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.