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Potential genetic modifiers of the cystic fibrosis intestinal inflammatory phenotype on mouse chromosomes 1, 9, and 10
Oxana Norkina, Robert C De Lisle
BMC Genetics , 2005, DOI: 10.1186/1471-2156-6-29
Abstract: CF mice on a mixed genetic background (95% C57Bl/6 and 5% 129Sv) were compared to CF mice congenic on the C57Bl/6 background for several parameters of the intestinal CF phenotype. CF mice on the mixed background exhibit significantly greater survival when fed dry mouse chow, have reduced intestinal inflammation as measured by quantitative RT-PCR for marker genes, have near normal body weight gain, and have reduced mucus accumulation in the intestinal crypts. There was an indication of a gender effect for body weight gain: males did not show a significant improvement at 4 weeks of age, but were of normal weight at 8 weeks, while females showed improvement at both 4 and 8 weeks. By a preliminary genome-wide PCR allele scanning, three regions were found to be potentially associated with the milder phenotype. One on chr.1, defined by marker D1Mit36, one on chr. 9 defined by marker D9Mit90, and one on chr. 10, defined by marker D10Mit14.Potential modifier regions were found that have a positive impact on the inflammatory phenotype of the CF mouse small intestine and animal survival. Identification of polymorphisms in specific genes in these regions should provide important new information about genetic modifiers of the CF intestinal phenotype.Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. Different mutations have a range of effects on the levels of CFTR protein and its proper functioning in epithelial transport of Cl- and HCO3- [2,3]. The severity of the pancreatic phenotype in human CF is well correlated with the extent of impaired CFTR function caused by specific mutations. Loss of CFTR function results in destruction of the exocrine tissue and eventual pancreatic insufficiency. On the other hand, the effects of CF on organs including the airways and intestines is less well correlated with specific CFTR mutations and their effects on CFTR protein function [4-8]. This indicates that other genes are
Genetic Influences on Cystic Fibrosis Lung Disease Severity  [PDF]
Colleen A. Weiler,Mitchell L. Drumm
Frontiers in Pharmacology , 2013, DOI: 10.3389/fphar.2013.00040
Abstract: Understanding the causes of variation in clinical manifestations of disease should allow for design of new or improved therapeutic strategies to treat the disease. If variation is caused by genetic differences between individuals, identifying the genes involved should present therapeutic targets, either in the proteins encoded by those genes or the pathways in which they function. The technology to identify and genotype the millions of variants present in the human genome has evolved rapidly over the past two decades. Originally only a small number of polymorphisms in a small number of subjects could be studied realistically, but speed and scope have increased nearly as dramatically as cost has decreased, making it feasible to determine genotypes of hundreds of thousands of polymorphisms in thousands of subjects. The use of such genetic technology has been applied to cystic fibrosis (CF) to identify genetic variation that alters the outcome of this single gene disorder. Candidate gene strategies to identify these variants, referred to as “modifier genes,” has yielded several genes that act in pathways known to be important in CF and for these the clinical implications are relatively clear. More recently, whole-genome surveys that probe hundreds of thousands of variants have been carried out and have identified genes and chromosomal regions for which a role in CF is not at all clear. Identification of these genes is exciting, as it provides the possibility for new areas of therapeutic development.
Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC  [PDF]
XueLiang Guo, Rhonda G. Pace, Jaclyn R. Stonebraker, Clayton W. Commander, Anthony T. Dang, Mitchell L. Drumm, Ann Harris, Fei Zou, Dallas M. Swallow, Fred A. Wright, Wanda K. O'Neal, Michael R. Knowles
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025452
Abstract: Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2×10?4 after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.
CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity
Carol J Blaisdell, Timothy D Howard, Augustus Stern, Penelope Bamford, Eugene R Bleecker, O Colin Stine
BMC Medical Genetics , 2004, DOI: 10.1186/1471-2350-5-26
Abstract: The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%).PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene.CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity.Although greater than 1000 mutations of the CF gene product, CFTR are known, none of these can be used to make predictions about the occurrence of common complications, the severity, or course of pulmonary disease. The identification of a gene, which modifies the phenotypic expression of CF would be very important for understanding this complex disease. Because CF is a disease of chloride transport in respiratory epithelia, alternative chloride channels present in the airway may be able to partially compensate for the CF defect.CLC-2 is one candidate alternative chloride channel in respiratory epithelia. Localization to the luminal surface of the airway and perinatal downregulation of CLC-2 in mammalian lung suggests a role in lung morphogenesis [1,2]. Persistent expression of CLC-2 mRNA and protein in tissues unaffected in CF suggests that CLC-2 may compensate for defects in CFTR expression [1]. CLC-2 has the capacity to conduct chloride in mature respiratory epithelia [3,4]. The rat CLC-2 promoter has SP-1 domains that are important for gene regulation [5]. A splice variant of CLC-2 skipping exon 20 occurs in rat lung, suggesting that alternative splicing may have functional significance in this tissue [6]. Because investigation of human CLC-2 genomic structure would be important
Shwachman-Kulczycki score still useful to monitor cystic fibrosis severity
Stollar, Fabíola;Adde, Fabíola Villac;Cunha, Maristela T.;Leone, Claudio;Rodrigues, Joaquim C.;
Clinics , 2011, DOI: 10.1590/S1807-59322011000600010
Abstract: introduction: the shwachman-kulczycki score was the first scoring system used in cystic fibrosis to assess disease severity. despite its subjectivity, it is still widely used. objective: to study correlations among forced expiratory volume in one second (fev1), chest radiography, chest computed tomography, 6-minute walk test, and shwachman-kulczycki score in patients with cystic fibrosis and to test whether the shwachman-kulczycki score is still useful in monitoring the severity of the disease. methods: a cross-sectional prospective study was performed to analyze the correlations (spearman). patients with clinically stable cystic fibrosis, aged 3-21 years, were included. results: 43 patients, 19f/24m, mean age 10.5 + 4.7 years, with a median shwachman-kulczycki score of 70 were studied. the median brasfield and bhalla scores were 17 and 10, respectively. the mean z score for the 6-minute walk test was -1.1 + 1.106 and the mean fev1 was 59 + 26 (as percentage of predicted values). the following significant correlations versus the shwachman-kulczycki score were found: fev1 (r = 0.76), 6-minute walk test (r = 0.71), chest radiography (r = 0.71) and chest computed tomography (r = -0.78). when patients were divided according to fev1, a statistically significantly correlation with the shwachman-kulczycki score was found only in patients with fev1 <70% (r = 0.67). conclusions: the shwachman-kulczycki score remains an useful tool for monitoring the severity of cystic fibrosis, adequately reflecting the functional impairment and chest radiography and tomography changes, especially in patients with greater impairment of lung function. when assessing patients with mild lung disease its limitations should be considered and its usefulness in such patients should be evaluated in larger populations.
The ACE gene D/I polymorphism as a modulator of severity of cystic fibrosis
Fernando A L Marson, Carmen S Bertuzzo, Taís D R Hortencio, José D Ribeiro, Luciana C Bonadia, Ant?nio F Ribeiro
BMC Pulmonary Medicine , 2012, DOI: 10.1186/1471-2466-12-41
Abstract: A cross-sectional study was performed, from 2009 to 2011, at University of Campinas – UNICAMP. We analyzed 180 patients for the most frequent mutations in the CFTR gene, presence of the ACE gene D/I polymorphism and clinical characteristics of CF.There was an association of the D/D genotype with early initiation of clinical manifestations (OR: 1.519, CI: 1.074 to 2.146), bacterium Burkholderia cepacia colonization (OR: 3.309, CI: 1.476 to 6.256) and Bhalla score (BS) (p?