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Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease: A Mendelian Randomization Study.

ABSTRACT: Importance:Individually, higher body mass index (BMI) and alcohol consumption increase the risk of liver disease. Evidence of a joint association is mixed; however, previous studies have not used causal inference methods robust to confounding and reverse causation. Understanding any true effect is key to developing effective interventions to reduce liver disease. Objective:To investigate the joint association of BMI and alcohol consumption with liver injury biomarkers and incident liver disease using factorial mendelian randomization (MR). Design, Setting, and Participants:A population-based cohort study (Copenhagen General Population Study) recruited a random sample of Copenhagen, Denmark, residents aged 20 years or older of white, Danish descent (N?=?98 643) between November 25, 2003, and July 1, 2014. Data were also obtained from ongoing links to national registers, and then analyzed from September 30, 2016, to April 23, 2018. Exposures:High and low BMI and alcohol consumption categories from baseline-measured or self-reported observational data and genetic variants predicting BMI and alcohol consumption. Main Outcomes and Measures:Plasma biomarkers of liver injury (alanine aminotransferase [ALT] and ?-glutamyltransferase [GGT]) and incident cases of liver disease from hospital records were the outcomes. Results:Of the 98?643 individuals recruited, 91?552 (54 299 [45.2%] women; mean [SD] age, 58 [13.05] years) with no baseline liver disease were included in main analyses. Individuals had a mean (SD) BMI of 26.2 (4.3) and consumed a mean (SD) of 10.6 (10.2) U/wk of alcohol. In factorial MR analyses, considering the high BMI/high alcohol group as the reference, mean circulating ALT and GGT levels were lowest in the low BMI/low alcohol group (ALT: -2.32%; 95% CI, -4.29% to -0.35%, and GGT: -3.56%; 95% CI, -5.88% to -1.24%). Individuals with low BMI/high alcohol use and high BMI/low alcohol use also had lower mean circulating ALT levels (low BMI/high alcohol use: -1.31%; 95% CI, -1.88% to -0.73%, and high BMI/low alcohol use: -0.81%; 95% CI, -2.86% to 1.22%) and GGT levels (low BMI/high alcohol use: -0.91%; 95% CI, -1.60% to -0.22%, and high BMI/low alcohol use: -1.13%; 95% CI, -3.55% to 1.30%) compared with the high BMI/high alcohol use reference group. These patterns were similar in multivariable factorial analyses. For incident liver disease (N?=?580), factorial MR results were less conclusive (odds ratio of liver disease vs high BMI/high alcohol group: 1.01; 95% CI, 0.84 to 1.18, for the low BMI/high alcohol group, 1.22; 95% CI, 0.56 to 1.88 for the high BMI/low alcohol group, and 0.99 (95% CI, 0.41 to 1.56 for the low BMI/low alcohol group). Conclusions and Relevance:Interventions to reduce both BMI and alcohol consumption might reduce population levels of biomarkers of liver injury more than interventions aimed at either BMI or alcohol use alone. However, it is not clear whether this intervention will directly translate to a reduced risk of liver disease.

SUBMITTER: Carter AR

PROVIDER: S-EPMC6484655 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease: A Mendelian Randomization Study.

Carter Alice R AR Borges Maria-Carolina MC Benn Marianne M Tybjærg-Hansen Anne A Davey Smith George G Nordestgaard Børge G BG Lawlor Debbie A DA

JAMA network open 20190301 3

<h4>Importance</h4>Individually, higher body mass index (BMI) and alcohol consumption increase the risk of liver disease. Evidence of a joint association is mixed; however, previous studies have not used causal inference methods robust to confounding and reverse causation. Understanding any true effect is key to developing effective interventions to reduce liver disease.<h4>Objective</h4>To investigate the joint association of BMI and alcohol consumption with liver injury biomarkers and incident ...[more]

PMID: 30848805

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Project description:Background: Observational evidence has shown that smoking, alcohol consumption, type 2 diabetes, and body mass index (BMI) are risk factors for peptic ulcer disease (PUD), including gastric ulcer (GU) and duodenal ulcer (DU). However, the observed associations may be confounding factors. Herein, we use Mendelian randomization (MR) to examine causal associations such as smoking, alcohol, type 2 diabetes, BMI, and risks of PUD. Methods: We used 8,17,41,325,82, 231, and 616 identified genetic variants as proxies for age of smoking initiation (AgeSmk), smoking cessation (SmkCes, current/former), number of cigarettes smoked per day (CigDay), smoking status (SmkIni, ever/never), alcohol consumption, type 2 diabetes, and BMI to obtain unconfounded effect estimates on the GU and DU levels among 452,264 participants from the Gene ATLAS. The causal relationship was estimated by using inverse-variance weighted (IVW) as the main method. Sensitivity analysis includes Cochran's Q test, the MR-Egger test, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-robust adjusted profile score (MR-RAPS). In addition, secondary MR analysis was conducted within summary data using genetic risk scores (GRSs) as instrumental variables (IVs). Results: In our two-sample MR analyses, genetic predisposition to smoking (SmkInit) and BMI were associated with an increased risk of GU. The beta values were 0.0035 (95% CI, 0.0021, 0.0049, p = 1.56E-06) for smoking (SmkInit) and 0.0021 (95% CI, 0.0009, 0.0033, p = 0.0008) for BMI. Genetic predisposition to smoking (SmkInit) and higher genetically predicted BMI were associated with an increased risk of DU. The beta values of DU were 0.0029 (95% CI, 0.0017, 0.0041, p = 2.43E-06) for smoking (SmkInit) and 0.0018 (95% CI, 0.0007, 0.0029, p = 0.001) for BMI. No other causal association between smoking (AgeSmk, CigDay, and SmkCes), alcohol consumption, type 2 diabetes, and GU or DU was observed. Consistent results were obtained in sensitivity analyses. Furthermore, the GRS approach showed similar results in the several MR methods. Conclusion: These findings do not support a causal role of AgeSmk, CigDay, SmkCes, alcohol consumption, and type 2 diabetes in the development of GU and DU. However, it is confirmed that SmkInit and BMI have a causal part in the development of GU and DU.

Project description:ImportanceAdvanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.ObjectiveTo assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD.Design, setting, participantsThis study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021.ExposuresSmoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin.Main outcomes and measuresAdvanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD.ResultsA 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD.Conclusions and relevanceThis study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.

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.

Project description:BackgroundWhether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases.MethodsGenetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption.ResultsGenetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation.ConclusionsThis study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases.FundingThe Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

Dataset Information

Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease: A Mendelian Randomization Study.

Publications

Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease: A Mendelian Randomization Study.

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