Chest
Volume 130, Issue 5, November 2006, Pages 1441-1447
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Original Research
CFTR Genotype as a Predictor of Prognosis in Cystic Fibrosis

https://doi.org/10.1378/chest.130.5.1441Get rights and content

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.

Section snippets

Materials and Methods

The study design is a retrospective cohort study using the Cystic Fibrosis Foundation patient registry,16, 17 measuring risk of death during an observation period from 1993 to 2002. The primary outcome of interest was all-cause mortality including patients who died after transplantation. Secondary outcome was all-cause mortality (excluding transplant-related deaths). All procedures were approved by the University of Washington Institutional Review Board.

Genotypes were classified into high-risk

Results

The patient population is outlined in Figure 1. There were a total of 30,396 patients included in the database, with 193,856 person-years at risk; 21,353 patients (70%) were genotyped. Of the genotyped patients, 15,651 patients had a CFTR genotype containing mutations with a known functional class. Of these, 14,525 patients (93%) had a high-risk CFTR genotype and 1,126 patients (7%) had a low-risk CFTR genotype. Median follow-up was 8.6 years for patients with a high-risk CFTR genotype vs 5.1

Discussion

The main findings of this study are that patients with CF can be classified into high-risk and low-risk genetic groups that have significant differences in survival and median age at death. These differences in survival are not fully explained by clinical measures of lung function, nutrition, and pancreatic insufficiency, suggesting that the CFTR genotype is an independent predictor of survival. In addition, using the CFTR genotype for risk stratification in CF may have some prognostic value,

ACKNOWLEDGMENT

We thank Bruce Marshall, Monica Brooks, Preston W. Campbell III, MD, and the Clinical Research Committee of the Cystic Fibrosis Foundation for access to the database. We also thank Wylie Burke MD, PhD, for her assistance in the preparation of this article.

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    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

    The authors have no conflicts of interest to disclose.

    Dr. McKone is supported by the Cystic Fibrosis Foundation and National Institutes of Health grant K23 HL/70849-01.

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