Effect of genotype on phenotype and mortality in cystic fibrosis

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Subject: Effect of genotype on phenotype and mortality in cystic fibrosis: a

retrospective cohort study

The Lancet

Volume 361, Issue 9370 , 17 May 2003, Pages 1671-1676

Copyright © 2003 Elsevier Science Ltd. All rights reserved. Articles

Effect of genotype on phenotype and mortality in cystic fibrosis: a

retrospective cohort study

F McKone, , a, S Emersonb, L c and Moira L

Aitkena

a Division of Pulmonary and Critical Care Medicine and Adult Cystic

Fibrosis Center, University of Washington, Seattle, WA, USA

b Department of Biostatistics, University of Washington, Seattle, WA, USA

c Department of Epidemiology, University of Washington, Seattle, WA, USA

Background Over 1000 mutations of the cystic fibrosis transmembrane

conductance regulator gene (CFTR) that cause cystic fibrosis have been

identified. We examined the effect of CFTR genotype on mortality and

disease phenotype.Methods Using the US Cystic Fibrosis Foundation

National Registry, we did a retrospective cohort study to compare

standardised mortality rates for the 11 most common genotypes

heterozygous for F508 with those homozygous for F508. Of the 28455

patients enrolled in the registry at the time of our analysis, 17853

(63%) were genotyped. We also compared the clinical phenotype, including

lung function, age at diagnosis, and nutritional measures, of 22 F508

heterozygous genotypes. Mortality rates and clinical phenotype were also

compared between genotypes classified into six classes on the basis of

their functional effect on CFTR production.Findings Between 1991 and

1999, genetic and clinical data were available for 17853 patients with

cystic fibrosis, which was 63% of the total cohort. There were 1547

deaths during the 9 years of follow-up. In the analysis of the 11 most

common genotypes, F508/R117H, F508/I507, F508/3849+10kbCT, and

F508/2789+5GA had a significantly lower mortality rate (4·7, 8·0, 11·9,

and 4·4, respectively) than the genotype homozygous for F508 (21·8,

P=0·0060). F508/R117H, F508/I507, F508/ 3849+10 kbCT, F508/2789+5GA, and

F508/A455E have a milder clinical phenotype. Outcomes for all functional

classes were compared with that of class II (containing F508 homozygotes)

and classes IV and V had a significantly lower mortality rate and milder

clinical phenotype.Interpretation Patients with cystic fibrosis have

distinct genetic subgroups that are associated with mild clinical

manifestations and low mortality. These differences in phenotype are also

related to the functional classification of CFTR genotype.

Corresponding author. Correspondence to: McKone, University of

Washington Medical Center, BB1253 Health Sciences Building, Box 356522, ,

Seattle, WA 98195-6522, , USA