, especially for current and former smokers.

Cohort Profile: The Melbourne Collaborative Cohort Study (Health 2020)

Cohort Profile: The Melbourne Collaborative Cohort Study (Health 2020) R L Milne,* A S Fletcher, R J MacInnis, A M Hodge, A H Hopkins, J K Bassett, F J Bruinsma, B M Lynch, P A Dugué, H Jayasekara, M T Brinkman, L V Popowski, L Baglietto, G Severi, K O’Dea, J L Hopper, M C Southey, D R English and G G Giles Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia, Centre for Epidemiology and Biostatistics, University of Melbourne, Parkville, VIC, Australia, Physical Activity Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia, Centre de Recherche en Epidémiologie et Santé des Populations, Université Paris-Saclay, Villejuif, France, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, Human Genetics Foundation (HuGeF), Turin, Italy, Centre of Population Health Research, University of South Australia, Adelaide, SA, Australia and Genetic Epidemiology Laboratory, University of Melbourne, Parkville, VIC, Australia

Epigenetic supersimilarity of monozygotic twin pairs

BackgroundMonozygotic twins have long been studied to estimate heritability and explore epigenetic influences on phenotypic variation. The phenotypic and epigenetic similarities of monozygotic twins have been assumed to be largely due to their genetic identity.ResultsHere, by analyzing data from a genome-scale study of DNA methylation in monozygotic and dizygotic twins, we identified genomic regions at which the epigenetic similarity of monozygotic twins is substantially greater than can be explained by their genetic identity. This “epigenetic supersimilarity” apparently results from locus-specific establishment of epigenotype prior to embryo cleavage during twinning. Epigenetically supersimilar loci exhibit systemic interindividual epigenetic variation and plasticity to periconceptional environment and are enriched in sub-telomeric regions. In case-control studies nested in a prospective cohort, blood DNA methylation at these loci years before diagnosis is associated with risk of developing several types of cancer.ConclusionsThese results establish a link between early embryonic epigenetic development and adult disease. More broadly, epigenetic supersimilarity is a previously unrecognized phenomenon that may contribute to the phenotypic similarity of monozygotic twins.

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.

Resting heart rate, temporal changes in resting heart rate, and overall and cause-specific mortality

Objective Most studies investigating the association between resting heart rate (RHR) and mortality have focused on cardiovascular disease (CVD) mortality, and measured RHR at only one time point. We aimed to assess associations of RHR and changes in RHR over approximately a decade with overall and cause-specific mortality. Methods We used data from participants in the Melbourne Collaborative Cohort Study with RHR measures at baseline (1990–1994; n=41 386; 9846 deaths) and at follow-up (2003–2007; n=21 692; 2818 deaths). RHR measures were taken by trained staff, using Dinamap monitors. Cox models were used to estimate HR and 95% CI for the associations between RHR and mortality. Vital status and cause of death were ascertained until August 2015 and December 2013, respectively. Results After adjustment for confounders, including blood pressure and known medical conditions but not arrhythmias or atrial fibrillation, RHR was associated with a higher risk of death of similar magnitude for CVD (HR per 10 beats per minute (bpm)=1.11, 95% CI 1.07 to 1.16), cancer (HR=1.10, 95% CI 1.06 to 1.13) and other causes (HR=1.20, 95% CI 1.16 to 1.25). Higher mortality was observed for most cancer sites, including breast (HR=1.16, 95% CI 1.03 to 1.31), colorectal (HR=1.18, 95% CI 1.08 to 1.29), kidney (HR=1.27, 95% CI 1.03 to 1.57) and lung cancer (HR=1.19, 95% CI 1.10 to 1.29). Temporal increases in RHR were associated with higher mortality, particularly for individuals whose RHR increased by more than 15 bpm. Conclusions RHR and changes in RHR over a decade are associated with mortality risk, including from causes other than CVD such as breast, colorectal or lung cancer. Monitoring of RHR may have utility in identifying individuals at higher mortality risk.

