Modifier genes in cystic fibrosis lung disease

doi:10.1067/mlc.2003.29

Journal of Laboratory and Clinical Medicine

Volume 141, Issue 4, April 2003, Pages 237-241

https://doi.org/10.1067/mlc.2003.29 Get rights and content

Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by progressive bronchiectatic lung disease and pancreatic exocrine insufficiency. A broad spectrum of disease severity exists; some individuals with CF die early in childhood, whereas others live well into adulthood with only mild lung disease. It is now clear that CFTR genotype alone does not account for the wide diversity in CF pulmonary phenotype. Evidence is accumulating that secondary genetic factors separate from the CFTR locus significantly influence the severity of CF lung disease. The general classes of these potential modifier genes include inflammatory and antiinflammatory mediators, antioxidants, mediators of airway reactivity, molecules involved in CFTR trafficking, and alternative ion channels. The best-studied CF candidate modifiers include mannose-binding lectin, glutathione-S-transferase, transforming growth factor-β1, tumor necrosis factor-α, β2-adrenegic receptor, and HLA class II antigens. Ongoing studies designed to identify genetic modifiers of CF pulmonary phenotype may offer new insights into the pathophysiology of CF lung disease and provide leads for new CF therapeutic interventions. (J Lab Clin Med 2003;141:237-41)

Section snippets

CFTR genotype/phenotype correlation

Many studies in recent years have contributed to the conclusion that although CFTR genotype determines whether an individual will have pancreatic exocrine insufficiency, it does not determine the severity of lung disease. Greater understanding of the effect of CFTR mutations on the gene's expression and function have led the mutations to be grouped into five classes of CFTR dysfunction⁸: Class I mutations result in little or no protein production and typically are mutations causing premature

Environment and genetics: Contributors to CF-phenotype variability

Why the variability in lung-disease severity among CF patients with identical CFTR genotype? Environmental exposure initially seemed an obvious answer. But even though studies have identified environmental factors such as mucoid Pseudomonas aeruginosa,¹¹ Burkholderia cepacia,¹² nutritional support,¹³ tobacco use,¹⁴ and socioeconomic status¹⁵ as influences in pulmonary phenotype, these factors do not come close to accounting for the degree of variability observed in individuals with identical

CF modifier genes

The CFTR-knockout mouse provided the first concrete evidence of a CF-modifier gene. The CF mouse is classically characterized not by lung disease but by intestinal obstruction that develops shortly after birth, usually leading to death. This intestinal obstruction is similar to the meconium ileus present in 20% of CF newborns.³ In 1996, Rozmahel and coworkers determined that variability in a CFTR-independent locus on mouse chromosome 7 determined the severity and lethality of intestinal

Summary/current research directions

Although evidence suggests that genetic modifiers of CF lung disease exist, significantly more work will be required to identify and fully establish specific genes as modifiers. Most of the association studies described have involved relatively small populations and have not focused on comparing allele frequencies in CF cohorts with particularly severe or mild lung disease. Evaluation of possible interactions between candidate modifiers has been limited by study size. Knowles, Drumm, and

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Cited by (64)

Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids
2019, Drug Discovery Today
Citation Excerpt :
This study highlights the clinical potential of rAAV-CFTR-ΔR in the management of patients with all types of CF, with the hope of achieving a cure. An increasing body of evidence suggests that altered non-CFTR genetic factors also contribute to the severity of clinical phenotypes of patients with CF. Several known modifiers of CF include the epithelial sodium channel (ENaC), transforming growth factor-β1 (TGF-β1), mannose-binding lectin (MBL), and β2-adrenergic receptor (reviewed in Ref. [82–84]). Markedly, the modes of action of these CFTR modifiers differ in terms of their underlying mechanisms.
Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.
Influence of SNPs in Genes that Modulate Lung Disease Severity in a Group of Mexican Patients with Cystic Fibrosis
2018, Archives of Medical Research
The variation in cystic fibrosis (CF) lung disease not always is explained by the CFTR genotype, so it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of CF, so we investigated the association of allelic variants in modifier genes that modulate the severity of lung function in a group of Mexican patients diagnosed with CF.
We included 140 CF patients classified according to lung phenotype and analyzed 17 single nucleotide polymorphisms (SNPs) by TaqMan^® allelic discrimination.
We demonstrated that patients with GG or GC genotype of the allelic variant rs11003125 (MBL2-550) of the MBL2 gene exhibit most of the lung manifestations at an earlier age; and the rs1042713 allelic variant of ADRB2 gene, showed statistical difference only with the age of first spirometry. When we used the dominant model, the MBL2 allele rs11003125 (MBL2-550; p = 0.022, Odds Ratio (OR) 2.87, 95% CI 1.14–7.27) was significantly associated with CF patients as risk factor, and the ADRB2 allele rs1042713 (p.Arg16Gly; p = 0.005, Odds Ratio (OR) 0.37, 95% CI 0.19–0.75) was significantly associated with CF patients as protect factor.
Our findings suggest that the MBL2 and ADRB2 genes exerts an important genetic influence on the lung disease in our patients. Taking into account our results, we insist on not leaving aside this type of studies, since having techniques such as GWAS or WES will be able to advance in achieving a better quality of life for CF patients with severe lung disease.
Cystic fibrosis in the era of precision medicine
2018, Paediatric Respiratory Reviews
The treatment of people with cystic fibrosis (CF) has been transformed by the availability of drugs that target the basic chloride defect in the disease. The use of drugs that target specific molecular defects embodies the goals of precision medicine, which incorporate preventive and therapeutic strategies and takes into account differences among individuals. However, the entirety of CF care, from diagnosis to understanding the clinical phenotype and developing a therapeutic strategy, depends on taking into account individual characteristics to achieve optimal outcomes. Future therapies are likely to be even more individualized ushering in a new era of precision medicine.
Selection Through Standing Genetic Variation
2016, Biology and Evolution of the Mexican Cavefish
Cytokine gene polymorphisms and severity of CF lung disease
2014, Journal of Cystic Fibrosis
The search for modifier genes to explain inconsistencies in cystic fibrosis (CF) genotype–phenotype relationships has yielded mixed results. In a previous cross-sectional study from our centre the clinical effect (as described by FEV₁, BMI z-score, admitted days and NIH score) of single nucleotide polymorphisms (SNPs) of four cytokine genes (IL-8, TNF-α, IL-1β and IL-10) was examined in 158 children with CF. No association between cytokine genotype and any biological outcome measure was found. In this present study a cross-sectional and longitudinal examination of this relationship was undertaken to test the hypothesis that pro-inflammatory SNPs would affect longitudinal changes in CF lung disease.
Using the cohort examined in our earlier study we performed both longitudinal and cross-sectional data analyses examining the relationship between SNPs (TNF-α, IL-8, IL-10 and IL-1β) and clinical outcome measurements. In the first part of this current study, lung function data (annual decline of FEV₁ percent predicted) was compared with the cytokine genotype over a 13 year period. In the second part of this current study multiple regression was used to assess associations between clinical outcomes (best FEV₁ percent predicted and BMI at the age of 10 years) and alleles of cytokine genes, adjusting for gender, CF genotype and lung infection status.
A total of 152 patients with CF were analysed in the longitudinal study and data from 130 patients at the age of 10 years were analysed in the cross-sectional study. There was evidence for an association between pro-inflammatory SNPs of the IL-8, IL-10 and IL-1β genes and more severe lung disease. Multiple regression of the longitudinal data with a total of 10,956 lung function measurements showed an additional annual decline of the percentage predicted FEV₁ of − 1.15 (IL-8, p < 0.001), − 0.24 (IL-10, p = 0.049) and − 0.41 (IL-1β, p < 0.001) for patients with any of the pro-inflammatory alleles. None of the cross-sectional data showed a significant association between the cytokine genotypes and the clinical outcomes.
Pro-inflammatory alleles of three cytokine genotypes, IL-8, IL-10 and IL-1β, appear to be associated with slightly more severe lung disease in patients with CF over a 13 year period. Further studies are required to exclude influence of confounders on the severity of lung disease.
Genetic Causes of Bronchiectasis
2012, Clinics in Chest Medicine
Citation Excerpt :
Modifier genes contributing to disease manifestation include inflammatory and antiinflammatory mediators, antioxidants, mediators of airway reactivity, molecules involved in CFTR trafficking, and alternative ion channels.35 The best-studied CF candidate modifiers include mannose-binding lectin 2 (MBL2), glutathione S-transferase, transforming growth factor β1 (TGF-β1), tumor necrosis factor α, β2-adrenergic receptor, and HLA class II antigens.36 The modifier genes MBL2 and TGF-β1 seem to have significant contributory effects on CF lung disease.

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^☆: Reprint requests: Michael P. Boyle, MD, FCCP, Assistant Professor of Medicine, Director, Adult Cystic Fibrosis Program, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Jefferson B1-170, 600 N Wolfe Street, Baltimore, MD 21205; e-mail: [email protected].

^☆☆: 0022-2143/2003 $30.00 + 0

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Review ArticleModifier genes in cystic fibrosis lung disease☆,☆☆

Abstract

Section snippets

CFTR genotype/phenotype correlation

Environment and genetics: Contributors to CF-phenotype variability

CF modifier genes

Summary/current research directions

Med Clin North Am

J Pediatr

Lancet

Lancet

Lancet

J Biol Chem

Mol Immunol

Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

Science

CFTR, a regulator of channels

J Membr Biol

Cystic Fibrosis Foundation, Patient Registry 2000 Annual Report

Bethesda, MD

Identification of the cystic fibrosis gene: genetic analysis

Science

The relation between genotype and phenotype in cystic fibrosis: analysis of the most common mutation (delta F508)

N Engl J Med

The molecular basis for disease variability in cystic fibrosis

Eur J Hum Genet

Type I, II, III, IV, and V cystic fibrosis transmembrane conductance regulator defects and opportunities for therapy

Curr Opin Pulm Med

Genetic determination of exocrine pancreatic function in cystic fibrosis

Am J Hum Genet

Genotype and phenotype in cystic fibrosis

Respiration

Determinants of mortality from cystic fibrosis in Canada, 1970-1989

Am J Epidemiol

Modelling survival in cystic fibrosis

Thorax

Passive smoking and lung function in cystic fibrosis

Am Rev Respir Dis

The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States

Am J Respir Crit Care Med

Categories of deltaF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics

Twin Res

Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings

J Clin Invest

Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor

Nat Genet

Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13

Nat Genet

Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease

J Exp Med

Review Article
Modifier genes in cystic fibrosis lung disease☆,☆☆