The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

Background: Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D) in large groups of obese and non-obese subjects. Methods: We genotyped RETN, KCNJ11, HNF4A, HNF1A, GCK, SLC30A8, ENPP1, ADIP0Q, PPARG, and TCF7L2 polymorphisms in 1,283 normoglycemic ( NG) and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI. Results: Amongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [ odds ratio ( OR) = 1.14, P = 0.04], GCK - 30G > A ( OR = 1.23, P = 0.01), SLC30A8 R325W ( OR = 0.87, P = 0.04), and TCF7L2 rs7903146 ( OR = 1.89, P = 4.5 x 10(-23)), and non-significant associations with PPARG Prol2Ala ( OR = 0.85, P = 0.14), ADIPOQ - 11,377C > G ( OR = 1.00, P = 0.97) and ENPP1 K121Q ( OR = 0.99, P = 0.94). In obese subjects, associations with T2D were detected with PPARG Prol2Ala ( OR = 0.73, P = 0.004), ADIPOQ - 11,377C > G ( OR = 1.26, P = 0.02), ENPP1 K121Q ( OR = 1.30, P = 0.003) and TCF7L2 rs7903146 ( OR = 1.30, P = 1.1 x 10(-4)), and nonsignificant associations with HNF1A I27L ( OR = 0.96, P = 0.53), GCK - 30G > A ( OR = 1.15, P = 0.12) and SLC30A8 R325W ( OR = 0.95, P = 0.44). However, a genotypic heterogeneity was only found for TCF7L2 rs7903146 ( P = 3.2 x 10(-5)) and ENPP1 K121Q ( P = 0.02). No association with T2D was found for KCNJ11, RETN, and HNF4A polymorphisms in non-obese or in obese individuals. Conclusion: Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.