SEQUENCE VARIANTS IN THE SULFONYLUREA RECEPTOR (SUR) GENE ARE ASSOCIATED WITH NIDDM IN CAUCASIANS

NIDDM is a common heterogeneous disorder, the genetic basis of which h as yet to be determined, The sulfonylurea receptor (SUR) gene, now kno wn to encode an integral component of the pancreatic beta-cell ATP-sen sitive potassium channel, I-KATP, was investigated as a logical candid ate for this disorder, The two nucleotide-binding fold (NBF) regions o f SUR are known to be critical for normal glucose regulation of insuli n secretion, Thus, single-strand conformational polymorphism analysis was used to find sequence changes in the two NBF regions of the SUR ge ne in 35 NIDDM patients, Eight variants were found; and three were eva luated in two Northern European white populations (Utah and the U.K.): 1) a missense mutation in exon 7 (S1370A) was found with equal freque ncy in patients (n = 223) and control subjects (n = 322); 2) an ACC--> 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, od ds ratio (OR) 3.01, 95% CI 1.54-5.87); and 3) an intronic t-->c change located at position -3 of the exon 24 splice acceptor site was also m ore 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 -3c/-3c occurred in 8.9% of patients and 0.5% o f control subjects (P < 0.0001, OR 21.5, 95% CI 2.91-159.6), These res ults suggest that defects at the SUR locus may be a major contributor to the inherited basis of NIDDM in Northern European Caucasians.