Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals.
Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30-1.50], P = 6.74 x 10(-20)). In nondiabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P = 0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes.
Saxena
Richa
R
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, MA, USA.
Gianniny
Lauren
L
Burtt
Noël P
NP
Lyssenko
Valeriya
V
Giuducci
Candace
C
Sjögren
Marketa
M
Florez
Jose C
JC
Almgren
Peter
P
Isomaa
Bo
B
Orho-Melander
Marju
M
Lindblad
Ulf
U
Daly
Mark J
MJ
Tuomi
Tiinamaija
T
Hirschhorn
Joel N
JN
Ardlie
Kristin G
KG
Groop
Leif C
LC
Altshuler
David
D
D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose