ArticlesEffect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study
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.
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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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