Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients

Abstract

G Ge en no ot ty yp pe e--p ph he en no ot ty yp pe e r re el la at ti io on ns sh hi ip ps s i in n a a c co oh ho or rt t One hundred and ten adult CF patients were classified according to the expected effect of their mutations on cystic fibrosis transmembrane conductance regulator (CFTR) protein: Group 1 (n=48) included ∆F508 homozygotes; Group 2 (n=26), patients with two " "severe" " mutations and no expected CFTR production; Group 3 (n=17), patients with expected partly functional CFTR corresponding to at least one " "mild" " mutation; Group 4 (n=19), patients with no mutation identified or only one identified " "severe" " mutation.As compared to Groups 1 and 2: patients from Groups 3 and 4 had higher arterial oxygen tension (Pa,O 2 ) (9.5±1.9 and 9.9±1.5 vs 8.8±1.5 and 8.3±1.7 kPa, respectively p<0.02); and a slower decline in their pulmonary function, estimated by the mean annual loss in forced vital capacity (FVC) (1.2±1.0 and 1.5±1.1 vs 2.0±0.9 and 2.2±1.0%, respectively; p<0.01) and in forced expiratory volume in one second (FEV1) (1.7±1.1 and 1.9±1.3 vs 2.6±1.0 and 2.8±1.0%, respectively; p<0.005). They had fewer episodes of colonization of the airways by Pseudomonas aeruginosa, and colonization occurred at a more advanced age (median age 25 and 19 vs 15 and 17 yrs, respectively; p<0.01) and required fewer intravenous antibiotic courses (p<0.01). Pancreatic insufficiency was less frequent in Groups 3 (23%) and 4 (63%) than in Groups 1 (100%) and 2 (96%).This study suggests that the phenotype of adult cystic fibrosis patients, including the severity of the lung disease, is related to the severity of the cystic fibrosis transmembrane conductance regulator mutations.

Rhinosinusitis in cystic fibrosis: Not a simple story

“…The tests were performed in the Institute for Mother and Child in Warsaw. The sample was divided into four groups according to the genotype effect on the chloride canal function [18]. The patients with homozygote DF508, where production of protein CFTR was deficient, were counted among group 1.…”

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

“…Modifier genes may play a significant role in determining the severity of CF. Furthermore, for a single mutation such as F508del, the pulmonary status may range from insignificant to severe [19, 20]. It is therefore obvious that, whereas classic genotype-phenotype studies in CF are important, they are not sufficient and have to be complemented by the search for environmental effects on the phenotype of patients, to increase the basic knowledge of the disease and to develop new therapeutic approaches.…”

Genotype and Phenotype in Cystic Fibrosis

“…Studies focusing on the pulmonary status as a function of the ΔF508 allele dosage reported a whole range of effects from detectable impact of CFTR genotype [37, 39]to none or statistically insignificant [38, 40, 41, 44, 51]. Of the studies using more refined assessment of CFTR mutations, such as those classifying their molecular mechanisms, or extent of the CFTR chloride channel function, some have shown statistically significant correlations between CFTR genotypes and pulmonary status [42, 49, 50]while others have failed to detect a significant association [43, 47]. Some of these discrepancies can be ascribed to differences in experimental design, the size and demographics of the study populations, selection of clinical parameters, the prevalence of ΔF508 and the spectrum of other CFTR mutations in the study populations, methods of statistical evaluation and a variety of factors associated with treatment modalities adopted in a given center.…”

“…Initially, cross-sectional studies focused on the impact of the most common mutation ΔF508. Later, with improvement in mutation screening techniques, studies were extended to evaluate the effects of other mutations [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50]. Studies focusing on the pulmonary status as a function of the ΔF508 allele dosage reported a whole range of effects from detectable impact of CFTR genotype [37, 39]to none or statistically insignificant [38, 40, 41, 44, 51].…”