Causal effects from non-alcoholic fatty liver disease on kidney function: A Mendelian randomization study

Abstract Background & aims An observational association between nonalcoholic fatty liver disease (NAFLD) and kidney function impairment has been reported. A genetic variant linked to an increased risk of NAFLD, the G allele of rs738409, has been reported to be associated with a reduction in estimated glomerular filtration rate (eGFR). Approach & Results In this Mendelian randomization (MR) study, we first performed single-variant MR with rs738409 as a genetic instrument to predict NAFLD. Another genetic instrument was developed from a previous genome-wide association study for the NAFLD phenotype in the Million Veteran Program cohort among individuals of European ancestry (68,725 cases and 95,472 controls). The eGFR outcome was assessed in individuals of white British ancestry included in the UK Biobank (N = 321,405). Further, the associations were reassessed in two negative control subgroups (body mass index < 25 kg/m 2 and serum alanine aminotransferase level < 20 IU/mL) with a low probability of developing NAFLD. As a replication analysis, a summary-level MR was performed with the European ancestry CKDGen dataset (N = 567,460). In the UK Biobank dataset, a genetic predisposition for NAFLD, either by rs738409 or a group of variants, was significantly associated with a reduced eGFR even with adjustment for major metabolic disorders. Although the associations were not significant in the negative control subgroups with a low probability of developing NAFLD, they were significant in the subgroups with a remaining risk of NAFLD, suggesting the absence of a horizontal pleiotropic pathway. The summary-level MR from the CKDGen dataset supported the causal effects of NAFLD on reduced eGFR. Conclusions This MR analysis supports the causal reduction in kidney function by NAFLD.