Elsevier

The Lancet

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

Articles
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study

https://doi.org/10.1016/S0140-6736(03)13368-5Get rights and content

Summary

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 ΔF508 with those homozygous for ΔF508. Of the 28455 patients enrolled in the registry at the time of our analysis, 17 853 (63%) were genotyped. We also compared the clinical phenotype, including lung function, age at diagnosis, and nutritional measures, of 22 ΔF508 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 17 853 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, ΔF508/R117H, Δ F508/AI507, Δ F508/3849+10 kbC←T, and ΔF508/2789+5G←A had a significantly lower mortality rate (4·7, 8·0, 11·9, and 4·4, respectively) than the genotype homozygous for ΔF508 (21·8, p=0·0060). ΔF508/R117H, ΔF508/AI507, ΔF508/ 3849+10 kbC←T, ΔF508/2789+5G←A, and ΔF508/A455E have a milder clinical phenotype. Outcomes for all functional classes were compared with that of class II (containing δF508 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.

Introduction

Cystic fibrosis is one of the most common lethal genetic conditions.1 It is associated with recurrent respiratory infections, resulting in progressive decline of pulmonary function and premature death.1 Since the gene responsible for cystic fibrosis was identified on the long arm of chromosome 7,2 over 1000 mutant alleles have been identified.3 The most common mutation, δF508, is the deletion of a phenylalanine residue at codon 508 in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This mutation results in a severe reduction in CFTR function, and leads to the classic cystic fibrosis phenotype of raised sweat chloride, recurrent respiratory infection with bronchiectasis, and early-onset pancreatic insufficiency.1

The clinical manifestations of the disease vary greatly between affected individuals, which has led to interest in the relation between genotype and phenotype.4, 5 Patients homozygous for ΔF508 have more severe disease than those heterozygous for ΔF508 and those with two non-ΔF508 alleles.6, 7, 8 Mild features have also been described in some of the more common genotypes heterozygous for ΔF508.9, 10, 11, 12, 13, 14 The differences in CF phenotype could be related to the effect of the cystic fibrosis genotype on CFTR protein production and function.11, 15

Because of the rarity of most mutations of CFTR, studies so far have been small, and have not been able to address whether genotype affects mortality. We used the database of the US Cystic Fibrosis Foundation National Registry to examine the relation between CFTR genotype and phenotype of disease, including mortality.

Section snippets

Patient population

Since 1964, the Cystic Fibrosis Foundation has maintained a database of demographic and clinical data obtained from CF accredited centres throughout the USA. This database contains clinical and genetic data for over 85% of all patients with cystic fibrosis in that country.16, 17, 18, 19 All patients enrolled in this registry from Jan 1, 1991, to Dec 31, 1999, were included in our cohort. These years were chosen because, before 1991, genotyping was not widely available in most centres. Inclusion

Results

Of 28455 patients enrolled in the registry, 17 853 (63%) were genotyped. The total at-risk time was 96 870 person-years in genotyped patients. Of the 1547 deaths in the genotyped cohort, 185 happened after organ transplantation (table 1).

We examined the relation between mortality and CFTR genotype. The mutations termed other, are those that were neither ΔF508 nor the 11 most common non-ΔF508. Table 2 shows crude and standardised mortality rates for the 11 most common genotypes heterozygous for

Discussion

Our main finding was that patients with cystic fibrosis had distinct genetic subgroups, some of which were associated with milder clinical manifestations and reduced mortality than others. Our results also showed that the functional classification of CFTR genotype is associated with differences in phenotype and mortality.

Kerem and colleagues6 examined the effect of genotype on phenotype in patients with cystic fibrosis in Toronto. They showed that patients homozygous for ΔF508 had more severe

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