Genetic Modifiers of Cystic Fibrosis–Related Diabetes

  1. Garry R. Cutting2
  1. 1Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  2. 2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
  3. 3Cystic Fibrosis–Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  4. 4Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  5. 5Program in Child Health Evaluative Sciences, the Hospital for Sick Children, Toronto, Ontario, Canada
  6. 6Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada
  7. 7Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  8. 8Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada
  9. 9Program in Physiology and Experimental Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada
  10. 10Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
  11. 11Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio.
  1. Corresponding author: Scott M. Blackman, sblackman{at}jhmi.edu.

Abstract

Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5′ to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 × 10−8). Replication was demonstrated in 694 individuals (124 with CFRD) (HR, 1.47; P = 0.007), with combined analysis significant at P = 9.8 × 10−10. SLC26A9 is an epithelial chloride/bicarbonate channel that can interact with the CF transmembrane regulator (CFTR), the protein mutated in CF. We also hypothesized that common SNPs associated with type 2 diabetes also might affect risk for CFRD. A previous association of CFRD with SNPs in TCF7L2 was replicated in this study (P = 0.004; combined analysis P = 3.8 × 10−6), and type 2 diabetes SNPs at or near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with CFRD (P < 0.004). These five loci accounted for 8.3% of the phenotypic variance in CFRD onset and had a combined population-attributable risk of 68%. Diabetes is a highly prevalent complication of CF, for which susceptibility is determined in part by variants at SLC26A9 (which mediates processes proximate to the CF disease-causing gene) and at four susceptibility loci for type 2 diabetes in the general population.

Footnotes

  • Received March 29, 2013.
  • Accepted May 5, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 62 no. 10 3627-3635
  1. Supplementary Data
  2. All Versions of this Article:
    1. db13-0510v1
    2. 62/10/3627 most recent