Sixty-Five Common Genetic Variants and Prediction of Type 2 Diabetes

Abstract

We developed a 65 type 2 diabetes (T2D) variant–weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38–99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12–3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58–0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10−7). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m2, 27.6% [95% CI 17.7–37.5], P = 4.82 × 10−8; 24.5–27.5 kg/m2, 11.6% [95% CI 5.8–17.4], P = 9.88 × 10−5; >27.5 kg/m2, 2.6% [95% CI −1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.

Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score

“…T2D among people with European ancestry (Talmud et al, 2015) whereas a 62-loci GRS equally predicted T2D in both blacks and whites (Vassy et al, 2014).…”

“…Compared to single genetic variants, a combination of genetic variants may contribute more substantially to disease risk and might thus be useful to better characterize high-risk populations (Talmud et al, 2015;Vassy et al, 2014). Few studies have explored the impact of the T2D genetic risk score on its associated phenotypes such as coronary artery disease (Hamad et al, 2015), or explored its modifying effect on the diabetes association with basic risk factors including age, sex, physical activity (Langenberg et al, 2014), weight gain , obesity and family history (Cornelis et al, 2009b;Langenberg et al, 2014).…”

Role of Conventional Childhood Risk Factors Versus Genetic Risk in the Development of Type 2 Diabetes and Impaired Fasting Glucose in Adulthood: The Cardiovascular Risk in Young Finns Study

“…Although genetic variants are strongly associated with incident type 2 diabetes, only limited added clinical value has been reported in the short-term prediction of type 2 diabetes in adulthood (9,(26)(27)(28). However, a recent large U.K.-based consortium of prospective studies concluded that the addition of genetic risk score to the type 2 diabetes risk score derived from the Framingham Offspring Study leads to a potentially clinically important improvement in discrimination of incident type 2 diabetes over a median of 10 years of follow-up (29). Furthermore, genetic variants may be better predictors in younger individuals and even over longer follow-up periods (27,30).…”

Double trouble: T2DM genetic risk factors play a causal role in CAD

“…In the prediction of T2DM itself, the addition of a 65 T2DM SNP weighted gene score to the phenotypic risk model has recently been shown to give an improvement of potential clinical relevance [12]. However, the lower ORs and significance of T2DM SNPs for CAD mean that the T2DM genetic data are unlikely to be immediately helpful in CAD prediction.…”