Is there an association between season of birth and blood DNA methylation in adulthood

In a recent article published in your journal (1), Lockett et al. concluded that DNA methylation in adulthood is associated with season of birth and suggested that this association arises postnatally and could mediate the effect of season of birth on allergy. Their epigenome-wide association study was based on methylation measured in whole-blood DNA from 367 participants aged 18 from the United Kingdom. The authors reported that 92 CpG sites were associated with specific seasons of birth and that four of these associations were replicated in an independent series of 207 children aged eight from the Netherlands. We attempted to replicate these 92 associations using 2774 adults aged 40–70 who were selected as controls in one of six case–control studies nested in the Melbourne Collaborative Cohort Study (2). Season of birth was defined as in Lockett et al. for individuals born in the Northern Hemisphere (UK, n = 186; Italy, Greece and Malta, n = 712) and reversed for people born in the Southern Hemisphere (Australia and New Zealand, n = 1876). We used linear mixed-effects models for methylation M-values (measured using the same HM450K assay) including as fixed effects the variables used in Lockett et al. (except maternal socio-economic status), as well as age at blood draw, country of birth and sample type (peripheral blood mononuclear cells, dried blood spots, buffy coats), and as random effects the study in which the sample was processed and the plate and chip of the assay (3). Results for four of the 92 CpG sites were consistent in direction with those of Lockett et al. and had a P-value less than 0.05 (Table 1), but none was significant after Bonferroni correction for multiple testing. Neither the four signals that Lockett et al. reported as replicated in the Dutch study nor the strongest hit from their discovery phase (cg07175945) was nominally significant in our data (P > 0.05). Our results were consistent in sensitivity analyses which included the following: further adjusting for blood cell composition derived from the Houseman algorithm; further adjusting for smoking, BMI and alcohol drinking; and stratifying the analyses by region of birth (Australia/NZ, UK, Southern Europe). We did not find clear evidence of seasonassociated differences in methylation at other CpGs on the HM450K assay (P > 10 ). A possible explanation for the general lack of replication of the Lockett et al. findings in our study is the older and

The repeatability of DNA methylation measures may also affect the power of epigenome-wide association studies

The repeatability of DNA methylation measures may also affect the power of epigenome-wide association studies From Pierre-Antoine Dugué,* Dallas R English, Robert J MacInnis, Jihoon E Joo, Chol-Hee Jung and Roger L Milne Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, Australia and VLSCI Life Sciences Computation Centre, University of Melbourne, Carlton VIC, Australia

Heritable DNA methylation marks associated with susceptibility to breast cancer

Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.DNA methylation is associated with breast cancer risk. Here the authors measure DNA methylation in the blood of individuals from 25 Australian families with multiple cases of breast cancer but not known mutations associated with breast cancer risk to identify possible heritable methylation markers.

Alcohol consumption is associated with widespread changes in blood DNA methylation: analysis of cross-sectional and longitudinal data

Background: DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Methods: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined using baseline peripheral blood samples from 5,606 adult Melbourne Collaborative Cohort Study (MCCS) participants. For a subset of 1,088 of them, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. Independent data from the LOLIPOP (N=4,042) and KORA (N=1,662) cohorts were used to replicate associations discovered in the MCCS. Results: Cross-sectional analyses identified 1,414 CpGs associated with alcohol intake at P<10-7, 1,243 of which had not been reported previously. Of these 1,243 novel associations, 1,078 were replicated (P<0.05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated (P<0.05) 403 of 518 associations that had been reported previously. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1,414 CpGs, 530 were differentially methylated (P<0.05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1,414 cross-sectional associations. Conclusion: Our study indicates that, for middle-aged and older adults, alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with changes in alcohol consumption.

Heritable methylation marks associated with breast and prostate cancer risk.

DNA methylation can mimic the effects of germline mutations in cancer predisposition genes. Recently, we identified twenty‐four heritable methylation marks associated with breast cancer risk. As breast and prostate cancer share genetic risk factors, including rare, high‐risk mutations (eg, in BRCA2), we hypothesized that some of these heritable methylation marks might also be associated with the risk of prostate cancer.