Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs

Abstract

A recent meta-analysis on three genome-wide association (GWA) scans identified six loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) highly associated with type II diabetes (T2D) in Caucasians. This investigation seeks to confirm this association with diabetes and related metabolic traits in Khatri Sikh diabetics of North India. We genotyped highly significant variants from each locus in a case-control cohort consisting of 680 T2D cases and 637 normoglycemic (NG) controls. Only CDC123/CAMKID (rs12779790) replicated earlier evidence of association with T2D under a dominant model (odds ratio (OR): 1.27; 95% confidence interval (CI): 1.02-1.57; P¼0.031) during initial testing. However, we could not confirm this association using multiple testing corrections. In a multiple linear-regression analysis, the same variant in the CDC123/CAMKID revealed a marked decrease in fasting insulin levels among 'G' (risk) allele carriers independently in NG controls (P¼0.030) and in T2D cases (P¼0.009), as well as in the combined sample (P¼0.003) after adjusting for covariates. Evidence of impaired b-cell function was also observed among 'G' (risk) allele carriers in T2D cases (P¼0.008) and in a combined cohort (P¼0.026). Our data could not confirm the role of the remaining variants with risk either for T2D or quantitative phenotypes measuring insulin secretion or insulin resistance. These findings suggest that CDC123/CAMKID could be a major risk factor for the development of T2D in Sikhs by affecting b-cell function. To our knowledge, this is the first study reporting the role of recently emerging loci in this high-risk population from the South Asian subcontinent.

Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese

“…3 Replication studies in other Asian populations just identified marginal significance of type 2 diabetes risk associated with some of these novel loci. [11][12][13] We thought that the possible reasons for no or marginal significance were the limited sample size of these Asian population studies. To identify the effects of these genes on type 2 diabetes, we conducted a meta-analysis by pooling our data with those reported in the previous studies of East Asians.…”

Reduced body weight in male Tspan8-deficient mice

“…However, no association of this locus with prediabetic traits could be identified in Southern German individuals at an increased risk for T2D; 9 replication of this T2D risk locus could also not be established in a Japanese cohort and an Asian Indian Sikh population containing type 2 diabetics. 10,11 None of the three genes in the T2D risk locus 12q15 (LGR5, PTPRR and TSPAN8) have previously been shown to have a role in the onset or progression of T2D.…”

Pharmacogenetics for T2DM and Anti-Diabetic Drugs

“…G risk allele of rs12779790 was associated with a lower insulin genic index, corrected insulin response, and area under the insulin/glucose curve during OGTTs and a lower DI in carriers of the G allele [51]. In Asian Indian descent subjects also found the -cell defect [34]. Trend toward lower -cell function could be observed in Caucasians population [35,38,52].…”

“…WFS1 gene polymorphism rs10010131 was confirmed with T2DM in several GWA studies [19][20][21][22][23][24][25]. In the Diabetes Prevention Program, it is noted a trend towards increased insulin secretion in carriers of the protective rs10010131 variants [34]. Rare mutations in WFS1 cause Wolfram syndrome, variation in WFS1 also predisposes to common T2DM.…”