Abstract
AimsEast Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population.MethodsWe genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2−R3HDML−HNF4A, rs6467136 near GCCI−PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis.ResultsWith the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10-4, OR = 1.05, 95% confidence interval: 1.02–1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits.ConclusionsThese results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.
Highlights
Diabetes mellitus affects more than 300 million individuals worldwide, and its prevalence is progressively increasing, in the East Asia, South Asia and Western Pacific regions [1]
We did not observe a significant association of 9 single nucleotide polymorphisms (SNPs) with type 2 diabetes by themselves, a genetic risk score (GRS) constructed from the 9 SNPs was significantly associated with type 2 diabetes in the present Japanese population (p = 0.002, per allele OR = 1.04, 95% CI 1.01–1.07, unadjusted data, p = 0.0004, per allele OR = 1.05, 95% CI 1.02–1.09, adjusted for age, sex and body mass index (BMI))
We examined the association of 9 SNP loci derived from an East Asian genome-wide association studies (GWAS) meta-analysis with type 2 diabetes in an independent Japanese population, and found that a GRS that was constructed with the 9 SNPs was significantly associated with type 2 diabetes in the present Japanese population
Summary
Diabetes mellitus affects more than 300 million individuals worldwide, and its prevalence is progressively increasing, in the East Asia, South Asia and Western Pacific regions [1]. Genetic studies of type 2 diabetes have made rapid progress through genome-wide association studies (GWAS) [4,5], and the number of susceptibility loci identified for type 2 diabetes has been increased through GWAS to nearly 70 [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. To evaluate the contribution of these 9 loci identified in East Asian GWAS meta-analysis to conferring susceptibility to type 2 diabetes in an independent population, we performed a replication study for the association of these 9 susceptibility loci with type 2 diabetes in an independent Japanese population using the GRS that was constructed from the 9 loci
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