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

By Sehoon Park, Soojin Lee, Yaerim Kim, Semin Cho, Kwangoo Kim, Yong Chul Kim, Seung Seok Han, Hajeong Lee, Jung Pyo Lee, Kwon Wook Joo, Chun Soo Lim, Yon Su Kim, Dong Ki Kim

Posted 25 Feb 2021
medRxiv DOI: 10.1101/2021.02.22.21252263

Background & aimsAn 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). MethodsIn this Mendelian randomization (MR) study, we selected rs738409 as a genetic instrument to predict NAFLD. The genetic variant rs13107325, which is strongly associated with the steatohepatitis marker liver MRI corrected T1 score, was introduced as an alternate genetic instrument for the NAFLD-related phenotype. The eGFR outcome was assessed in individuals of white British ancestry included in the UK Biobank (N = 321,260), and associations adjusted for major metabolic disorder and income grades were investigated. Further, the associations were reassessed in two negative control subgroups (body mass index < 25 kg/m2 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). ResultsIn the UK Biobank dataset, a genetic predisposition for NAFLD or an increased liver T1 score was significantly associated with a reduced eGFR 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. ConclusionsThis MR analysis supports the causal reduction in eGFR by NAFLD.

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