Heterogeneity in effects of genetically determined adiposity on insulin resistance and type 2 diabetes: The atherosclerosis risk in communities study

Background: A recent genome-wide association study has identified 12 genetic variants robustly associated with body fat percentage (BF%) with diverse cardiometabolic consequences. We developed three genetic risk scores (GRSs) according to the associations of the 12 individual variants with type 2 diabetes (T2D) and test the GRSs' associations with insulin resistance and T2D in the Atherosclerosis Risk in Communities Study.

Methods: In 6895 European-American participants, we calculated GRS-I as the number of BF%-increasing alleles from variants associated with increased risk of T2D, GRS-D from variants associated with decreased risk of T2D, and GRS-ALL from all 12 variants. Linear and logistic regression models were used to evaluate associations of the GRSs with insulin resistance and risk of T2D, respectively, adjusted for age, sex, smoking, and drinking, and additionally for body mass index (BMI).

Results: GRS-D was significantly associated with decreased levels of fasting insulin (P = 0.014) and homeostasis assessment of insulin resistance (P = 0.023). While GRS-I was not associated with insulin resistance measures, it was with T2D (P = 0.002). Further adjustment for BMI did not substantially change the above associations. GRS-ALL was inversely associated with insulin resistance after controlling for covariates including BMI; GRS-ALL was not associated with T2D.

Conclusion: Genetically determined BF% has differential effects on cardiometabolic risk, which may partly explain the heterogeneity in obesity-induced cardiometabolic risk and have implications for developing new strategies mitigating obesity-induced cardiometabolic consequences.