Affiliation:
1. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
2. Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
3. MRC Integrative Epidemiology Unit (IEU) Bristol Medical School, University of Bristol Bristol UK
Abstract
AbstractBackground & AimsThe causal association of lower birthweight with non‐alcoholic fatty liver disease (NAFLD) and the mediating pathways remain unclear. We aimed to investigate the causal, independent association of lower birthweight with NAFLD and identify potential metabolic mediators and their mediation effects in this association.MethodsWe performed two‐step, two‐sample Mendelian randomization (MR) using genome‐wide association study (GWAS) summary statistics for birthweight from the Early Growth Genetics Consortium of 298 142 Europeans, NAFLD from a GWAS meta‐analysis of 8434 NAFLD cases and 770 180 controls of Europeans, and 25 candidate mediators from corresponding reliable GWASs.ResultsGenetically determined each 1‐SD lower birthweight was associated with a 45% (95% CI: 1.25–1.69) increased risk of NAFLD, and this causal association persisted after adjusting for childhood obesity or adult adiposity traits in multivariable MR. Two‐step MR identified 6 of 25 candidate mediators partially mediate the effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.05%), leucine (17.29%), isoleucine (13.55%), valine (11.37%), alanine (10.01%) and monounsaturated fatty acids (MUFA; 7.23%). Bidirectional MR suggested a unidirectional effect of insulin resistance on isoleucine, leucine and valine and a unidirectional effect of alanine on insulin resistance.ConclusionsThis MR study elucidated the causal impact of lower birthweight on subsequent risk of NAFLD, independently of later‐life adiposity and identified mediators including insulin resistance, branched‐chain amino acids, alanine and MUFA in this association pathway. Our findings shed light on the pathogenesis of NAFLD and imply additional targets for prevention and intervention of NAFLD attributed to low birthweight.
Funder
National Natural Science Foundation of China
Shanghai Shenkang Hospital Development Center
Ruijin Hospital
Cited by
8 articles.
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