Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53)

Aims The beta-cell ATP-sensitive potassium channel consists of two subunits , SUR1 and Kir6.2. Population association studies have shown that three var iants in SUR1 and one in Kir6.2 are associated with Type 2 diabetes. These polymorphisms do not result in a functional change or affect splicing, sugg esting that they could be in linkage disequilibrium with a pathogenic mutat ion. The present study aimed firstly to screen the promoter regions of SUR1 and Kir6.2 to determine whether mutations in linkage disequilibrium with t he silent variants lie in regulatory regions, which might lead to changes i n gene expression. Secondly, novel and previously described variants associ ated with Type 2 diabetes (SUR1 exon 16-3t, exon 18 T, and Kir6.2 (EK)-K-23 ) were investigated in the UKPDS cohort. Methods The promoter sequences of both genes were screened by single-strand ed conformational polymorphism analysis for variants associated with Type 2 diabetes. The previously reported variants were evaluated in 364 Type 2 di abetic and 328 normoglycaemic control subjects. Results Two variants were detected in the SUR1 promoter, a three base inser tion (caa) at -522 bp and a single base substitution at -679 bp (c -->g). N either of the variants were associated with diabetes, nor were they in a se quence consensus region for transcription factors. No association with diab etes was observed for either SUR1 variant. However, in contrast, analysis o f the Kir6.2 (EK)-K-23 variant showed that the KK homozygosity was more fre quent in Type 2 diabetic than control subjects. Variants were not associate d with clinical characteristics nor did they affect response to sulphonylur ea therapy. Conclusion There is no support at present for mutation in either Kir6.2 or SUR1 promoter sequences contributing to Type 2 diabetes. However, the minim al promoter region of SUR1 has yet to be investigated. The (EK)-K-23 varian t of Kir6.2 is associated with Type 2 diabetes mellitus in the UKPDS cohort .