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

Abstract

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 (PRST2D) and fasting glucose (PRSFG) 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 PRST2D‐triglyceride (TG) and PRST2D‐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. PRST2D‐based classification of the participants into four groups showed that the fasting glucose levels in groups with higher PRST2D 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.

Insights into the metabolic consequences of type 2 diabetes

“…Our findings also provide insights into the role of lipoprotein classes in T2D etiology. For example, TG levels have been described to be positively associated with T2D 41 and are known to positively correlate with glucose levels, a relationship that may be exacerbated in individuals with high polygenic risk scores for T2D 49 . TG levels, which we found to be causally affected by T2D liability and for some of the related percentages significant in our interaction QTL analysis, may therefore contribute to increased glucose levels.…”

Polygenic risk scores and personalized approaches to cardiometabolic disease prevention and treatment: A short review

“…Likewise, López-Portillo et al demonstrated that fasting glucose levels were higher in non-diabetic individuals with increased genetic risk for T2D and higher consumption of sugary beverages, compared to those with lower genetic risk scores and reduced intakes of the latter 29 . Biochemical interactions have also been studied, where PRS for T2D have been found to significantly interact with triglyceride and cholesterol levels in the subsequent formation of fasting glucose levels 30 . Merino et al showed the dominating effect of unhealthy diet in increasing T2D risk even by 30%, again irrespective of genetic risk 31 .…”