Insulin Receptor Substrate 1 Gene Variation Modifies Insulin Resistance Response to Weight-Loss Diets in a 2-Year Randomized Trial

<jats:sec> <jats:title>Background—</jats:title> <jats:p> Common genetic variants in the insulin receptor substrate 1 ( <jats:italic>IRS1</jats:italic> ) gene have been recently associated with insulin resistance and hyperinsulinemia. We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> We genotyped <jats:italic>IRS1</jats:italic> rs2943641 in 738 overweight adults (61% were women) who were randomly assigned to 1 of 4 diets varying in macronutrient contents for 2 years. We assessed the progress in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and weight loss by genotypes. At 6 months, participants with the risk-conferring CC genotype had greater decreases in insulin ( <jats:italic>P</jats:italic> =0.009), HOMA-IR ( <jats:italic>P</jats:italic> =0.015), and weight loss ( <jats:italic>P</jats:italic> =0.018) than those without this genotype in the highest-carbohydrate diet group whereas an opposite genotype effect on changes in insulin and HOMA-IR ( <jats:italic>P</jats:italic> ≤0.05) was observed in participants assigned to the lowest-carbohydrate diet group. No significant differences were observed across genotypes in the other 2 diet groups. The tests for genotype by intervention interactions were all significant ( <jats:italic>P</jats:italic> <0.05). At 2 years, the genotype effect on changes in insulin and HOMA-IR remained significant in the highest-carbohydrate diet group ( <jats:italic>P</jats:italic> <0.05). The highest carbohydrate diet led to a greater improvement of insulin and HOMA-IR ( <jats:italic>P</jats:italic> for genotype–time interaction ≤0.009) in participants with the CC genotype than those without this genotype across 2-year intervention. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> Individuals with the <jats:italic>IRS1</jats:italic> rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet. </jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trial Registration—</jats:title> <jats:p> <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">http:www.clinicaltrials.gov</jats:ext-link> . Unique identifier: NCT00072995. </jats:p> </jats:sec>