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Objective Nonalcoholic fatty liver disease (NAFLD), which is an emerging global chronic liver disease, has a close association with insulin resistance. We aimed to determine whether the Gly1057Asp (rs1805097) polymorphism of the insulin receptor substrate 2 (IRS2) gene is associated with NAFLD. Methods Using the polymerase chain reaction-restriction fragment length polymorphism method, 135 patients with biopsy-proven NAFLD and 135 controls underwent IRS2 genotype analysis. Results Genotype and allele distributions of the IRS2 gene Gly1057Asp variant conformed to the Hardy-Weinberg equilibrium in both the case and control groups (P >.05). The Asp/Asp genotype of IRS2 gene Gly1057Asp polymorphism compared with Gly/Gly genotype was associated with a 2.1-fold increased risk for NAFLD after adjustment for confounding factors (P =.029; odds ratio = 2.10, 95% CI = 1.23-3.97). Conclusion Our findings revealed for the first time that the Gly1057Asp Asp/Asp genotype of the IRS2 gene is a marker of increased NAFLD susceptibility; however, studies in other populations are required to confirm the results. [ABSTRACT FROM AUTHOR]