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(Chest. 2006;130:1441-1447.)
© 2006 American College of Chest Physicians

CFTR Genotype as a Predictor of Prognosis in Cystic Fibrosis*

Edward F. McKone, MD, MS; Christopher H. Goss, MD, MS, FCCP and Moira L. Aitken, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine and Adult Cystic Fibrosis Center, University of Washington, Seattle, WA.

Correspondence to: Edward McKone, MD, University of Washington Medical Center, BB1253 Health Sciences Building, Box 356522, Seattle, WA 98195-6522; e-mail: emckone{at}u.washington.edu

Abstract

Study rationale: Certain CFTR genotypes are associated with reduced mortality. The accuracy of using CFTR genotype as a predictor of survival and the mechanisms through which CFTR genotype influences survival are unknown.

Participants: All patients with cystic fibrosis (CF) enrolled in the US Cystic Fibrosis Foundation national registry between 1993 and 2002.

Design: We examined the prognostic value of CFTR genotype, grouped into "high-risk" and "low-risk" categories based on the effect of their CFTR genotype on phenotype and protein production.

Measurements and results: Clinical and genetic data were available from 15,651 patients with CF. Patients with a high-risk CFTR genotype had a greater than twofold increased risk of death compared to patients with a low-risk CFTR genotype (relative risk, 2.25; 95% confidence interval [CI], 1.77 to 2.84; p < 0.001). This association was partly explained by lung function, nutritional status, pancreatic insufficiency, and Pseudomonas aeruginosa colonization. Of the 1,672 patients who died, median age at death for the high-risk CFTR genotype was 24.2 years (interquartile range, 18.4 to 32.0 years) and for the low-risk CFTR genotype was 37.6 years (interquartile range, 28.8 to 47.9 years; p < 0.001). The positive predictive value of this classification method as a test to identify patients who died before or after their 30th birthday was 69% (95% CI, 67 to 72%) with a negative predictive value of 71% (95% CI, 60 to 80%).

Conclusions: Grouping patients into high-risk and low-risk CFTR genotype categories is associated with significant differences in survival and median age at death. These differences are not fully explained by lung function, nutritional measures, pancreatic insufficiency, or P aeruginosa colonization. Modest reassurance about the likelihood of a milder than average course can be provided for CF patients with a low-risk CFTR genotype, although it should be acknowledged that substantial phenotypic variability exists.

Key Words: epidemiology • genetics • survival






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