Non-alcoholic fatty liver disease and estimated insulin resistance in obese youth: a Mendelian randomization analysis.

Non-alcoholic 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. To test the hypothesis that NAFLD is causally related to IR. We performed a Mendelian Randomization (MR) in 904 obese children/adolescents, using a NAFLD-related genetic risk score (GRS) as 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 (i.e., the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a two-sample MR with two large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD). NAFLD prevalence increased by 20% for every increase in the GRS (β-coefficient=0.20,p&0.001). NAFLD was associated with ln-HOMA-IR (β-coefficient=0.28,p&0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected β-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 two-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD. 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. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journal[email protected]