TY - JOUR
T1 - Lifestyle and metabolic factors for nonalcoholic fatty liver disease
T2 - Mendelian randomization study
AU - Yuan, Shuai
AU - Chen, Jie
AU - Li, Xue
AU - Fan, Rongrong
AU - Arsenault, Benoit
AU - Gill, Dipender
AU - Giovannucci, Edward L
AU - Zheng, Ju-Sheng
AU - Larsson, Susanna C
N1 - Funding Information:
Open access funding provided by Karolinska Institute. This study is supported by research grants from the Swedish Heart–Lung Foundation (Hjärt-Lungfonden; Grant No. 20210351), the Swedish Research Council for Health, Working Life and Welfare (Forte; Grant No. 2018‐00123), and the Swedish Research Council (Vetenskapsrådet; Grant No. 2019-00977). DG is supported by the British Heart Foundation Research Centre of Excellence (RE/18/4/34215) at Imperial College London and by a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St George's, University of London. Funders had no roles in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7/1
Y1 - 2022/7/1
N2 - The risk factors for nonalcoholic fatty liver disease (NAFLD) have not been clearly identified. We conducted a Mendelian randomization (MR) study to explore this. Independent genetic variants strongly associated with 5 lifestyle and 9 metabolic factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for NAFLD were obtained from a GWAS meta-analysis of 8434 cases and 770,180 non-cases (discovery dataset) and another GWAS meta-analysis of 1483 cases and 17,781 non-cases (replication dataset). Univariable and multivariable MR analyses were performed. There were associations with NAFLD for lifetime smoking index (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.31-1.93 per SD-increase), body mass index (BMI, OR 1.33, 95% CI 1.23-1.43 per SD-increase), waist circumference (OR 1.82; 95% CI 1.48-2.24 per SD-increase), type 2 diabetes (OR 1.21, 95% CI 1.15-1.27 per unit increase in log-transformed odds), systolic blood pressure (OR 1.17; 95% CI 1.07-1.26 per 10 mmHg increase), high-density lipoprotein cholesterol (OR 0.84, 95% CI 0.77-0.90 per SD-increase), and triglycerides (OR 1.23, 95% CI 1.15-1.33 per SD-increase). The associations for type 2 diabetes, systolic blood pressure, triglycerides, but not for high-density lipoprotein cholesterol remained strong after adjusting for genetically-predicted BMI. Genetic liability to type 2 diabetes mediated 51.4% (95% CI 13.4-89.3%) of the BMI-effects on NAFLD risk. There were suggestive inverse associations of genetically-predicted alcohol, coffee, and caffeine consumption, and vigorous physical activity with NAFLD risk. This study identified several lifestyle and metabolic factors that may be causally implicated in NAFLD.
AB - The risk factors for nonalcoholic fatty liver disease (NAFLD) have not been clearly identified. We conducted a Mendelian randomization (MR) study to explore this. Independent genetic variants strongly associated with 5 lifestyle and 9 metabolic factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for NAFLD were obtained from a GWAS meta-analysis of 8434 cases and 770,180 non-cases (discovery dataset) and another GWAS meta-analysis of 1483 cases and 17,781 non-cases (replication dataset). Univariable and multivariable MR analyses were performed. There were associations with NAFLD for lifetime smoking index (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.31-1.93 per SD-increase), body mass index (BMI, OR 1.33, 95% CI 1.23-1.43 per SD-increase), waist circumference (OR 1.82; 95% CI 1.48-2.24 per SD-increase), type 2 diabetes (OR 1.21, 95% CI 1.15-1.27 per unit increase in log-transformed odds), systolic blood pressure (OR 1.17; 95% CI 1.07-1.26 per 10 mmHg increase), high-density lipoprotein cholesterol (OR 0.84, 95% CI 0.77-0.90 per SD-increase), and triglycerides (OR 1.23, 95% CI 1.15-1.33 per SD-increase). The associations for type 2 diabetes, systolic blood pressure, triglycerides, but not for high-density lipoprotein cholesterol remained strong after adjusting for genetically-predicted BMI. Genetic liability to type 2 diabetes mediated 51.4% (95% CI 13.4-89.3%) of the BMI-effects on NAFLD risk. There were suggestive inverse associations of genetically-predicted alcohol, coffee, and caffeine consumption, and vigorous physical activity with NAFLD risk. This study identified several lifestyle and metabolic factors that may be causally implicated in NAFLD.
KW - Body Mass Index
KW - Cholesterol, HDL/genetics
KW - Diabetes Mellitus, Type 2/epidemiology
KW - Genome-Wide Association Study
KW - Humans
KW - Life Style
KW - Mendelian Randomization Analysis
KW - Non-alcoholic Fatty Liver Disease/epidemiology
KW - Polymorphism, Single Nucleotide
KW - Risk Factors
KW - Triglycerides
U2 - 10.1007/s10654-022-00868-3
DO - 10.1007/s10654-022-00868-3
M3 - Article
C2 - 35488966
VL - 37
SP - 723
EP - 733
JO - European Journal of Epidemiology
JF - European Journal of Epidemiology
SN - 0393-2990
IS - 7
ER -