Haplotype Structure and Genotype-Phenotype Correlations of the Sulfonylurea Receptor and the Islet ATP-Sensitive Potassium Channel Gene Region

Abstract

The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself-or other variant(s) in either of these two closely linked genes-influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P ‫؍‬ 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P ‫؍‬ 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r 2 > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby ␤-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator-activated receptor ␥, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment. T he sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated potassium channel (Kir6.2; encoded by KCNJ11) have been implicated in susceptibility to type 2 diabetes on the basis of the clinical efficacy of sulfonylurea medications, the genetics of the rare human disorder familial hyperinsulinemic hypoglycemia of infancy (reviewed in 1), and the putative association of common variation in one or both genes with the common form of type 2 diabetes. ABCC8 and KCNJ11 reside adjacent to one another on human chromosome 11p15.1, and their gene products form a heterodimer that regulates the transmembrane potential in the pancreatic ␤-cell, thus providing a key intracellular signal resulting in vesicular fusion and insulin secretion (1). Several studies have assessed the possible association of single-nucleotide polymorphisms (SNPs) in ABCC8 and KCNJ11 with type 2 diabetes. The E23K polymorphism was not significantly associated in initial reports (2-5), but studies with larger sample sizes (6 -9) and subsequen...

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

“…A Pearson w 2 goodness-of-fit test to assess the level of genetic heterogeneity among sample populations was applied to both the study's data and data used in the pooled analyses as described previously. 62 …”

A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus

“…In addition, we and others have demonstrated that gestational diabetes mellitus shares some genetic risk factors with type 2 diabetes [2]. For example, potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11 E23K), glucokinase (GCK −30G>A) and transcription factor 1, hepatic; LF-B1, hepatic nuclear factor (HNF1), albumin proximal factor (TCF1, also known as hepatocyte nuclear factor 1-α [HNF1A I27L]) polymorphisms, all of which have been associated with type 2 diabetes [7][8][9], also increase the risk of gestational diabetes mellitus with a modest effect size [10,11].…”

Latent autoimmune diabetes in adults (LADA)—more than a name

“…However, still lacking is knowledge on whether patients with LADA have the same frequency of the few type 2 diabetes susceptibility genes that have reproducibly been associated with type 2 diabetes, e.g. the Pro12Ala single-nucleotide polymorphism in PPARG, the E23K SNP in KCNJ11, or the recently described polymorphisms in TCF7L2 [13][14][15].…”