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Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

2012; American Diabetes Association; Volume: 61; Issue: 8 Linguagem: Inglês

10.2337/db11-1515

1939-327X

Liana K. Billings, Yi‐Hsiang Hsu, Rachel Ackerman, Josée Dupuis, Benjamin F. Voight, Laura J. Rasmussen‐Torvik, Serge Herçberg, Mark Lathrop, Daniel R. Barnes, Claudia Langenberg, Jennie Hui, Mao Fu, Nabila Bouatia‐Naji, Cécile Lecœur, Ping An, Patrik K. E. Magnusson, Ida Surakka, Samuli Ripatti, Lene Christiansen, Christine Dalgård, Lasse Folkersen, Elin Grundberg, Per Eriksson, Jaakko Kaprio, Kirsten Ohm Kyvik, Nancy L. Pedersen, Ingrid B. Borecki, Michael A. Province, Beverley Balkau, Philippe Froguel, Alan R. Shuldiner, Lyle J. Palmer, Nicholas J. Wareham, Pierre Meneton, Toby Johnson, James S. Pankow, David Karasik, James B. Meigs, Douglas P. Kiel, Jose C. Florez,

Metabolism, Diabetes, and Cancer

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 (r2 > 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.