Abstract
OBJECTIVE—
Type 2 diabetes is a common complex disorder with environmental and genetic components. We used a candidate gene–based approach to identify single nucleotide polymorphism (SNP) variants in 222 candidate genes that influence susceptibility to type 2 diabetes.
RESEARCH DESIGN AND METHODS—
In a case-control study of 1,161 type 2 diabetic subjects and 1,174 control Finns who are normal glucose tolerant, we genotyped 3,531 tagSNPs and annotation-based SNPs and imputed an additional 7,498 SNPs, providing 99.9% coverage of common HapMap variants in the 222 candidate genes. Selected SNPs were genotyped in an additional 1,211 type 2 diabetic case subjects and 1,259 control subjects who are normal glucose tolerant, also from Finland.
RESULTS—
Using SNP- and gene-based analysis methods, we replicated previously reported SNP-type 2 diabetes associations in
PPARG
,
KCNJ11
, and
SLC2A2
; identified significant SNPs in genes with previously reported associations (
ENPP1
[rs2021966,
P
= 0.00026] and
NRF1
[rs1882095,
P
= 0.00096]); and implicated novel genes, including
RAPGEF1
(rs4740283,
P
= 0.00013) and
TP53
(rs1042522, Arg72Pro,
P
= 0.00086), in type 2 diabetes susceptibility.
CONCLUSIONS—
Our study provides an effective gene-based approach to association study design and analysis. One or more of the newly implicated genes may contribute to type 2 diabetes pathogenesis. Analysis of additional samples will be necessary to determine their effect on susceptibility.