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 has yet to be determined. The sulfonylurea receptor (SUR) gene, now known to encode an integral component of the pancreatic beta-cell ATP-sensitive potassium channel, IKATP, was 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, single-strand 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 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, odds 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 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 -3c/-3c 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.
Inoue
H
H
Division of Metabolism, Diabetes and Endocrinology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ferrer
J
J
Welling
C M
CM
Elbein
S C
SC
Hoffman
M
M
Mayorga
R
R
Warren-Perry
M
M
Zhang
Y
Y
Millns
H
H
Turner
R
R
Province
M
M
Bryan
J
J
Permutt
M A
MA
Aguilar-Bryan
L
L
D018528:ATP-Binding Cassette Transporters; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005787:Gene Frequency; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D016364:Reading Frames; D011955:Receptors, Drug / Q000235:genetics*; D012016:Reference Values; D064233:Sulfonylurea Receptors; D006113:United Kingdom; D014589:Utah; D044465:White People / Q000235:genetics*
D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors