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Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes

dc.contributor.authorCarr, J. Jeffrey
dc.identifier.citationBarata, L., Feitosa, M.F., Bielak, L.F., Halligan, B., Baldridge, A.S., Guo, X., Yerges‐Armstrong, L.M., Smith, A.V., Yao, J., Palmer, N.D., VanWagner, L.B., Carr, J.J., Chen, Y.‐D.I., Allison, M., Budoff, M.J., Handelman, S.K., Kardia, S.L., Mosley, T.H., Jr., Ryan, K., Harris, T.B., Launer, L.J., Gudnason, V., Rotter, J.I., Fornage, M., Rasmussen‐Torvik, L.J., Borecki, I.B., O’Connell, J.R., Peyser, P.A., Speliotes, E.K. and Province, M.A. (2019), Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes. Hepatol Commun, 3: 894-907. doi:10.1002/hep4.1353en_US
dc.descriptionOnly Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, access the version of record at
dc.description.abstractThe accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, body mass index (BMI), and waist-to-hip ratio adjusted for BMI interact with genetic variants in or near the patatin-like phospholipase domain containing 3 (PNPLA3) gene, the glucokinase regulatory protein (GCKR) gene, the neurocan/transmembrane 6 superfamily member 2 (NCAN/TM6SF2) gene, and the lysophospholipase-like 1 (LYPLAL1) gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population-based cohorts separately and then meta-analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that PNPLA3-rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, GCKR-rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of PNPLA3-rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, PNPLA3-rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Conclusion: Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the PNPLA3-rs738409-G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying PNPLA3-rs738409-G may preferentially decrease hepatic steatosis.en_US
dc.description.sponsorshipSupported by the National Institutes of Health (NIH) through the Age, Gene/Environment Susceptibility-Reykjavik study (contracts N01-AG-1-2100 and 271201200022C), the National Institute of Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Amish studies are supported by grants and contracts from NIH (including U01 HL072515, U01 HL84756, U01 HL137181, and P30 DK72488). Funding for the Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), Johns Hopkins University School of Medicine (HHSN268200900041C), and Vanderbilt University Medical Center (R01 HL 098445). CARDIA is also partially supported by the Intramural Research Program of NIA and an intra-agency agreement between NIA and NHLBI (AG0005). The National Human Genome Research Institute (NHGRI) supported genotyping of CARDIA participants (grants U01-HG-004729, U01-HG-004446, and U01-HG-004424). The Family Heart Study (FamHS) was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grant R01-DK-089256) and NHLBI (grant R01HL117078). L.B. VW is supported by the NIH (grant K23 HL136891), and E.K.S and B.H. are supported by the NIH (grants R01 DK106621, R01 DK107904) and the University of Michigan Department of Internal Medicine. L.F.B. and P.A.P. are supported, in part, by NIH grants R01 DK106621 and R01 DK107904. Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) study was provided by NHLBI (HL054457, HL054464, HL054481, HL087660, and HL085571). The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by NHLBI in collaboration with MESA investigators. This research was supported by R01 HL071739, and MESA was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Research Resources. The provision of exome chip genotyping data was supported in part by the NHLBI (contract N02-HL-64278), National Center for Advancing Translational Sciences, (CTSI grant UL1TR001881), and the NIDDK Diabetes Research Center (DRC) (grant DK063491 to the Southern California Diabetes Endocrinology Research Center). Funding support for MESA's NAFLD dataset was provided by the NHLBI (grant HL071739-05A2).en_US
dc.titleInsulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetesen_US

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