Billings LK, Hsu YH, Ackerman RJ, Dupuis J, Voight BF, Rasmussen-Torvik LJ, Hercberg S, Lathrop M, Barnes D, Langenberg C, Hui J, Fu M, Bouatia-Naji N, Lecoeur C, An P, Magnusson PK, Surakka I, Ripatti S, Christiansen L, Dalgård C, Folkersen L, Grundberg E, MAGIC Investigators , DIAGRAM + Consortium , MuTHER Consortium , ASCOT Investigators , GEFOS Consortium , Eriksson P, Kaprio J, Ohm Kyvik K, Pedersen NL, Borecki IB, Province MA, Balkau B, Froguel P, Shuldiner AR, Palmer LJ, Wareham N, Meneton P, Johnson T, Pankow JS, Karasik D, Meigs JB, Kiel DP, Florez JC
Diabetes 61 (8) 2176-2186 [2012-08-00; online 2012-06-16]
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.