Joint Effects of Common Genetic Variants on the Risk for Type 2 Diabetes in U.S. Men and Women of European Ancestry

TLDR: A genetic risk score for type 2 diabetes was developed that combined data on 10 polymorphisms and the score improved risk prediction modestly when considered in addition to conventional risk factors.

Abstract: Type 2 diabetes is a rapidly growing public health issue with a major impact on morbidity and premature mortality worldwide (1). The recent increase in the prevalence of this disease is largely attributable to environmental factors; however, convincing evidence shows that genetic factors also play an important role in causing type 2 diabetes (2, 3). Initial efforts to identify type 2 diabetes susceptibly genes favored genome-wide linkage and candidate gene association studies. These approaches identified common single nucleotide polymorphisms (SNPs) in PPARG, KCNJ11, and TCF7L2, which have been widely replicated in populations of various ethnicity (4 – 6). The advent of genome-wide association studies promises more efficient identification of susceptibility genes. Recent genome-wide association studies have discovered several new potential loci, including HHEX, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and WFS1 (7–14). Variants in FTO and MC4R were also associated with type 2 diabetes, but the associations were entirely mediated by body mass index (BMI) (15, 16). Given our growing knowledge of the genetic factors that predispose to type 2 diabetes and the decreasing costs of genotyping, genetic screening for persons at high risk for type 2 diabetes has received considerable attention. The risk attributable to an individual variant is modest and unlikely to have important clinical utility. However, a combination of the major genetic factors may contribute substantially to the disease risk and will be useful in characterizing high-risk populations. Although the joint effects of type 2 diabetes loci identified from genome-wide association studies have been investigated previously (17–22), few studies have comprehensively investigated the impact of conventional risk factors, such as BMI, lifestyle, and family history, on these genetic effects. We sought to confirm associations reported by genome-wide association studies and to examine the joint genetic effects of established type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts: the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS).