The Influence of Genetics on Cystic Fibrosis Phenotypes

Cystic Fibrosis-Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514.
Cold Spring Harbor Perspectives in Medicine (Impact Factor: 9.47). 12/2012; 2(12). DOI: 10.1101/cshperspect.a009548
Source: PubMed


Technological advances in genetics have made feasible and affordable large studies to identify genetic variants that cause or modify a trait. Genetic studies have been carried out to assess variants in candidate genes, as well as polymorphisms throughout the genome, for their associations with heritable clinical outcomes of cystic fibrosis (CF), such as lung disease, meconium ileus, and CF-related diabetes. The candidate gene approach has identified some predicted relationships, while genome-wide surveys have identified several genes that would not have been obvious disease-modifying candidates, such as a methionine sulfoxide transferase gene that influences intestinal obstruction, or a region on chromosome 11 proximate to genes encoding a transcription factor and an apoptosis controller that associates with lung function. These unforeseen associations thus provide novel insight into disease pathophysiology, as well as suggesting new therapeutic strategies for CF.

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    • "Cystic fibrosis (CF) (MIM: number 219700) is an autosomal disorder with high clinical variability that is associated with CFTR mutations, environmental effects, and modifier genes [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]. Since 1989 [13] [14] [15], the discovery of the CFTR (cystic fibrosis transmembrane regulator; 7q31.2 region) gene and medical advances in CF knowledge have shown that CF is a disease with complex clinical presentation [1] [2] [3]. Since 1959, CF diagnosis has been obtained using the Gibson and Cooke test, that is, the sweat test [16]. "
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    ABSTRACT: The gold standard for diagnosing cystic fibrosis (CF) is a sweat chloride value above 60 mEq/L. However, this historical and important tool has limitations; other techniques should be studied, including the nasal potential difference (NPD) test. CFTR gene sequencing can identify CFTR mutations, but this method is time-consuming and too expensive to be used in all CF centers. The present study compared CF patients with two classes I-III CFTR mutations (10 patients) (G1), CF patients with classes IV-VI CFTR mutations (five patients) (G2), and 21 healthy subjects (G3). The CF patients and healthy subjects also underwent the NPD test. A statistical analysis was performed using the Mann-Whitney, Kruskal-Wallis, χ 2, and Fisher’s exact tests, α = 0.05 . No differences were observed between the CF patients and healthy controls for the PDMax, Δamiloride, and Δchloride + free + amiloride markers from the NPD test. For the finger value, a difference between G2 and G3 was described. The Wilschanski index values were different between G1 and G3. In conclusion, our data showed that NPD is useful for CF diagnosis when classes I-III CFTR mutations are screened. However, if classes IV-VI are considered, the NPD test showed an overlap in values with healthy subjects.
    Full-text · Article · Jan 2015 · Disease markers
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    • "Two different approaches have been used to identify modifiers in CF, ie, case-control association studies on the one hand and family-based linkage studies on the other. As both methods have their advantages and disadvantages, eg, higher robustness regarding detection of common genetic variants (case-control association studies) or better differentiation between environmental versus genetic effects (family-based studies), complementary studies employing both methodologies are highly recommended.44 Moreover, any association between a chromosomal region, a specific gene locus, or a single gene variant should, if ever possible, be replicated in one or more separate patient and control cohorts,10 although differences in ethnic background, treatment procedures, environmental factors, and socioeconomic influences may weaken or even hide any significant findings. "
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    ABSTRACT: The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.
    Full-text · Article · Jul 2014 · The Application of Clinical Genetics
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    • "Further modifier loci (e.g. beta-defensins) have been reported and seem to be equally important in penetrance of MI and in lung function as disease defining gene mutations [5,9]. "
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    ABSTRACT: In term newborns meconium ileus is frequently associated with cystic fibrosis. Reports on meconium ileus in preterm infants being diagnosed with cystic fibrosis early after birth are very scarce. Associations between genotype and phenotype in cystic fibrosis and its particular comorbidities have been reported. Two extremely preterm twin infants (26 weeks of gestation) born from a Malaysian mother and a Caucasian father were presented with typical signs of meconium ileus. Despite immediate surgery both displayed a unique and finally lethal course. Mutation analysis revealed a novel, probably pathogenic cystic fibrosis mutation, p.Cys524Tyr. The novel mutation might explain the severity of disease next to typical sequelae of prematurity. Preterm neonates with meconium ileus have to be evaluated for cystic fibrosis beyond ethnical boundaries, but may take devastating clinical courses despite early treatment. The novel, potentially pathogenic CF mutation p.Cys524Tyr might be associated with severe meconium ileus in neonates. Disease-modifying loci are important targets for intestinal comorbidity of cystic fibrosis.
    Full-text · Article · Jan 2014 · BMC Pediatrics
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