Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis

doi:10.1016/0140-6736(90)92566-Z

The Lancet

Volume 336, Issue 8723, 3 November 1990, Pages 1081-1084

https://doi.org/10.1016/0140-6736(90)92566-Z Get rights and content

Abstract

The concordance of pancreatic and pulmonary status among siblings with cystic fibrosis, the cystic fibrosis genotype, and non-genetic factors were analysed in adult patients with cystic fibrosis. Genetic factors were more important than non-genetic factors in affecting the severity of pancreatic and lung disease. The genetic factors were independent of each other and did not invariably cosegregate with specific mutations at the cystic fibrosis locus.

References (20)

H. Shwachman
Gastrointestinal manifestations of cystic fibrosis
Pediatr Clin North Am
(1975)
M. Corey et al.
Familial concordance of pancreatic function in cystic fibrosis
J Pediatr
(1989)
M. Devoto et al.
Haplotypes in cystic fibrosis patients with or without pancreatic sufficiency from four European populations
Genomics
(1989)
M. Dean et al.
Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients
Cell
(1990)
M. Stuhrmann et al.
Genotype analysis of cystic fibrosis patients in relation to pancreatic sufficiency
Lancet
(1990)
H. Kopelman et al.
Genetic analysis and pancreatic function in cystic fibrosis
Lancet
(1990)
G. Santis et al.
Linked marker haplotypes and the ΔF₅₀₈ mutation in adults with mild pulmonary disease and cystic fibrosis
Lancet
(1990)
K. Gaskin et al.
Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption
J Pediatr
(1982)
E. Kerem et al.
Pulmonary function and clinical course in patients with cystic fibrosis after pulmonary colonisation with Pseudomonas aeruginosa.
J Pediatr
(1990)

There are more references available in the full text version of this article.

Cited by (119)

