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

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: Investigate the joint association of BMI and alcohol consumption on liver injury biomarkers and incident liver disease using factorial Mendelian randomization (MR).

Design: Population-based cohort study (Copenhagen General Population Study), recruited between 2003-2014 and ongoing links to national registers(analysed September 2017-April 2018).

Setting: Copenhagen, Denmark

Participants: Random sample of Copenhagen residents aged ≥20 years of White, Danish descent (N=98 643).

Exposures: High and low BMI and alcohol consumption categories from baseline measured/self-report 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). Incident cases of liver disease from hospital records.

Results: 91,552 individuals (45% female; mean age 58 years) with no baseline liver disease were included in main analyses. Individuals had a mean BMI of 26.2 kg/m2 and consumed a mean of 10.6 units of alcohol per week. 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 (-2.32% (-4.29, -0.35) and -3.56% (-5.88, -1.24) for ALT and GGT respectively). Individuals with low BMI-high alcohol and high BMI-low alcohol also had lower mean circulating ALT (-1.31% (-1.88, -0.73) and -0.81% (-2.86, 1.22) respectively) and GGT (-0.91% (-1.60, -0.22) and -1.13% (-3.55, 1.30) respectively) compared to the high BMI-high alcohol 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 compared to high BMI-high alcohol group: 1.01 (0.84, 1.18) [low BMI-high alcohol group], 1.22 (0.56, 1.88) [high BMI-low alcohol group], 0.99 (0.41, 1.56) [low BMI-low alcohol group]).

Conclusions and Relevance: Interventions to reduce both risk factors might reduce population levels of biomarkers of liver injury greater than interventions aimed at either BMI or alcohol alone. However, it is not clear whether this will directly translate to a reduced risk of liver disease.