Variants in the sulphonylurea receptor gene: association of the exon 16-3t variant with Type II diabetes mellitus in Dutch Caucasians

Abstract

Type II (non-insulin-dependent) diabetes mellitus is a phenotypic and genetic heterogeneous disorder. Both defects in insulin action and insulin secretion are involved [1]. Mutations in a wide variety of genes, such as the genes for glucokinase, insulin receptor, hepatocyte nuclear factors and the mitochondrial DNA, contribute to deregulation of glucose homeostasis. One study has provided evidence for an association between two single nucleotide polymorphisms (SNPs) in the SUR1 gene and Type II diabetes in Caucasians [2]. Additional studies have corroborated this association with Type II diabetes in populations with different ethnic backgrounds [3±5].It is known from other studies that even in study groups confined to Caucasians of north-western European descent, differences occur in the degree of as- Diabetologia (1999) Abstract Aims/hypothesis. We have analysed to what extent two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene (SUR1) are associated with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands. Furthermore, we estimated haplotype frequencies in control and diabetic populations, including data extracted from three other studies. Methods. Subjects with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were randomly selected from two population-based studies, the Hoorn and Rotterdam studies. DNA was typed for variants in exon 16 (-3c®t variant in the splice acceptor site) and exon 18 (Thr 759 Thr, ACC®ACT). Results. The genotype frequencies in both populations were similar. We observed an association of the exon 16±3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in NGT and Type II diabetes, respectively, p = 0.01). There was no association between Type II diabetes and the variant in exon 18 or the combination of both variants (p > 0.5). A strong linkage disequilibrium between the exon 16 and exon 18 variants was observed in the diabetic groups but not, or less pronounced, in the control groups from the different studies. Haplotype estimation shows that several different risk haplotypes exist in different Caucasian populations. Conclusion/interpretation. The exon 16±3t allele of the SUR1 gene is associated with Type II diabetes in the Netherlands. Based on estimated haplotype frequencies in different Caucasian populations we conclude that multiple haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes in Caucasians. [Diabetologia (1999)

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

“…The genotype and allele frequencies for the exon 16 polymorphism are presented in Table 1, next to the results of t Hart et al [1]. We could not detect a significant association between the t-allele of exon 16 and Type II diabetes mellitus in our cohort of patients (p = 0.31).…”

“…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).…”

Role of Common Sequence Variants in Insulin Secretion in Familial Type 2 Diabetic Kindreds

“…Despite linkage disequilibrium between the variants, most studies found an association of either the exon 16 (intronic) variant (14,15) or the silent exon 18 variant (14,16,17) but not both. Furthermore, the allele associated with diabetes has been inconsistent (15).…”

“…Despite linkage disequilibrium between the variants, most studies found an association of either the exon 16 (intronic) variant (14,15) or the silent exon 18 variant (14,16,17) but not both. Furthermore, the allele associated with diabetes has been inconsistent (15). No functional variant in the ABCC8 gene or in the adjacent KCNJ11 (KIR 6.2) subunit (14,17,31,32) has been identified to explain this association.…”

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

“…The evidence for association of SUR1 polymorphisms is less clear, with a variety of results implicating an exon 16 polymorphism at the Ϫ3 position (12)(13)(14)(15), an exon 18 silent mutation (T759T) (12,16,17), and an exon 31 silent mutation (R1273R) (18) in type 2 diabetes. A subsequent meta-analysis of all published data concerning the exon 16 and exon 18 variants, however, yielded negative results (8).…”