The E23K variation in the KCNJ11 gene is associated with type 2 diabetes in Chinese and East Asian population

Abstract

The genes (ABCC8 and KCNJ11) have a key role in glucose-stimulated insulin secretion and thus have always been considered as excellent susceptibility candidates for involvement in type 2 diabetes. Common polymorphisms (KCNJ11 E23K and ABCC8 exon16-3t/c) in these genes have been reported to be associated with type 2 diabetes in various European-descent populations. However, there were inconsistent results in previous studies in East Asian populations and no large case-control studies have been carried out in the Chinese Han population. In this study, these two variants were genotyped in about 4000 Chinese by using TaqMan technology on an ABI7900 system. A meta-analysis was also used to assess the results of association between the two variants and type 2 diabetes in East Asian populations. Our investigation confirmed the association between the KCNJ11 E23K variant and type 2 diabetes under a recessive model (KK vs EK+EE) in the Chinese Han population (odds ratio (OR)¼1.25, 95% confidence interval (95% CI) 1.04-1.50, P¼0.017). The meta-analysis of East Asian populations also showed a strong significant association of the K allele with diabetes (OR¼1.15, P¼3Â10 À9 ), whereas the exon16-3t/c variant (rs1799854) in ABCC8 showed no significant association. Thus, the common E23K variant is considered as a strong candidate for type 2 diabetes susceptibility across different ethnicities. Keywords: association study; Chinese population; KCNJ11; meta-analysis; type 2 diabetes Type 2 diabetes is a polygenic disorder characterized by defects in insulin secretion and peripheral insulin resistance. The pancreatic b-cell adenosine triphosphate (ATP)-sensitive potassium channel (KATP), which is composed of Kir6.2 subunits (the KCNJ11 gene) and Sur1 subunits (the ABCC8 gene), has a central role in the regulation of glucose-induced insulin secretion by linking signals derived from glucose metabolism to cell membrane depolarization and insulin exocytosis. 1 Mutations in both genes can cause familial persistent hyperinsulinemic hypoglycemia in infancy and permanent neonatal diabetes. The KCNJ11 and ABCC8 genes are located at the same chromosome locus, 11p15.1, and are only 4.5 kb apart. Moreover, the strong linkage disequilibrium (LD) across the KCNJ11 gene also extends into the ABCC8 gene. Two representative common variants (KCNJ11 E23K and ABCC8 exon16-3t/c), which were in different LD blocks, have also been reported to be associated with type 2 diabetes in various ethnic populations, with fairly consistent results for the KCNJ11 E23K variant and conflicting results for the ABCC8 exon16-3t/c variant. [1][2][3][4] However, a large-scale association study of these genes has not been carried out in the Chinese Han population; and there was much inconsistency in results in East Asian studies before. [5][6][7][8][9]

Polymorphism E23K (rs5219) in the KCNJ11 gene in Euro-Brazilian subjects with type 1 and 2 diabetes

“…Despite some reports, which found an association between the E23K polymorphism of Kir6.2 and the development of T2D (Nielsen et al, 2003;Alsmadi et al, 2008;Tabara et al, 2009;Zhou et al, 2009;Abdelhamid et al, 2014), our results showed no association, which was in agreement with other studies (Inoue et al, 1997;Yokoi et al, 2006;Cejková et al, 2007;Cauchi et al, 2008;Keshavarz et al, 2014). The MAF (A-allele) in our study of EuroBrazilians overlaps the 95% confidence interval for several European populations (Table 3), suggesting consistency.…”

“…E23K is a common polymorphism worldwide and each copy of the susceptibility allele has a modest effect (odds ratio ~1.15) on T2D (Zhou et al, 2009), but due to its high allele frequency, it is likely to have a large effect on population attributable risk (Gloyn et al, 2003). Therefore, the small sample size of our study could be a limitation of the statistical power of the test.…”

“…A variant of KCNJ11, known as E23K, results from a G → A transition in codon 23 promoting a substitution of glutamine (E) by lysine (K), Lys23Gln, at the NH 2 -terminal tail of Kir6.2 (Haghvirdizadeh et al, 2015). Association studies of rs5219 have not conclusively connected the polymorphism and susceptibility to T2DM; some studies demonstrated associations (Nielsen et al, 2003;Alsmadi et al, 2008;Tabara et al, 2009;Zhou et al, 2009;Abdelhamid et al, 2014) and others did not confirm this finding (Cauchi et al, 2008;Ezzidi et al, 2009;Nikolac et al, 2009;Neuman et al, 2010;Danquah et al, 2013).…”

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

“…Moreover, more than 50% of type 2 diabetes patients were diagnosed at the age of 45-65 years and have 5-15 years duration of disease. In all, 2041 controls (635 men, 1406 women; age 58.1 ± 9.4 years), 4,20,21 with a FPG concentration o6.1 mmol l À1 , were enrolled from the same geographical area with cases. The overall age and sex distribution of controls were matched with that of case group.…”

No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population

“…15,16 To reach sufficient statistical power, another 1152 healthy individuals were selected from a previously studied control set from communities in Pudong District, Shanghai, China. [17][18][19][20][21][22][23] All the samples were enrolled concurrently from 2007 to 2008 and represented as southeastern Han Chinese population; therefore, we combined the two sets of controls in the following statistical analyses. AMD clinical diagnosis was defined strictly in accordance with the International Classification of AgeRelated Maculopathy and Macular Degeneration.…”