Impact of common variation in bone-related genes on type 2 diabetes and related traits

Diabetes. 2012 Aug;61(8):2176-86. doi: 10.2337/db11-1515. Epub 2012 Jun 14.

Abstract

Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.

Publication types

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

MeSH terms

  • Adipose Tissue / metabolism
  • Adult
  • Blood Glucose / genetics
  • Blood Glucose / metabolism
  • Body Mass Index
  • Bone Density / genetics*
  • Diabetes Mellitus, Type 2 / genetics*
  • Endonucleases
  • Female
  • Fractures, Bone / etiology*
  • Fractures, Bone / genetics
  • Genome-Wide Association Study
  • Humans
  • Insulin / genetics
  • Integrin alpha1 / genetics*
  • Linkage Disequilibrium
  • Liver / metabolism
  • Microfilament Proteins / genetics
  • Nuclear Proteins
  • Osteoporosis / genetics
  • Polymorphism, Single Nucleotide

Substances

  • Blood Glucose
  • Insulin
  • Integrin alpha1
  • Microfilament Proteins
  • Nuclear Proteins
  • Endonucleases
  • pelo protein, human

Grant support