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

  1. Jose C. Florez1,2,3,8
  1. 1Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  2. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
  3. 3Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts
  4. 4Hebrew SeniorLife Institute for Aging Research and Harvard Medical School, Boston, Massachusetts
  5. 5Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, Massachusetts
  6. 6Framingham Heart Study, Framingham, Massachusetts
  7. 7Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  8. 8Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
  9. 9Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  10. 10INSERM, National Institute of Agronomic Research, University of Paris, Bobigny, France
  11. 11National Genotyping Center, Atomic Energy Commission, Institute of Genomics, Evry, France
  12. 12Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, U.K.
  13. 13Molecular Genetics, PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia, Australia
  14. 14School of Population Health and School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia
  15. 15Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
  16. 16Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
  17. 17National Center for Scientific Research, UMR 8199, Genomics and Metabolic Diseases, Lille Pasteur Institute, Lille Nord de France University, Lille, France
  18. 18Division of Statistical Genomics and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
  19. 19Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  20. 20Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  21. 21Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland
  22. 22Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark
  23. 23Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark
  24. 24Atherosclerosis Research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden
  25. 25Wellcome Trust Sanger Institute, Hinxton, U.K.
  26. 26Department of Twin Research and Genetic Epidemiology, King’s College London, London, U.K.
  27. 27Erasmus Medical College (Coordinating Center), Rotterdam, the Netherlands
  28. 28Unit for Child and Adolescent Mental Health, National Institute for Health and Welfare, Helsinki, Finland
  29. 29Department of Public Health, University of Helsinki, Helsinki, Finland
  30. 30Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark
  31. 31Odense Patient Data Explorative Network, Odense University Hospital, Odense, Denmark
  32. 32INSERM, CESP Center for Research in Epidemiology and Health of Populations, U1018, Epidemiology of Diabetes, Obesity and Chronic Kidney Disease Over the Life Course, INSERM, Villejuif, France and Université Paris-Sud 11, UMRS 1018, Villejuif, France
  33. 33Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K.
  34. 34Geriatrics Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland
  35. 35Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  36. 36Cordeliers Center of Research, INSERM, Paris, France
  37. 37Clinical Pharmacology and the Genome Centre, William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.
  38. 38Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
  1. Corresponding author: Jose C. Florez, jcflorez{at}partners.org.

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 (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.

Footnotes

  • Received October 27, 2011.
  • Accepted March 9, 2012.

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  1. Diabetes vol. 61 no. 8 2176-2186
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