Alcohol consumption, blood DNA methylation and breast cancer: a Mendelian randomisation study.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhou X
PROVIDER: S-EPMC9329409 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed ?=?0.78; 95% confidence interval (95%CI):0.66,0.91; p values?=?0.002); rs12910509, HRfixed ?=?0.76; 95%CI:0.64,0.91; p values?=?0.003); and rs8041922 (HRfixed ?=?0.76; 95%CI:0.64,0.91; p values?=?0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed ?=?1.43; 95%CI:1.14,1.79; p values?=?0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression.
| S-EPMC5111609 | biostudies-literature
Project description:OBJECTIVES:The objective of this study was to evaluate the association of genetically determined leptin with lipids. DESIGN:We conducted a Mendelian randomisation study to assess a potential causal relationship between serum leptin and lipid levels. We also evaluated whether alcohol drinking modified the associations of genetically determined leptin with blood lipids. SETTING AND PARTICIPANTS:3860 participants of the Framingham Heart Study third generation cohort. RESULTS:Both genetic risk scores (GRSs), the GRS generated using leptin loci independent of body mass index (BMI) and GRS generated using leptin loci dependent of BMI, were positively associated with log-transformed leptin (log-leptin). The BMI-independent leptin GRS was associated with log-transformed triglycerides (log-TG, β=-0.66, p=0.01), but not low-density lipoprotein cholesterol (LDL-C, p=0.99), high-density lipoprotein cholesterol (HDL-C, p=0.44) or total cholesterol (TC, p=0.49). Instrumental variable estimation showed that per unit increase in genetically determined log-leptin was associated with 0.55 (95% CI: 0.05 to 1.00) units decrease in log-TG. Besides significant association with log-TG (β=-0.59, p=0.009), the BMI-dependent GRS was nominally associated with HDL-C (β=-10.67, p=0.09) and TC (β=-28.05, p=0.08). When stratified by drinking status, the BMI-dependent GRS was associated with reduced levels of LDL-C (p=0.03), log-TG (p=0.004) and TC (p=0.003) among non-current drinkers only. Significant interactions between the BMI-dependent GRS and alcohol drinking were identified for LDL-C (p=0.03), log-TG (p=0.03) and TC (p=0.02). CONCLUSION:These findings together indicated that genetically determined leptin was negatively associated with lipid levels and the association may be modified by alcohol consumption.
| S-EPMC6858149 | biostudies-literature
Project description:BACKGROUND:Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers. METHODS AND FINDINGS:We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio [OR] 1.80; 95% confidence interval [CI] 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers. CONCLUSIONS:Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.
| S-EPMC7377370 | biostudies-literature
Project description:Alcohol consumption is associated with the development of cardiovascular diseases, cancer, and liver disease. The biological mechanisms are still largely unclear. Here, we aimed to use an agnostic approach to identify phenotypes mediating the effect of alcohol on various diseases.MethodsWe performed an agnostic association analysis between alcohol consumption (red and white wine, beer/cider, fortified wine, and spirits) with over 7800 phenotypes from the UK biobank comprising 223,728 participants. We performed Mendelian randomisation analysis to infer causality. We additionally performed a Phenome-wide association analysis and a mediation analysis between alcohol consumption as exposure, phenotypes in a causal relationship with alcohol consumption as mediators, and various diseases as the outcome.ResultsOf 45 phenotypes in association with alcohol consumption, 20 were in a causal relationship with alcohol consumption. Gamma glutamyltransferase (GGT; β = 9.44; 95% CI = 5.94, 12.93; Pfdr = 9.04 × 10-7), mean sphered cell volume (β = 0.189; 95% CI = 0.11, 0.27; Pfdr = 1.00 × 10-4), mean corpuscular volume (β = 0.271; 95% CI = 0.19, 0.35; Pfdr = 7.09 × 10-10) and mean corpuscular haemoglobin (β = 0.278; 95% CI = 0.19, 0.36; Pfdr = 1.60 × 10-6) demonstrated the strongest causal relationships. We also identified GGT and physical inactivity as mediators in the pathway between alcohol consumption, liver cirrhosis and alcohol dependence.ConclusionOur study provides evidence of causality between alcohol consumption and 20 phenotypes and a mediation effect for physical activity on health consequences of alcohol consumption.
