Melbourne School of Population and Global Health - Research Publications
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ItemNo Preview AvailableDoes genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?(TAYLOR & FRANCIS INC, 2022-12-02)Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N = 7,431) and validation (N = 4,307) samples. Using paired genetic-methylation data (N = 4,307), gene-environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge. In the validation sample, PGS explained ~1.4% (P = 1 × 10-14), ~0.6% (P = 2 × 10-7), and ~8.7% (P = 7 × 10-87) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P < 0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption, and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAge and GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAge was attenuated in participants genetically predisposed to smoking (interaction term: -0.022, standard error [SE] = 0.012, P = 0.058) and that the association of alcohol consumption with PhenoAge was attenuated in those genetically predisposed to drink alcohol (interaction term: -0.030, SE = 0.015, P = 0.041). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify the association between observed lifestyle behaviour and blood DNA methylation. Potential associations were observed for epigenetic ageing measures, which should be replicated in additional studies.
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ItemNo Preview AvailableMethylation scores for smoking, alcohol consumption and body mass index and risk of seven types of cancer(WILEY, 2023-08-01)Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction.
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ItemMethylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies(BMC, 2022-09-06)BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.
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ItemEpigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking(SPRINGER, 2022-06)Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.
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ItemDNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies(WILEY, 2018-04-15)The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them "age acceleration." We aimed to assess the associations of age acceleration with risk of and survival from seven common cancers. Seven case-control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B-cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five-year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B-cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five-year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15-30% for the fourth versus first quartile of age acceleration. DNA methylation-based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.
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ItemThe blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium(PUBLIC LIBRARY SCIENCE, 2021-09)BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
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ItemAlcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data(WILEY, 2021-01)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. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10-7 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .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 1414 cross-sectional associations. Our study indicates that 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 alcohol consumption changes in adulthood.
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ItemCirculating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)(WILEY, 2020-05-01)Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
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ItemMaternal educational inequalities in measured body mass index trajectories in three European countries(WILEY, 2019-05)BACKGROUND: Social inequalities in the prevalence of childhood overweight and obesity are well-established, but less is known about when the social gradient first emerges and how it evolves across childhood and adolescence. OBJECTIVE: This study examines maternal education differentials in children's body mass trajectories in infancy, childhood and adolescence using data from four contemporary European child cohorts. METHODS: Prospective data on children's body mass index (BMI) were obtained from four cohort studies-Generation XXI (G21-Portugal), Growing Up in Ireland (GUI) infant and child cohorts, and the Millennium Cohort Study (MCS-UK)-involving a total sample of 41,399 children and 120,140 observations. Children's BMI trajectories were modelled by maternal education level using mixed-effect models. RESULTS: Maternal educational inequalities in children's BMI were evident as early as three years of age. Children from lower maternal educational backgrounds were characterised by accelerated BMI growth, and the extent of the disparity was such that boys from primary-educated backgrounds measured 0.42 kg/m2 (95% CI 0.24, 0.60) heavier at 7 years of age in G21, 0.90 kg/m2 (95% CI 0.60, 1.19) heavier at 13 years of age in GUI and 0.75 kg/m2 (95% CI 0.52, 0.97) heavier in MCS at 14 years of age. The corresponding figures for girls were 0.71 kg/m2 (95% CI 0.50, 0.91), 1.31 kg/m2 (95% CI 1.00, 1.62) and 0.76 kg/m2 (95% CI 0.53, 1.00) in G21, GUI and MCS, respectively. CONCLUSIONS: Maternal education is a strong predictor of BMI across European nations. Socio-economic differentials emerge early and widen across childhood, highlighting the need for early intervention.