Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes

Abstract

AimWe performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes.MethodsWe genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis.ResultsAll SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10-4, binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037–1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10-4, adjusted for sex, age and BMI).Conclusions ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.

Effects of variants of 50 genes on diabetes risk among the Chinese population born in the early 1960s

“…However, in a population‐based prospective cohort study from northern Sweden, rs2191349 was associated with elevated IFG risk . In the present study we found that rs10842994 was associated with a reduced risk of IFG, but a study conducted in a Japanese population examined the association of rs10842994 near KLHDC5 with susceptibility to diabetes . These two SNPs need to be evaluated further in a larger sample of the Chinese or in different populations.…”

“…60 In the present study we found that rs10842994 was associated with a reduced risk of IFG, but a study conducted in a Japanese population examined the association of rs10842994 near KLHDC5 with susceptibility to diabetes. 34 These two SNPs need to be evaluated further in a larger sample of the Chinese or in different populations. The direction of the effect of most SNPs in the present study was the same as reported in previous studies.…”

“…The weighted GRS was calculated on the basis of the 50 SNPs by using a previously described weighted method . Each SNP was weighted by β coefficients obtained from published meta‐analyses . (The original β coefficients can be found in the references listed in Table S2.)…”

“…3 Each SNP was weighted by β coefficients obtained from published metaanalyses. 4,7,[10][11][12]16,17,[24][25][26][27][28][29][30][31][32][33][34][35] (The original β coefficients can be found in the references listed in Table S2.) The weighted GRS was calculated by multiplying each β coefficients by the number of corresponding risk alleles and summing the products, then dividing the sum by twice the sum of the β coefficients and multiplying by 50.…”

East Asian Genome-wide association study derived loci in relation to type 2 diabetes in the Han Chinese population

“…ides; DM, diabetes mellitus; IR, insulin resistance; T2DM, type 2 diabetes mellitus; WGAS, whole genome association study; ANTIGAD, anti glutamic acid decarboxylase; WHO, World Health Organization BACKGROUND Type 2 diabetes (T2D) is more prevalent in Asians than in Europeans (Sakai et al, 2013). The highest incidences of T2D (about 80%) are seen in developing countries.…”