A Variant in CDKAL1 Influences Insulin Response and Risk of Type 2 Diabetes

Nat Genet. 2007 Jun;39(6):770-5. doi: 10.1038/ng2043. Epub 2007 Apr 26.

Abstract

We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / metabolism
  • Carrier Proteins / genetics*
  • Case-Control Studies
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Gene Frequency
  • Genome, Human
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Insulin Secretion
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • TCF Transcription Factors / genetics
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factor 7-Like 2 Protein

Substances

  • Blood Glucose
  • CDK5RAP1 protein, human
  • Carrier Proteins
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • TCF Transcription Factors
  • TCF7L1 protein, human
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factor 7-Like 2 Protein