ADH1B and ADH1C Genotype, Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in 58,313 European Origin Danes

PLOS ONE, Dec 2019

Background The 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. 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), γ-glutamyl-transferase (γ-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56). Results In 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. Conclusions Our 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.

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ADH1B and ADH1C Genotype, Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in 58,313 European Origin Danes

C Genotype, Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in ADH1B and ADH1C Genotype, Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in 58,313 European Origin Danes Debbie A. Lawlor * 0 1 6 7 Marianne Benn 2 3 4 6 7 Luisa Zuccolo 0 1 6 7 N. Maneka G. De Silva 0 6 7 Anne Tybjaerg-Hansen 2 3 5 6 7 George Davey Smith 0 1 6 7 Brge G. Nordestgaard 2 3 4 6 7 0 MRC Integrative Epidemiology Unit at the University of Bristol , Bristol , United Kingdom, 1 School of Social and Community Medicine, University of Bristol , Bristol , United Kingdom, 2 The Copenhagen General Population Study, Herlev Hospital , Copenhagen , Denmark, 3 Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark, 4 Department of Clinical Biochemistry, Herlev Hospital , Copenhagen , Denmark, 5 Department of Clinical Biochemistry , Rigshospitalet, Copenhagen , Denmark 6 Funding: This study was supported by Herlev Hospital, Copenhagen University Hospital, The Copenhagen County Research Fund, and The Danish Medical Research Council. DAL, LZ and GDS work in a Unit that receives funding from the UK Medical Research Council (MRC) (MC_UU_12013/5 and MC_UU_12013/1). The contributions of DAL to this paper were also supported by an additional grant from the UK MRC (G0601625). LZ is funded by an MRC Population Health Scientist postdoctoral fellowship (G0902144). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript 7 Editor: Silvia C. Sookoian, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET) , Argentina Background: The 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. 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. Analyses were undertaken on 58,313 Danes (mean age 56). Results: In 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% (24.5, 11.9) from genetic-IV analyses] and c-GT [8.2% (7.8, 8.5) and 6.8% (22.8, 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 c-GT (both pdiff.0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [21.5% (21.7, 21.3)], 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. Conclusions: Our results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, c-GT and ALP, but not to clotting or bilirubin. 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]. It has been suggested that clinically apparent health damaging effects of consumption occur at levels of 80 g/day of alcohol for 1012 years [2], but there is debate about whether lower levels also have adverse effects [3]. Most countries recommend safe drinking levels of up to 30 g/day for men and 20 g/day for women, but whether regular consumption at even these relatively low levels across a substantial part of adult life might result in liver damage is unclear [4]. Examining the association of long-term alcohol consumption with outcomes using conventional observational epidemiology methods is likely to be biased by: (i) confounding by characteristics related both to alcohol consumption and liver function/disease; (ii) ill health causing people to change their drinking behaviour (so called reverse causality) and (iii) systematic mis-reporting, such that those who are ill or are concerned about their drinking are likely to underreport intake [2]. Randomised controlled trials of different levels of long-term consumption of alcohol are not feasible. However, 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]. R (...truncated)


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Debbie A. Lawlor, Marianne Benn, Luisa Zuccolo, N. Maneka G. De Silva, Anne Tybjaerg-Hansen, George Davey Smith, Børge G. Nordestgaard. ADH1B and ADH1C Genotype, Alcohol Consumption and Biomarkers of Liver Function: Findings from a Mendelian Randomization Study in 58,313 European Origin Danes, PLOS ONE, 2014, Volume 9, Issue 12, DOI: 10.1371/journal.pone.0114294