Gene-environment interaction in type 2 diabetes in Korean cohorts: Interaction of a type 2 diabetes polygenic risk score with triglyceride and cholesterol on fasting glucose levels

Type 2 diabetes (T2D) is caused by genetic and environmental factors as well as gene-environment interactions. However, these interactions have not been systematically investigated. We analyzed these interactions for T2D and fasting glucose levels in three Korean cohorts, HEXA, KARE, and CAVAS, using the baseline data with a multiple regression model. Two polygenic risk scores for T2D (PRS_T2D) and fasting glucose (PRS_FG) were calculated using 488 and 82 single nucleotide polymorphisms (SNP) for T2D and fasting glucose, respectively, which were extracted from large-scaled genome-wide association studies with multiethnic data. Both lifestyle risk factors and T2D-related biochemical measurements were assessed. The effect of interactions between PRS_T2D-triglyceride (TG) and PRS_T2D-total cholesterol (TC) on fasting glucose levels was observed as follows: β ± SE = 0.0005 ± 0.0001, p = 1.06 × 10⁻¹⁹ in HEXA, β ± SE = 0.0008 ± 0.0001, p = 2.08 × 10⁻⁸ in KARE for TG; β ± SE = 0.0006 ± 0.0001, p = 2.00 × 10⁻⁶ in HEXA, β ± SE = 0.0020 ± 0.0004, p = 2.11 × 10⁻⁶ in KARE, β ± SE = 0.0007 ± 0.0004, p = 0.045 in CAVAS for TC. PRS_T2D-based classification of the participants into four groups showed that the fasting glucose levels in groups with higher PRS_T2D were more adversely affected by both the TG and TC. In conclusion, blood TG and TC levels may affect the fasting glucose level through interaction with T2D genetic factors, suggesting the importance of consideration of gene-environment interaction in the preventive medicine of T2D.