Nonalcoholic Fatty Liver Disease and Estimated Insulin Resistance in Obese Youth: A Mendelian Randomization Analysis

Context: Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa. Objective: To test the hypothesis that NAFLD is causally related to IR. Design and Methods: We performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR).We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD). Results: Nonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (β-coefficient = 0.20, P < 0.001), and NAFLD was associated with ln-HOMA-IR (β-coefficient = 0.28, P<0.001).Thus,theexpectedincreaseinln-HOMA-IRforeveryincreaseintheGRS(expectedβ-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (β-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR.The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD. Conclusions: Our study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not “captured” by our MR design might underpin the association between NAFLD and HOMA-IR.