Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes in Pima Indians

Diabetes. 2007 May;56(5):1454-9. doi: 10.2337/db06-0640. Epub 2007 Feb 7.

Abstract

A prior genome-wide linkage scan in Pima Indians indicated a young-onset (aged <45 years) type 2 diabetes susceptibility locus on chromosome 1q21-q23. ARHGEF11, which encodes the Rho guanine nucleotide exchange factor 11, was analyzed as a positional candidate gene for this linkage because this protein may stimulate Rho-dependent signals, such as the insulin signaling cascade. The ARHGEF11 gene, and two adjacent genes NTRK1 and INSRR, were sequenced in 24 Pima Indians who were not first-degree relatives. Sequencing of the coding regions, 5' and 3' untranslated regions and putative promoter regions of these genes, identified 28 variants in ARHGEF11, 11 variants in NTRK1, and 8 variants in INSSR. These 47 variants, as well as 84 additional public database variants within/between these genes, were genotyped for association analysis in the same group of Pima Indians who had participated in the linkage study (n = 1,228). An R1467H in ARHGEF11, and several additional noncoding variants that were in high linkage disequilibrium with this variant, were nominally associated with young-onset type 2 diabetes (P = 0.01; odds ratio 3.39) after adjusting for sex, family membership, and Pima heritage. The risk allele H had a frequency of 0.10. In a subgroup of 262 nondiabetic, full-heritage Pima Indians who had undergone detailed metabolic testing, the risk allele H also was associated with a lower mean insulin-mediated glucose disposal rate and a lower mean nonoxidative glucose storage rate after adjusting for age, sex, nuclear family membership, and percentage of body fat (P < or = 0.01). These findings suggest that variation within ARHGEF11 nominally increases risk of type 2 diabetes, possibly as a result of increased insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arizona
  • Chromosomes, Human, Pair 1*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Linkage*
  • Genetic Variation*
  • Genome, Human
  • Genotype
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Indians, North American / genetics
  • Insulin Resistance / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Rho Guanine Nucleotide Exchange Factors

Substances

  • ARHGEF11 protein, human
  • Guanine Nucleotide Exchange Factors
  • Rho Guanine Nucleotide Exchange Factors