title: Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals.
abstract: 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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, MA, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Lauren
authors.initials: L
authors.lastname: Gianniny
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Candace
authors.initials: C
authors.lastname: Giuducci
authors.forename: Marketa
authors.initials: M
authors.lastname: Sjögren
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindblad
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Leif C
authors.initials: LC
authors.lastname: Groop
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: 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
chemical_list: D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose