We investigated the effect of variants in the first three genes in the insulin signaling pathway and genes identified from genome wide association studies (GWAS) of T2D quantitative traits with IR (fasting insulin and the homeostasis model assessment of IR, HOMA‐IR) and evaluated gene–environment interactions with IR traits among 1879 nondiabetic middle‐aged men from a population‐based study conducted in Shanghai, China.

One candidate gene, IGF1, was associated with fasting insulin and HOMA‐IR. We observed four BMI–gene interactions (P < 0.05) with HOMA‐IR (INRS rs7254060, INRS rs7254358, GLU4 rs2113050, and GLU4 rs7713127) and seven BMI–gene interactions with fasting insulin (INRS rs7254060, INRS rs7254358, INRS rs10417205, INRS rs1799817, GLU4 rs12054720 GLU4 rs2113050, and GLU4 rs7713127). There were four WHR–gene interactions with HOMA‐IR (INRS rs10417205, INRS rs12971499, INRS rs7254060, and INRS rs7254358), five WHR–gene interactions with fasting insulin (INRS rs10417205, INRS rs7254060, INRS rs7254358, GLU4 rs2113050, and GLU4 rs7713127), eight physical activity–gene interactions with HOMA‐IR (INRS rs10411676, INRS rs11671297, INRS rs2229431, INRS rs12461909, INRS rs6510950, INRS rs10420382, IRS2 rs913949, and IRS2 rs2241745) and five physical activity–gene interactions with fasting insulin (INRS rs2229431, INRS rs12461909, INRS rs10420382, IRS2 rs913949, and IRS2 rs2241745).

Our results suggest that BMI, WHR and physical activity may modify IR‐associated variants.