Abstract
BackgroundThe effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol.MethodsWe used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), γ-glutamyl-transferase (γ-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56).ResultsIn both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (−4.5, 11.9) from genetic-IV analyses] and γ-GT [8.2% (7.8, 8.5) and 6.8% (−2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and γ-GT (both pdiff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [−1.5% (−1.7, −1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (pdiff<0.0001). In both multivariable and genetic-IV analyses associations with bilirubin and protrombin action were weak and close to the null.ConclusionsOur results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, γ-GT and ALP, but not to clotting or bilirubin.
Highlights
Alcoholic liver disease is a major global health problem, but the effects of lifetime differences in alcohol consumption in the general population are unclear [1]
With 13% of women reporting no consumption and 3% reporting 25 or more drinks per week, compared with 6% of men reporting no consumption and 17% reporting 25 or more drinks per week (p,0.0001). Both genotypes were in Hardy-Weinberg Equilibrium (HWE) (p50.5 and 0.7 for ADH1B and ADH1C, respectively)
The first stage F-statistic for all instrumental variable analyses521. aTest of null hypothesis that there is no difference in association of alcohol with each outcome between the confounder adjusted multivariable association and the instrumental variable association using the control function; p-value obtained from the bootstrap distribution. doi:10.1371/journal.pone.0114294.t004. In this large study we used genetic variants that are related to alcohol consumption as genetic-instrumental variables (IVs) to determine the effect of long-term alcohol intake on liver function
Summary
Alcoholic liver disease is a major global health problem, but the effects of lifetime differences in alcohol consumption in the general population are unclear [1]. Mendelian randomization, in which genetic variants that are robustly related to alcohol intake are used as instrumental variables (IVs) to determine the life-time causal impact of different levels of intake, could help address this question [5, 6]. Results from this method are unlikely to be influenced by confounding or reverse causality [5, 7]. Methods: We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), c-glutamyl-transferase (c-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [21.5% (21.7, 21.3)], which differed from the PLOS ONE | DOI:10.1371/journal.pone.0114294 December 15, 2014
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