Genetic modifiers of cystic fibrosis-related diabetes

Scott M. Blackman, Clayton W. Commander, Christopher Watson, Kristin M. Arcara, Lisa J. Strug, Jaclyn R. Stonebraker, Fred A. Wright, Johanna M. Rommens, Lei Sun, Rhonda G. Pace, Sarah A. Norris, Peter R. Durie, Mitchell L. Drumm, Michael R. Knowles, Garry R. Cutting

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3627-3635
Number of pages9
JournalDiabetes
Volume62
Issue number10
DOIs
StatePublished - Oct 1 2013

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Blackman, S. M., Commander, C. W., Watson, C., Arcara, K. M., Strug, L. J., Stonebraker, J. R., Wright, F. A., Rommens, J. M., Sun, L., Pace, R. G., Norris, S. A., Durie, P. R., Drumm, M. L., Knowles, M. R., & Cutting, G. R. (2013). Genetic modifiers of cystic fibrosis-related diabetes. Diabetes, 62(10), 3627-3635. https://doi.org/10.2337/db13-0510