Abstract
Recent genome-wide association studies (GWAS) and their meta-analyses have identified multiple genetic loci that are associated with type 2 diabetes (T2D). Except for variants in the TCF7L2 gene which had a modest effect on diabetic risk, most genetic variants identified so far have only a weak association with diabetes. It is possible that the combination of multiple variants may have a larger effect on disease risk and improve risk prediction. In this study, we focus on SNPs that had been robustly replicated in previous GWAS and were also genotyped in a large sample of 21,183 participants from three large prospective cohorts, including Atherosclerosis Risk in Communities (ARIC) Study, Framingham Offspring Study (FOS) and Multi-Ethnic Study of Atherosclerosis (MESA). Among these, we were able to successfully confirm the associations of 12 SNPs with baseline prevalent T2D in these two cohorts. A genotype risk score (GRS) using these12 risk variants was constructed to examine whether GRS predicts incident diabetes. In a combined meta-analysis, subjects in the highest tertile of GRS had a 1.62-fold increased risk of incident T2D (95% CI, 1.08-2.44, P=1.5×10-14) compared to those in the lowest tertile of GRS after adjustment for age, sex, race, smoking, body mass index (BMI), lipids (HDL and LDL) and systolic blood pressure. Moreover, GRS significantly improves risk prediction and reclassification in T2D beyond known risk factors.
Highlights
Type 2 diabetes (T2D) has reached epidemic proportions in almost all racial/ethnic groups
This study aims to confirm the association of these SNPs with prevalent T2D and evaluate the prognostic value of a combination of these validated SNPs in predicting incident T2D in a large sample comprising 21,183 subjects from three large prospective cohorts, including The Atherosclerosis Risk in Communities (ARIC) Study, the Framingham Offspring Study (FOS) and the Multi-Ethnic Study of Atherosclerosis (MESA)
A total of 276 participants (29%) with T2D at 10–20% risk estimated using only known coronary risk factors were reclassified into ≥20% category when genotype risk score (GRS) was added to the model, and 932 participants (20%) without T2D were reclassified from ≥20% into the 10–20% category when GRS was included
Summary
Type 2 diabetes (T2D) has reached epidemic proportions in almost all racial/ethnic groups. TCF7L2 gene which had a modest effect on diabetic risk (odds ratio 1.40–1.56) [8,9], most genetic variants identified so far have only a weak association with diabetes (odds ratios ranging from 1.1 to 1.3) [10,11,12]. It is possible that the combination of multiple variants may have a larger effect and potentially improves risk prediction over established risk factors. This study aims to confirm the association of these SNPs with prevalent T2D and evaluate the prognostic value of a combination of these validated SNPs in predicting incident T2D in a large sample comprising 21,183 subjects from three large prospective cohorts, including The Atherosclerosis Risk in Communities (ARIC) Study, the Framingham Offspring Study (FOS) and the Multi-Ethnic Study of Atherosclerosis (MESA)
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