Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease: A Mendelian Randomization Study - PubMed (original) (raw)

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

Alice R Carter et al. JAMA Netw Open. 2019.

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 γ-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.

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Figures

Figure 1.. Flow Diagram for the Generation of Factorial Groups, Using Observational and Genetic Data

Factorial multivariable: both body mass index (BMI) and weekly alcohol consumption were dichotomized based on the median of measured or self-reported values. Values equal to or below the median were categorized as the low group, and those above the median were categorized as the high group. Factorial mendelian randomization (MR): For genetic propensity, BMI was categorized according to the median of the weighted allele score for BMI, with values equal to or below the median categorized as low BMI and those above the median categorized as high BMI. Alcohol propensity was determined according to ADH1B alleles. Individuals who were homozygous for the alcohol-decreasing traits and heterozygous individuals were combined, as determined to be appropriate based on previous MR analyses of these traits on alcohol intake, to create the low alcohol-propensity group. The high alcohol-propensity group contains all individuals homozygous for the alcohol-increasing trait. Adapted from Ference et al.

Figure 2.. Missing Data and Total Number of Participants for Each Analysis

Participants could have had missing data for more than 1 variable at each stage; hence, the additive numbers missing for each variable can total more than the number removed at that stage. ALT indicates alanine aminotransferase; BMI, body mass index; GGT, γ-glutamyltransferase; MR, mendelian randomization.

Figure 3.. Multivariable and Mendelian Randomization Analyses of the Individual Associations of Body Mass Index (BMI) and Alcohol Consumption With Liver Enzyme Levels Associated With Injury and Incident Liver Disease

A, The percentage difference in mean alanine aminotransferase (ALT) level per 1-SD higher BMI or per 1 U/wk increase in alcohol consumption. B, The percentage difference in mean γ-glutamyltransferase (GGT) level per 1-SD higher BMI or per 1-U increase in alcohol consumption. C, The difference in odds ratio (OR) of incident liver disease per 1-SD higher BMI or per 1-U/wk increase in alcohol consumption. The BMI is measured as age and sex SD units. Alcohol measured as units of alcohol consumed per week, where 1 U is equivalent to 12 g of alcohol. Multivariable analyses were adjusted for age, sex, smoking, educational level, income, and physical activity. Mendelian randomization used weighted allele score for BMI and ADH1B alleles for alcohol consumption. Prevalent cases of liver disease were excluded from all analyses.

Figure 4.. Multivariable and Mendelian Randomization (MR) Factorial Analyses Assessing the Joint Associations of Body Mass Index (BMI) and Alcohol With Biomarkers of Liver Injury and Incident Liver Disease

A, Multivariable regression of percentage difference in mean alanine aminotransferase (ALT) level by joint observational BMI and alcohol categories. B, MR of percentage difference in mean ALT level by joint genetic BMI and alcohol categories. C, Multivariable regression of percentage difference in mean γ-glutamyltransferase (GGT) level by joint observational BMI and alcohol categories. D, MR of percentage difference in mean GGT level by joint genetic BMI and alcohol categories. E, Multivariable regression of odds ratio (OR) of liver disease by joint observational BMI and alcohol categories. F, MR of OR of liver disease by joint genetic BMI and alcohol categories. Low vs high BMI (calculated as weight in kilograms divided by height in meters squared), 1.49-SD difference in multivariable analyses and 0.51 SD in MR analyses. Low vs high alcohol, 14.68 U/wk difference in multivariable analyses and 1.78 U/wk difference in MR analyses, where 1 U of alcohol is equivalent to 12 g. Multivariable analysis was adjusted for age, sex, smoking, educational level, income, and physical activity.

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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 - PubMed (original) (raw)