Abstract
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. To investigate the joint association of BMI and alcohol consumption with liver injury biomarkers and incident liver disease using factorial mendelian randomization (MR). 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. High and low BMI and alcohol consumption categories from baseline-measured or self-reported observational data and genetic variants predicting BMI and alcohol consumption. Plasma biomarkers of liver injury (alanine aminotransferase [ALT] and γ-glutamyltransferase [GGT]) and incident cases of liver disease from hospital records were the outcomes. 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). 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.
Highlights
The risk of liver disease has increased, and the age at first diagnosis has decreased in many highincome countries in recent decades.[1]
In factorial mendelian randomization (MR) analyses, considering the high body mass index (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%)
For incident liver disease (N = 580), factorial MR results were less conclusive
Summary
The risk of liver disease has increased, and the age at first diagnosis has decreased in many highincome countries in recent decades.[1]. Consistent with these findings, several studies have found that greater body mass index (BMI) and alcohol consumption positively interact in association with biomarkers of liver injury, such as alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase (GGT).[6,7] By contrast, in a study of British women (approximately 1.2 million women with 1811 occurrences of a first hospital admission or death from liver cirrhosis), there was no evidence of an interaction between BMI and alcohol associated with cirrhosis.[8]
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