Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals

OBJECTIVE

We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes.

RESEARCH DESIGN AND METHODS

We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features.

RESULTS

Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10⁻²¹). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = −0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = −0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = −0.031, SE = 0.012, P = 0.0125).

CONCLUSIONS

Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell–preserving therapy.Type 2 diabetes affects nearly 300 million individuals worldwide, and its prevalence continues to increase in many countries, including Japan (1). Although the precise mechanisms underlying the development and progression of type 2 diabetes have not been elucidated, a combination of multiple genetic and/or environmental factors contribute to the pathogenesis of the disease (2,3). Impaired insulin secretion and insulin resistance, the two main pathophysiological mechanisms leading to type 2 diabetes, have a significant genetic component (4).Recent studies have confirmed ~40 genetic loci associated with type 2 diabetes (5); most of these loci were discovered in genome-wide association studies (6–16), with the exception of PPARG (17), KCNJ11 (18), and WFS1 (19), which were identified using candidate gene approaches, and TCF7L2, which was discovered using a linkage-positional cloning strategy (20). Among them, many loci (at least 10), such as MTNR1B, SLC30A8, THADA, TCF7L2, KCNQ1, CAMK1D, CDKAL1, IGF2BP2, HNF1B, and CENTD2, have been shown to be associated with impaired β-cell functions, whereas only a few loci such as PPARG, IRS1, and FTO have been associated with insulin resistance (13).Although the molecular mechanisms responsible for the susceptibility effect can be well assigned for some loci, such as those at KCNJ11 and SLC30A8, the mechanisms by which most genetic loci contribute to the development of type 2 diabetes are not understood.Recently, the construction of a genetic risk score (GRS) using information on these diabetes susceptibility loci has been shown to be useful for evaluating the risk of the development of type 2 diabetes in individuals (21–26). However, the currently available genetic information is obviously insufficient for predicting the development of type 2 diabetes, and little is known about the detailed relationship between the GRS and the clinical features of type 2 diabetes. In the current study, we selected 14 well-replicated and well-established genetic variants associated with type 2 diabetes in the Japanese population (25,27–32) and constructed a GRS, which may predict mechanism (β-cell function and insulin resistance) of diabetes development, to evaluate the possibility that currently available genetic information can be translated into clinical practice.