Genetic modifiers of cystic fibrosis-related diabetes

Scott Blackman, Clayton W. Commander, Christopher Watson, Kristin 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 2013

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Cystic Fibrosis
Single Nucleotide Polymorphism
Type 2 Diabetes Mellitus
Modifier Genes
Chloride Channels
Genome-Wide Association Study
Bicarbonates
Population
Genes
Proteins

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Blackman, S., Commander, C. W., Watson, C., Arcara, K., Strug, L. J., Stonebraker, J. R., ... Cutting, G. R. (2013). Genetic modifiers of cystic fibrosis-related diabetes. Diabetes, 62(10), 3627-3635. https://doi.org/10.2337/db13-0510

Genetic modifiers of cystic fibrosis-related diabetes. / Blackman, Scott; Commander, Clayton W.; Watson, Christopher; Arcara, Kristin; Strug, Lisa J.; Stonebraker, Jaclyn R.; Wright, Fred A.; Rommens, Johanna M.; Sun, Lei; Pace, Rhonda G.; Norris, Sarah A.; Durie, Peter R.; Drumm, Mitchell L.; Knowles, Michael R.; Cutting, Garry R.

In: Diabetes, Vol. 62, No. 10, 10.2013, p. 3627-3635.

Research output: Contribution to journalArticle

Blackman, S, Commander, CW, Watson, C, Arcara, K, Strug, LJ, Stonebraker, JR, Wright, FA, Rommens, JM, Sun, L, Pace, RG, Norris, SA, Durie, PR, Drumm, ML, Knowles, MR & Cutting, GR 2013, 'Genetic modifiers of cystic fibrosis-related diabetes', Diabetes, vol. 62, no. 10, pp. 3627-3635. https://doi.org/10.2337/db13-0510
Blackman S, Commander CW, Watson C, Arcara K, Strug LJ, Stonebraker JR et al. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes. 2013 Oct;62(10):3627-3635. https://doi.org/10.2337/db13-0510
Blackman, Scott ; Commander, Clayton W. ; Watson, Christopher ; Arcara, Kristin ; Strug, Lisa J. ; Stonebraker, Jaclyn R. ; Wright, Fred A. ; Rommens, Johanna M. ; Sun, Lei ; Pace, Rhonda G. ; Norris, Sarah A. ; Durie, Peter R. ; Drumm, Mitchell L. ; Knowles, Michael R. ; Cutting, Garry R. / Genetic modifiers of cystic fibrosis-related diabetes. In: Diabetes. 2013 ; Vol. 62, No. 10. pp. 3627-3635.
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