A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis

S. M. Blackman, S. Hsu, S. E. Ritter, K. M. Naughton, F. A. Wright, M. L. Drumm, M. R. Knowles, G. R. Cutting

Research output: Contribution to journalArticlepeer-review

Abstract

Aims/hypothesis: Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF. Methods: We tested whether a family history of type 2 diabetes affected diabetes risk in CF patients in 539 families in the CF Twin and Sibling family-based study. A type 2 diabetes susceptibility gene (transcription factor 7-like 2, or TCF7L2) was evaluated for association with diabetes in CF using 998 patients from the family-based study and 802 unrelated CF patients in an independent case-control study. Results: Family history of type 2 diabetes increased the risk of diabetes in CF (OR 3.1; p∈=∈0.0009). A variant in TCF7L2 associated with type 2 diabetes (the T allele at rs7903146) was associated with diabetes in CF in the family study (p∈=∈0.004) and in the case-control study (p∈=∈0.02; combined p∈=∈0.0002). In the family-based study, variation in TCF7L2 increased the risk of diabetes about three-fold (HR 1.75 per allele, 95% CI 1.3-2.4; p∈=∈0.0006), and decreased the mean age at diabetes diagnosis by 7 years. In CF patients not treated with systemic glucocorticoids, the effect of TCF7L2 was even greater (HR 2.9 per allele, 95% CI 1.7-4.9, p∈=∈0.00011). Conclusions/ interpretation: A genetic variant conferring risk for type 2 diabetes in the general population is a modifier of risk for diabetes in CF.

Original languageEnglish (US)
Pages (from-to)1858-1865
Number of pages8
JournalDiabetologia
Volume52
Issue number9
DOIs
StatePublished - Sep 2009

Keywords

  • Association
  • CFRD
  • Corticosteroid
  • Cystic fibrosis
  • Diabetes
  • Genetics
  • Glucocorticoid
  • Modifier gene
  • TCF7L2

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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