Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease: A Mendelian Randomization Study
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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. / Carter, Alice R; Borges, Maria-Carolina; Benn, Marianne; Tybjærg-Hansen, Anne; Davey Smith, George; Nordestgaard, Børge G; Lawlor, Debbie A.
In: JAMA Network Open, Vol. 2, No. 3, e190305, 2019.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Combined Association of Body Mass Index and Alcohol Consumption With Biomarkers for Liver Injury and Incidence of Liver Disease
T2 - A Mendelian Randomization Study
AU - Carter, Alice R
AU - Borges, Maria-Carolina
AU - Benn, Marianne
AU - Tybjærg-Hansen, Anne
AU - Davey Smith, George
AU - Nordestgaard, Børge G
AU - Lawlor, Debbie A
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Aged
KW - Alanine Transaminase/blood
KW - Alcohol Drinking/blood
KW - Biomarkers/blood
KW - Body Mass Index
KW - Cohort Studies
KW - Denmark/epidemiology
KW - Female
KW - Humans
KW - Incidence
KW - Liver Diseases/blood
KW - Liver Function Tests/methods
KW - Male
KW - Middle Aged
KW - Overweight/blood
KW - Risk Assessment
KW - Risk Factors
KW - gamma-Glutamyltransferase/blood
U2 - 10.1001/jamanetworkopen.2019.0305
DO - 10.1001/jamanetworkopen.2019.0305
M3 - Journal article
C2 - 30848805
VL - 2
JO - JAMA Network Open
JF - JAMA Network Open
SN - 2574-3805
IS - 3
M1 - e190305
ER -
ID: 235004167