Predictability of genetic risk score for insulin resistance is influenced by both BMI and race.

Objective: The study objective was to determine whether associations between a genetic risk score (GRS) for insulin resistance (IR) and measures of insulin sensitivity differ by race and/or BMI status in African American (AA) and European American (EA) adults without diabetes.

Methods: Fifty-three AA and 54 EA participants were classified into "high" or "low" BMI groups using the sample median (25.9 kg/m²) as the cut point. The GRS was derived from 52 previously identified genetic variants. Skeletal muscle insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp. The homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda index of insulin sensitivity were calculated from oral glucose tolerance test values to determine hepatic and whole-body insulin sensitivity, respectively. Linear regression models, stratified by race, assessed interactions between BMI status and GRS on measures of insulin sensitivity.

Results: In EA participants, associations of GRS with HOMA-IR and the Matsuda index differed by BMI status, where the GRS was associated with IR in the high-BMI group only. In AA participants, associations from the clamp differed by BMI status, but an association was observed only in the low-BMI group.

Conclusions: These results highlight the heterogeneity of IR and support the hypothesis that the relationship between genetic predisposition for IR and obesity is race- and tissue-specific.