Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns.
Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r(2)< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.
Bonnycastle
Lori L
LL
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-2152, USA.
Willer
Cristen J
CJ
Conneely
Karen N
KN
Jackson
Anne U
AU
Burrill
Cecily P
CP
Watanabe
Richard M
RM
Chines
Peter S
PS
Narisu
Narisu
N
Scott
Laura J
LJ
Enloe
Sareena T
ST
Swift
Amy J
AJ
Duren
William L
WL
Stringham
Heather M
HM
Erdos
Michael R
MR
Riebow
Nancy L
NL
Buchanan
Thomas A
TA
Valle
Timo T
TT
Tuomilehto
Jaakko
J
Bergman
Richard N
RN
Mohlke
Karen L
KL
Boehnke
Michael
M
Collins
Francis S
FS
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics*; D005260:Female; D005387:Finland; D005941:Glucokinase / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015534:Trans-Activators / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D005941:Glucokinase; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D015534:Trans-Activators; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C093970:NEUROD1 protein, human; C084010:pancreatic and duodenal homeobox 1 protein