| S-EPMC9317105 | biostudies-literature
Project description:BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER- breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91-0.97)], cg0760265 [OR = 1.07, 95% CI (1.03-1.11)], cg0420946 [OR = 0.95, 95% CI (0.93-0.98)], and cg2037583 [OR =1.09, 95% CI (1.04-1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p < 1.83 × 10-11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 > 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER- breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.
| S-EPMC8507148 | biostudies-literature
Project description:Aim: Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated. Materials & methods: In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip. Results: Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins. Conclusion: The hypermethylation of cg07326074, located in the tumor-promoting gene C16orf59, was associated with alcohol consumption.
| S-EPMC8147754 | biostudies-literature
Project description:Mendelian randomisation studies from Asia suggest detrimental influences of alcohol on cardiovascular risk factors, but such associations are observed mainly in men. The absence of associations of genetic variants (e.g. rs671 in ALDH2) with such risk factors in women - who drank little in these populations - provides evidence that the observations are not due to genetic pleiotropy. Here, we present a Mendelian randomisation study in a South Korean population (3,365 men and 3,787 women) that 1) provides robust evidence that alcohol consumption adversely affects several cardiovascular disease risk factors, including blood pressure, waist to hip ratio, fasting blood glucose and triglyceride levels. Alcohol also increases HDL cholesterol and lowers LDL cholesterol. Our study also 2) replicates sex differences in associations which suggests pleiotropy does not underlie the associations, 3) provides further evidence that association is not due to pleiotropy by showing null effects in male non-drinkers, and 4) illustrates a way to measure population-level association where alcohol intake is stratified by sex. In conclusion, population-level instrumental variable estimation (utilizing interaction of rs671 in ALDH2 and sex as an instrument) strengthens causal inference regarding the largely adverse influence of alcohol intake on cardiovascular health in an Asian population.
| S-EPMC4685310 | biostudies-literature
Project description:Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis. Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption. Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05-1.12, p = 1.51 × 10-5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27-1.52, p = 5.29 × 10-13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99-1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98-1.05, p = 0.545 by IVW). Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.
| S-EPMC9540194 | biostudies-literature
Project description:BackgroundDespite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.MethodsWe applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.ResultsGenetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.ConclusionOur MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
| S-EPMC8505411 | biostudies-literature
Project description:BackgroundOnly a few of the 34 biochemical biomarkers measured in the UK Biobank (UKB) have been associated with breast cancer, with many associations suffering from possible confounding and reverse causation. This study aimed to screen and rank all UKB biochemical biomarkers for possible causal relationships with breast cancer.MethodsWe conducted two-sample Mendelian randomisation (MR) analyses on ~420,000 women by leveraging summary-level genetic exposure associations from the UKB study (n = 194,174) and summary-level genetic outcome associations from the Breast Cancer Association Consortium (n = 228,951). Our exposures included all 34 biochemical biomarkers in the UKB, and our outcomes were overall, oestrogen-positive, and oestrogen-negative breast cancer. We performed inverse-variance weighted MR, weighted median MR, MR-Egger, and MR-PRESSO for 30 biomarkers for which we found multiple instrumental variables. We additionally performed multivariable MR to adjust for known risk factors, bidirectional MR to investigate reverse causation, and MR Bayesian model averaging to rank the significant biomarkers by their genetic evidence.ResultsIncreased genetic liability to overall breast cancer was robustly associated with the following biomarkers by decreasing importance: testosterone (odds ratio (OR): 1.12, 95% confidence interval (CI): 1.04-1.21), high-density lipoprotein (HDL) cholesterol (OR: 1.08, 95% CI: 1.04-1.13), insulin-like growth factor 1 (OR: 1.08, 95% CI: 1.02-1.13), and alkaline phosphatase (ALP) (OR: 0.93, 95% CI: 0.89-0.98).ConclusionsOur findings support a likely causal role of genetically predicted levels of testosterone, HDL cholesterol, and IGF-1, as well as a novel potential role of ALP in breast cancer aetiology. Further studies are needed to understand full disease pathways that may inform breast cancer prevention.
| S-EPMC9685978 | biostudies-literature