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Genetic Modifiers Play a Substantial Role in Diabetes Complicating Cystic Fibrosis

Division of Pediatric Endocrinology (S.M.B., S.H.) and McKusick-Nathans Institute of Genetic Medicine (S.M.B., J.M.C., S.E.R., K.N., G.R.C.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pediatrics (L.L.V.), National Naval Medical Center, Bethesda, Maryland 20889-5600; and Pediatric Respiratory Sciences (J.M.C.), Johns Hopkins University, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Garry R. Cutting, M.D., McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Broadway Research Building 559, Baltimore, Maryland 21205. E-mail: gcutting{at}jhmi.edu.

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 = 15.8 yr) 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.