23 February 2021 In Cancer

Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear.

We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings.

In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk.

Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.

23 November 2020 In Cancer

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 x 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 x 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 x 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 x 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 x 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 x 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.

25 August 2020 In Cancer

BACKGROUND: Alcohol consumption has been found to increase the risk of breast cancer in observation studies, yet it remains unknown if alcohol is related to other hormone-dependent cancers such as ovarian cancer. No Mendelian randomization (MR) studies have been performed to assess a potential causal relationship between alcohol use and risk of breast and ovarian cancer.

METHODS: We aim to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers, by using summary level genetic data from the hitherto largest genome-wide association studies (GWAS) conducted on alcohol consumption (N=~1.5 million individuals), breast (Ncase=122,977) and ovarian cancer (Ncase=25,509). We examined three different alcohol intake exposures, drinks per week (drinks/week), alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C), to reflect the general and harmful drinking behavior. We constructed updated and stronger instruments using ninety-nine drinks/week-related SNPs, nine AUD-related SNPs and thirteen AUDIT-C-related SNPs and estimated the causal relationship applying several two-sample MR methods.

RESULTS: We did not find any evidence to support for a causal association between alcohol consumption and risk of breast cancer [ORdrinks/week=1.01 (0.85-1.21), P=0.89; ORAUD=1.04 (95%CI: 0.89-1.21), P=0.62; ORAUDIT-C=1.07 (0.90-1.28), P=0.44]; neither with its subtypes including ER-positive and ER-negative breast cancer, using any of the three alcohol-related exposures. For ovarian cancer, however, we identified a reduced risk with alcohol consumption, where a borderline significance was found for AUDIT-C but not for drinks/week or AUC [ORdrinks/week=0.83 (0.63-1.10), P=0.19; ORAUD=0.92 (0.83-1.01), P=0.08; ORAUDIT-C=0.83 (0.71-0.97), P=0.02]. The effect attenuated to null excluding SNPs associated with potential confounders [ORdrinks/week=0.81(0.53-1.21), P=0.31; ORAUD=0.96(0.78-1.18), P=0.68; ORAUDIT-C=0.89(0.68-1.16), P=0.38].

CONCLUSION: We do not find any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol-related exposures. Future MR studies validating our findings are needed, when large-scale alcohol consumption GWAS results become available.

27 March 2020 In Dementia

INTRODUCTION: Observational studies have suggested that light-to-moderate alcohol consumption decreases the risk of Alzheimer's disease, but it is unclear if this association is causal.

METHODS: Two-sample Mendelian randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence, or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late-Onset Alzheimer's disease (LOAD) or Alzheimer's disease age of onset survival (AAOS). Additionally, gamma-glutamyltransferase levels were included as a positive control.

RESULTS: There was no evidence of a causal association between alcohol consumption, alcohol dependence, or AUDIT, and LOAD. Alcohol consumption was associated with an earlier AAOS and increased gamma-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS.

DISCUSSION: MR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias.

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