Circulating adipokine concentrations and risk of non-alcoholic fatty liver disease: A Mendelian randomization study

Abstract

Background and Aims : Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases of the liver. Elevated adipose tissue (AT) accumulation is an important risk factor for NAFLD. Adipocytes release cytokines called adipokines that stimulate anti and pro-inflammatory pathways which may influence liver steatosis and fibrosis. Adiponectin, leptin, resistin, and plasminogen activator inhibitor-1 [PAI-1] are well-known adipokines that may be involved in the pathogenesis of NAFLD. Epidemiological evidence suggests that these adipokines may be associated with the development of NAFLD, but it is unclear if these associations are causal. The aim of our study is to explore the potential causal associations of adipokines with NAFLD among individuals of European ancestry.Methods: We performed two-sample Mendelian randomization (MR) analyses using publicly available genome-wide association studies (GWAS) for adiponectin, leptin, soluble leptin receptor, resistin, and PAI-1. We used summary-level data from our recent GWAS on NAFLD (8434 cases and 770,180 controls). To construct the genetic instruments, we included genetic variants with the P-value for association with study exposures <5×10-6 and linkage disequilibrium (R2=0.01).Results: In the inverse-variance weighted models, out of all adipokines tested, only soluble leptin receptor was significantly associated with NAFLD with beta [95% CI] = -0.075 [-0.173 – -0.133]; and P-value = 0.01.Conclusions: The plasma level of the soluble leptin receptor, but not leptin levels or other adipokines might be significantly associated with the development of NAFLD. These results suggest that adipokines may not have a key role in the development of NAFLD. Background and Aims : Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases of the liver. Elevated adipose tissue (AT) accumulation is an important risk factor for NAFLD. Adipocytes release cytokines called adipokines that stimulate anti and pro-inflammatory pathways which may influence liver steatosis and fibrosis. Adiponectin, leptin, resistin, and plasminogen activator inhibitor-1 [PAI-1] are well-known adipokines that may be involved in the pathogenesis of NAFLD. Epidemiological evidence suggests that these adipokines may be associated with the development of NAFLD, but it is unclear if these associations are causal. The aim of our study is to explore the potential causal associations of adipokines with NAFLD among individuals of European ancestry. Methods: We performed two-sample Mendelian randomization (MR) analyses using publicly available genome-wide association studies (GWAS) for adiponectin, leptin, soluble leptin receptor, resistin, and PAI-1. We used summary-level data from our recent GWAS on NAFLD (8434 cases and 770,180 controls). To construct the genetic instruments, we included genetic variants with the P-value for association with study exposures <5×10-6 and linkage disequilibrium (R2=0.01). Results: In the inverse-variance weighted models, out of all adipokines tested, only soluble leptin receptor was significantly associated with NAFLD with beta [95% CI] = -0.075 [-0.173 – -0.133]; and P-value = 0.01. Conclusions: The plasma level of the soluble leptin receptor, but not leptin levels or other adipokines might be significantly associated with the development of NAFLD. These results suggest that adipokines may not have a key role in the development of NAFLD.