Genetic risk scores in the prediction of plasma glucose, impaired insulin secretion, insulin resistance and incident type 2 diabetes in the METSIM study.

Aims/hypothesis: Many SNPs have been associated with glycaemic traits and type 2 diabetes, but their joint effects on glycaemic traits and the underlying mechanisms leading to hyperglycaemia over time are largely unknown. We aimed to investigate the association of six genetic risk scores (GRSs) with changes in plasma glucose, insulin sensitivity, insulin secretion and incident type 2 diabetes in the prospective METabolic Syndrome In Men (METSIM) study.
Methods: We generated weighted GRSs for fasting plasma glucose ([FPG] GRS _FPG , 35 SNPs), 2 h plasma glucose ([2hPG] GRS _2hPG , 9 SNPs), insulin secretion (GRS _IS , 17 SNPs), insulin resistance (GRS _IR , 9 SNPs) and BMI (GRS _BMI , 95 SNPs) and a non-weighted GRS for type 2 diabetes (GRS _T2D , 76 SNPs) in up to 8749 non-diabetic Finnish men. Linear regression was used to test associations of the GRSs with changes in glycaemic traits over time.
Results: GRS _T2D , GRS _FPG and GRS _IS were associated with an increase in FPG, GRS _T2D with an increase in glucose AUC and a decrease in insulin secretion, and GRS _2hPG with an increase in 2hPG during the follow-up (p < 0.0017 for all models). GRS _T2D , GRS _FPG and GRS _IS were associated with incident type 2 diabetes (p < 0.008 for all models). GRS _BMI and GRS _IR were not significantly associated with any changes in glycaemic traits.
Conclusions/interpretation: In the METSIM follow-up study, GRS _T2D , GRS _FPG and GRS _IS were associated with the worsening of FPG and an increase in incident type 2 diabetes. GRS _T2D was additionally associated with a decrease in insulin secretion, and GRS _2hPG with an increase in 2hPG.