Sequence Variants in the Sulfonylurea Receptor (SUR) Gene Are Associated With NIDDM in Caucasians

Abstract

NIDDM is a common heterogeneous disorder, the genetic basis of which has yet to be determined. The sulfonylurea receptor (SUR) gene, now known to encode an integral component of the pancreatic P-cell ATP-sensitive potassium channel, IKATP> w a s investigated as a logical candidate for this disorder. The two nucleotide-binding fold (NBF) regions of SUR are known to be critical for normal glucose regulation of insulin secretion. Thus, singlestrand conformational polymorphism analysis was used to find sequence changes in the two NBF regions of the SUR gene in 35 NIDDM patients. Eight variants were found; and three were evaluated in two Northern European white populations (Utah and the U.K.): 1) a missense mutation in exon 7 (S1370A) was found with equal frequency in patients (n = 223) and control subjects (n = 322); 2 ) an ACf^ACT silent variant in exon 22 (T761T) was more common in patients than in control subjects (allele frequencies 0.07 vs. 0.02, P = 0.0008, odds ratio (OR) 3.01, 95% CI 1.54-5.87); and 5 ) an intronic t^c change located at position -3 of the exon 24 splice acceptor site was also more common in patients than in control subjects (0.62 vs. 0.46, P < 0.0001, OR 1.91, 95% Cl 1.50-2.44). The combined genotypes of exon 22 C/T or T/T and intron 24 -3 c / -3 c occurred in 8.9% of patients and 0.5% of control subjects (P < 0.0001, OR 21.5,95% CI 2.91-159.6). These results suggest that defects at the SUR locus may be a major contributor to the inherited basis of NIDDM in Northern European Caucasians.

Ser1369Ala Variant in Sulfonylurea Receptor Gene ABCC8 Is Associated With Antidiabetic Efficacy of Gliclazide in Chinese Type 2 Diabetic Patients

“…The Ser1369Ala variant is located in the second nucleotide-binding fold, a functionally important region of the ABCC8 gene. It has not been found to be associated with type 2 diabetes in either Caucasians (13) or Japanese (5,18). Interestingly, the ABCC8 Ser1369Ala polymorphism was recently reported to influence progression to diabetes (6).…”

“…Genetic variants of ABCC8, such as exon 16 Ϫ3t/c, exon 18 T759T, and most recently the missense mutation Y356C, have been reported to be associated with type 2 diabetes (3,5,12,13). Some missense mutations other than Ser1369Ala in the ABCC8 gene have been identified as causing neonatal diabetes (14).…”

The exon 16-3t variant of the sulphonylurea receptor gene is not a risk factor for Type II diabetes mellitus in the Dutch Breda cohort

“…Dear Sir, t Hart et al [1] analysed the association of two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) [2] with Type II (non-insulin-dependent) diabetes mellitus in the Netherlands [1]. They reported an association of the exon 16±3t variant with Type II diabetes mellitus by showing that the genotype frequencies between control subjects and Type II diabetic patients differed significantly (p < 0.05).…”

“…A study of 1037 children diagnosed between 1985 and 1996 from Oxford, United Kingdom [1] showed rising incidence was accounted for by children aged 0±4 years. A study of 2326 children diagnosed between 1984 and 1993 from Scotland, United Kingdom [2] has shown a rising incidence in all ages (0±14) and for each age-band (0±4, 5±9, 10±14). In Yorkshire, temporal trends between 1978 and 1993 showed the most statistically significant rise in 10±14 year olds [3].…”

Genetic variability of the SUR1 promoter in relation to beta-cell function and Type II diabetes mellitus

“…In contrast, evidence for linkage of the plasma glucose concentration 2 h after oral glucose administration was shown with markers near the SUR1 locus in Mexican-American families ascertained on a Type II diabetic proband [10]. Furthermore, screening of the coding region and intronexon boundaries of the SUR1 gene revealed several polymorphisms [11,12]. Two polymorphisms, a silent exon 18 Thr759Thr variant and a c®t intron variant in position ±3 of the exon 16 splice acceptor site have been reported to be associated with Type II diabetes or a prediabetic phenotype either alone or in combination [11±17].…”