Genetic Modifiers of Cystic Fibrosis–Related Diabetes
- Scott M. Blackman1,2⇑,
- Clayton W. Commander3,
- Christopher Watson2,
- Kristin M. Arcara1,
- Lisa J. Strug4,5,
- Jaclyn R. Stonebraker3,
- Fred A. Wright3,
- Johanna M. Rommens6,7,
- Lei Sun4,8,
- Rhonda G. Pace3,
- Sarah A. Norris3,
- Peter R. Durie9,10,
- Mitchell L. Drumm11,
- Michael R. Knowles3 and
- Garry R. Cutting2
- 1Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland
- 2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
- 3Cystic Fibrosis–Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- 4Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- 5Program in Child Health Evaluative Sciences, the Hospital for Sick Children, Toronto, Ontario, Canada
- 6Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada
- 7Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- 8Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada
- 9Program in Physiology and Experimental Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada
- 10Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
- 11Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio.
- Corresponding author: Scott M. Blackman, .
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.
See accompanying commentary, p. 3338.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0510/-/DC1.
- Received March 29, 2013.
- Accepted May 5, 2013.
- © 2013 by the American Diabetes Association.
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