Genetic modifiers play a substantial role in diabetes complicating cystic fibrosis

Scott Blackman, Stephanie Hsu, Lori Vanscoy, Michael Collaco, Sarah E. Ritter, Kathleen Naughton, Garry R Cutting

Research output: Contribution to journalArticle

Abstract

Context: Insulin-requiring diabetes affects 7-15% of teens and young adults, and more than 25% of older adults with cystic fibrosis (CF). Pancreatic exocrine disease caused by CF transmembrane conductance regulator (CFTR) dysfunction underlies the high rate of diabetes in CF patients; however, only a subset develops this complication, indicating that other factors are necessary. Objective: Our objective was to estimate the relative contribution of genetic and nongenetic modifiers to the development of diabetes in CF. Design/Patients: This was a twin and sibling study involving 1366 individuals at 109 centers in the CF Twin and Sibling Study, from which were derived 68 monozygous twin pairs, 23 dizygous twin pairs, and 588 sibling pairs, all with CF. Main Outcome Measure: Chronic, insulin-requiring diabetes in the setting of CF, as established using longitudinal clinical and biochemical data, was studied. Results: About 9% of this predominantly pediatric population (mean age = 15.8yr) had diabetes. Key independent risk factors identified by regression modeling included having a twin or sibling with CF and diabetes, increasing age, pancreatic exocrine insufficiency or two mutations causing severe CFTR dysfunction, decreased lung function or decreased body mass index, and longer duration of glucocorticoid treatment. The concordance rate for diabetes was substantially higher in monozygous twins (0.73) than in dizygous twins and siblings with CF (0.18; P = 0.002). Heritability was estimated as near one (95% confidence interval 0.42-1.0). Conclusions: Diabetes is a frequent complication of CF that is associated with worse outcomes. Although a nongenetic factor (steroid treatment) contributes to risk, genetic modifiers (i.e. genes other than CFTR) are the primary cause of diabetes in CF.

Original languageEnglish (US)
Pages (from-to)1302-1309
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume94
Issue number4
DOIs
StatePublished - Apr 2009

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Medical problems
Cystic Fibrosis
Siblings
Twin Studies
Insulin
Modifier Genes
Cystic Fibrosis Transmembrane Conductance Regulator
Pediatrics
Exocrine Pancreatic Insufficiency
Pancreatic Diseases
Glucocorticoids
Young Adult
Steroids
Body Mass Index
Outcome Assessment (Health Care)
Confidence Intervals
Lung
Mutation
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Genetic modifiers play a substantial role in diabetes complicating cystic fibrosis. / Blackman, Scott; Hsu, Stephanie; Vanscoy, Lori; Collaco, Michael; Ritter, Sarah E.; Naughton, Kathleen; Cutting, Garry R.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 4, 04.2009, p. 1302-1309.

Research output: Contribution to journalArticle

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