Real-world use of ivacaftor in Canada: A retrospective analysis using the Canadian Cystic Fibrosis Registry
2021, Journal of Cystic Fibrosis
: Ivacaftor is a CFTR potentiator with demonstrated efficacy in clinical trials and has been rapidly adopted within the CF community. Given the uptake of ivacaftor in eligible people, identifying a comparator group not on modulators to measure effectiveness is difficult. We evaluated health outcomes in individuals with G551D and non-G551D genotypes on ivacaftor using real-world longitudinal data.
: This population-based observational study compared clinical trajectories pre-post ivacaftor using the Canadian CF Registry from 2006 to 01–01 through 2018–12–31. Piece-wise linear mixed-effects models were used to compare lung function, nutritional status, pulmonary exacerbations, and Pseudomonas colonization pre- and post-ivacaftor. Multivariable models were used to adjust for confounding factors.
: Forced expiratory volume in 1 second (FEV1) increased significantly by 5.7 percent predicted (95% confidence interval (CI) 3.9, 7.5; p<0.001) after initiation of ivacaftor. FEV1 decline rate was attenuated to -0.30% (95% CI -0.9, 0.29; p = 0.32) predicted/year post-ivacaftor, compared with -0.75% (95% CI -1.12, -0.37; p<0.001) predicted/year pre-ivacaftor, although this difference did not reach statistical significance. BMI percentiles also increased post-ivacaftor (6.57 percentiles, 95% CI 3.91, 9.24; p<0.001). Pulmonary exacerbations showed a nonsignificant reduction of 18% (RR 0.82, 95% CI 0.61, 1.11; p = 0.19) and the odds of a positive sputum culture for Pseudomonas aeruginosa decreased in the post-ivacaftor period (odds ratio 0.44, 95% CI 0.30, 0.63; p<0.001).
: This real-world, observational study demonstrated improvement in health outcomes in a broad population of people with CF. Additional studies are needed to evaluate the impact of ivacaftor on quality of life and survival.
Cystic fibrosis - Comparison between patients in paediatric and adult age
2017, Revista Portuguesa de Pneumologia (English Edition)
Citation Excerpt :
It is recognized that homozygosity for delF508 mutation is associated with a high systemic repercussion of CF, a high level of pancreatic insufficiency and a low BMI. On the other hand, the greater heterogeneity in mutations of patients with a late diagnosis found in this study could be responsible for the greater variance in conditions leading to diagnosis and the overall better indexes of health in this group; it is a fact that patients diagnosed in adulthood had fewer hospitalizations and experience fewer complications than those diagnosed early in life and most of them were pancreatic sufficient, which is closely related to the type of CFTR mutation associated.27,28 In the study, as is common in the literature, most of those diagnosed early in life present with a combination of gastrointestinal and pulmonary symptoms, while in the late diagnosis group of patients most were diagnosed due to recurrent pulmonary infections and gastrointestinal symptoms were less frequent.25
Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians. Although most cases are diagnosed in childhood, diagnosis in adults is apparently increasing.
Evaluate the adult population with CF, comparing patients who were diagnosed before and after 18 years of age.
Retrospective analysis of patients followed in three main medical centres in Portugal in 2012. Comparison of two groups: G1 – patients diagnosed at <18 years and G2 – patients diagnosed at ≥18 years.
89 adults were identified: 61.8% in G1, 38.2% in G2. Gender distribution was similar in both groups. Average age in G2 was higher (38.3 ± 8.4 vs. 26.8 ± 6.1 years, p < 0.001). Respiratory symptoms most frequently led to CF diagnosis in all patients, mainly in adulthood. There was a greater percentage of patients homozygous for the mutation delF508 in G1 (43.6 vs. 8.8%, p = 0.02). Respiratory and pancreatic function, and body mass index (BMI) showed a higher severity in G1 (G1 vs. G2: FEV1: 54.6 ± 27.3 vs. 29.9 ± 64.6%, p = 0.177; pancreatic insufficiency 72.7 vs. 26.5%, p < 0.001; BMI 20.2 ± 3.4 vs. 22.2 ± 4.8, p = 0.018). Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus were the most frequently isolated microorganisms. Lung transplantation rate was higher in G2 (20.6 vs. 10.9%, p = 0.231) while mortality rate was higher in G1 (0 vs. 3.6%, p = 0.261). Hospital admission rate was higher in G1 as well as mortality rate.
The results suggest that patients with CF diagnosed in childhood have characteristics that distinguish them from those diagnosed in adulthood, and these differences may have implications for diagnosis, prognosis and life expectancy.
Cystic Fibrosis
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice
2008, Journal of Cystic Fibrosis
It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings.
Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders.
Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended.
The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.
CFTR genotype as a predictor of prognosis in cystic fibrosis
2006, Chest
Citation Excerpt :
In addition, a small number of individual CFTR genotypes have been described that are associated with milder phenotype.6,89,1011,1418,19 The main differences in phenotype appear to be related to the influence of CFTR genotype on pancreatic function, with ΔF508 homozygotes usually pancreatic insufficient at an earlier age and having worse nutritional measures and lung function.3,4,5 The reason for these phenotypic differences is likely to be due to the effect of CFTR mutation on protein production, with very low levels of CFTR associated with a severe phenotype and intermediate levels associated with milder CF.8,1121,22 We found that grouping CFTR alleles according to the functional classification system proposed by Tsui12 and Welsh and Smith13 is associated with differences in mortality rates.14
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.
All patients with cystic fibrosis (CF) enrolled in the US Cystic Fibrosis Foundation national registry between 1993 and 2002.
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.
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%).
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.
ERCP findings in idiopathic pancreatitis: Patients who are cystic fibrosis gene positive and negative
2006, Gastrointestinal Endoscopy
Citation Excerpt :
Compared with controls, cases had higher incidence of CP (62% vs. 48%, p = 0.05), grade III CP (35% vs. 18%, p = 0.004), pseudocysts (12% vs. 4%, p = 0.036), and pancreatic strictures (20% vs. 8%, p = 0.008). Studies that compared the genotypes and phenotypes of CF patients suggest a relationship between specific gene mutations and the extent of pancreatic disease.25-28 In this study, 12 different mutations were detected in the 69 patients, and 5 patients were found to have a compound heterozygous mutation.
Our series of patients with idiopathic pancreatitis (IP) found a cystic fibrosis (CF) gene abnormality in 19% compared with 3.5% in patients without pancreatitis.
The objective was to determine whether the CF gene predicts more severe ERP findings.
This was a retrospective case-control study.
From July 1998 to August 2004, CF gene analysis was performed in 819 patients with IP via Genzyme Genetics. The panel tests for 70 to 87 alleles and has a detection rate of more than 90% of the cases. Sixty-nine patients (8.4%) who had at least one CF gene positive mutation were the study cohort. A total of 218 patients with IP and negative CF gene mutation were randomly selected from our database to be in the control group.
Pancreatograms were evaluated for chronic pancreatitis (CP) based on Cambridge criteria. The results of the gene analysis were not available at the time of pancreatogram interpretation.
Among patients positive for the CF gene, 42 (61%) were women. The mean age at intervention was 40 years (range 14-80 years), and 48 patients (70%) had cholecystectomy. Among patients who were negative for the CF gene, 147 (67%) were women. The mean age at intervention was 41 years (range 9-89 years), and 125 patients (57%) had cholecystectomy. Compared with controls, cases had higher incidence of CP (62% vs. 48%, p = 0.05), grade III CP (35% vs. 18%, p = 0.004), pseudocysts (12% vs. 4%, p = 0.036) and pancreatic strictures (20% vs. 8%, p = 0.008).
The limitations of the study were (1) retrospective design and (2) the panel used tests only for 70 to 87 alleles (of approximately, 900 CF transmembrane conductance regulator genes known).
The mean age at intervention in both groups was similar. CP, grade III CP, pseudocysts, and pancreatic strictures were more common among patients who were CF gene positive.

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MEDICAL SCIENCEIndependent genetic determinants of pancreatic and pulmonary status in cystic fibrosis

Abstract

Pediatr Clin North Am

J Pediatr

Genomics

Cell

Lancet

Lancet

Lancet

J Pediatr

J Pediatr

MEDICAL SCIENCE
Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis