Association of a variant in exon 31 of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus in French Caucasians

Fondation Jean Dausset - CEPH, Paris, France
Human Genetics (Impact Factor: 4.82). 07/2000; 107(2):138-144. DOI: 10.1007/s004390000345


The sulfonylurea receptor (SUR1) of the pancreatic beta-cell ATP-sensitive potassium channel plays a key role in glucose-induced insulin secretion. The A-allele of a single nucleotide polymorphism (SNP) in exon 31 of the SUR1 gene (AGG&#77AGA; Arg1273Arg) has previously been shown to be associated with hyperinsulinemia in nondiabetic Mexican-American subjects. Here, we have investigated the association of this SNP with type 2 diabetes mellitus (T2DM) in French Caucasian subjects. We have observed an increased frequency of the A allele (37.1% vs 27.6%, P=0.0048; odds ratio 1.54), of the AA genotype (15.7% vs 9.8%; P=0.025), and of the combined AA/AG genotypes (58.5% vs 45.5%, P=0.0098; odds ratio 1.69) in patients compared with controls. This association is stronger in the subgroup of patients with age of diagnosis of diabetes equal to or less than 45 years: A allele 43.2% (P=0.0003 compared with controls; odds ratio 1.99), AA genotype 21.4% (P=0.0032), and combined AA/AG genotypes 65.1% (P=0.0022; odds ratio 2.23). Unexpectedly, the G allele is strongly associated with arterial hypertension in obese diabetic subjects (GG vs AA odds ratio 19.97). In conclusion, we have observed an association of an SNP in exon 31 of the SUR1 gene with T2DM. These data reinforce the hypothesis that insulin secretion defects in T2DM might be at least partially related to allelic variations in the SUR1 gene.

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    • "Furthermore, a large-scale meta-analysis of the data for the G716V and T759T markers yielded negative results [13]. Compared to these markers, a silent G-to-A nucleotide substitution in codon 1273 (R1273R; rs1799859) located in exon 31 of ABCC8 was assessed less frequently but showed consistent association with T2D [11] [14] [15] and diabetesrelated traits [16] [17] in several populations. Although T2D is a heterogeneous collection of metabolic syndromes, defects in β-cell function seem to play a major role in T2D etiology because the majority of genetic variants conferring susceptibility to this pathology are involved in control of β-cell development and function [18]. "
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    ABSTRACT: The KCNJ11 and ABCC8 genes encode components of the pancreatic ATP-sensitive potassium (KATP) channel. Previously, we reported association of the KCNJ11 E23K and ABCC8 R1273R G/A variants with type 2 diabetes (T2D) in a small Russian population sample (n=244). Here we replicated association between these genetic variants and T2D in a larger cohort (588 diabetic and 597 non-diabetic subjects). Using the ANCOVA analysis, Odds Ratios (ORs) and relationships between the carriage of a genotype and biochemical parameters of the patients were assessed and then adjusted for confounders (age, gender, HbA1c, hypertension, and obesity). The KCNJ11 K23 variant and the ABCC8 R1273R allele A showed association with higher risk of T2D (adjusted OR of 1.41 and 2.03, P<0.0001, respectively). Diabetic patients homozygous for K/K had lower 2h insulin (Padjusted=0.044). The ABCC8 A/A variant was associated with increased 2h serum insulin in diabetic and non-diabetic subjects (Padjusted=0.027 and 0.033, respectively). The carriage of the risk variant K/K of KCNJ11 E23K or A/A of ABCC8 G/A R1273R was associated with reduced response to nonsulfonylurea and sulfonylurea blockers of the pancreatic KATP channel. Adjusted attributable population risk was 3.0% (KCNJ11 E23K) and 4.8% (ABCC8 G/A) suggesting for the modest effects of these genetic variants on diabetes susceptibility.
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    • "Investigations using genome scan approaches have found novel genetic loci associated with CAD, which might provide additional insight to genetic factors contributing to atherosclerosis and coronary events [19] [20] [21] [22] [23]. There also are numerous studies that have found genetic associations or linkage with related disorders, such as hypertension [24] [25] [26] [27] [28] [29], obesity [30] [31] [32] [33] [34] [35] [36] [37] [38], diabetes [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49], lipids [50] [51] [52] [53], and oxidative stress [54]. "
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    • "Mutations and deficiencies in this protein were detected in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion (Thomas et al. 1995; Nestorowicz et al. 1996, 1998; Glaser et al. 1999; Verkarre et al. 1998). An arginine residue at codon 1273 was reported to be associated with hyperinsulinemia in Mexican American nondiabetic individuals (Goksel et al. 1998) and with type 2 diabetes mellitus in French Caucasians (Reis et al. 2000). ABCC9 (SUR2) is the primary regulatory subunit expressed in muscle cells and generates two splice variants, SUR2A (exon 38a) and SUR2B (exon 38b) (Isomoto et al. 1996). "
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