=?0.015). The association was observed in subgroups of patients which were defined by their CFTR mutation genotype (all patients; subgroup I: no mutation detected; subgroup II: one CFTR allele identified to mutation class I, II or III; subgroup III: both CFTR alleles identified to mutation class I, II and/or III).An association between the D allele in the ACE gene and the severity of CF was found in our study.CFTR gene mutations are crucial in modulating the severity of cystic fibrosis (CF), along with environmental factors and modifier genes [1-7]. CF occurs with heterogeneous clinical presentation. Among the clinical symptoms, that of highest variability is lung disease [5], and modifier genes have been analyzed and associated as possible factors that influence this clinical response [3,7].The ACE gene codifies the Angiotensin Converting Enzyme (ACE). Based on the pro-inflammatory property of the ACE protein [8,9], the ACE gene was selected as a possible genetic marker for clinical denotation in CF. The ACE enzyme catalyzes the conversion of angiotensin I to angiotensin II peptide, acting in the blood pressure control and the electrolyte balance of blood, being an important vasoconstrictor and stimulant of aldosterone [8,10].The ACE gene is located on region 17q23.3 [11]. A biallelic polymorphism, named as I (insertion) and D (deletion), with D allele characterized by a deletion of the 287 pb DNA fragment in intron 16, affects the level of the ACE enzyme. The polymorphism determines the amount of A
Matrix Metalloproteinase-1 Polymorphism (-1607G) and Disease Severity in Non-Cystic Fibrosis Bronchiectasis in Taiwan  [PDF]
Meng-Heng Hsieh, Pai-Chien Chou, Chun-Liang Chou, Shu-Chuan Ho, Wen-Ching Joa, Li-Fei Chen, Te-Fang Sheng, Horng-Chyuan Lin, Tsai-Yu Wang, Po-Jui Chang, Chun-Hua Wang, Han-Pin Kuo
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066265
Abstract: Objectives Bronchiectasis is characterized by an irreversible dilatation of bronchi and is associated with lung fibrosis. MMP-1 polymorphism may alter its transcriptional activity, and differentially modulate bronchial destruction and lung fibrosis. Design To investigate the association of MMP-1 polymorphisms with disease severity in non-cystic fibrosis (CF) bronchiectasis patients, 51 normal subjects and 113 patients with bronchiectasis were studied. The associations between MMP-1 polymorphisms, lung function, and disease severity evaluated by high resolution computed tomography (HRCT) were analyzed. Results The frequency of MMP-1(-1607G) allele was significantly higher in patients with bronchiectasis than normal subjects (70.8% vs 45.1%, p<0.01). Forced expiratory volume in 1 second (FEV1) was decreased in bronchiectasis patients with 1G/1G (1.2±0.1 L, n = 14) and 1G/2G (1.3±0.1 L, n = 66) genotypes compared to the 2G/2G genotype (1.7±0.1 L, n = 33, p<0.01). Six minute walking distance was decreased in bronchiectasis patients with 1G/1G and 1G/2G compared to that of 2G/2G genotype. Disease severity evaluated by HRCT score significantly increased in bronchiectasis patients with 1G/1G and 1G/2G genotypes compared to that of 2G/2G genotype. Bronchiectasis patients with at least one MMP-1 (-1607G) allele showed increased tendency for hospitalization. Serum levels of pro-MMP-1, active MMP-1 and TGF-β1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects. Under IL-1β stimulation, peripheral blood monocytes from subjects with 1G/2G or 1G/1G genotype secreted higher levels of TGF-β1compared to subjects with 2G/2G genotype. Conclusion This is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-CF bronchiectasis patients. Bronchiectasis patients with MMP-1(-1607G) polymorphism may be more vulnerable to permanent lung fibrosis or airway destruction due to the enhanced MMP-1 and TGF-β1 activity. Upregulated MMP-1 activity results in proteolytic destruction of matrix, and leads to subsequent fibrosis.
Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis
Fernando A L Marson, Carmen S Bertuzzo, Ant?nio F Ribeiro, José D Ribeiro
BMC Pulmonary Medicine , 2012, DOI: 10.1186/1471-2466-12-50
Abstract: Cross-sectional study of 122 CF patients subjected to analysis of mutations in the CFTR gene, polymorphisms in ADRB2 gene, along with clinical and laboratorial characteristics of severity.The Arg16Gly polymorphism in ADRB2 gene was associated with pancreatic insufficiency(p:0.009), Bhalla score(p:0.039), forced expiratory volume in the first second[FEV1(%)](p:0.003), forced expiratory flow between 25 and 75% of the forced vital capacity-FVC[FEF25-75(%)](p:0.008) and lower age at the first isolation of the Pseudomonas aeruginosa(p:0.012). The response to the BD spirometry was associated with clinical severity markers, FEV1(%)(p:0.011) and FEF25-75(%)(p:0.019), for the Arg16Gly polymorphism in the ADRB2 gene. The haplotype analysis showed association with the FEV1/FVC marker from the spirometry test, before and after using the BD, with higher values in the group with Gly/Gly and Glu/Glu, respectively, for the Arg16Gly and Gln27Glu polymorphisms. The analysis by MDR2.0 software, showed association with FEF25-75%; the response to Arg16Gly was respondent by 17.35% and Gln27Glu by 6.8% in variation found.There was an association between the Arg16Gly and Gln27Glu polymorphisms in ADRB2 gene with CF′s severity and bronchodilator response.Studies have confirmed the mechanisms though which cystic fibrosis (CF) patients with similar mutations show significantly different signs and symptoms [1-4]. Even among homozygous for classes I, II and/or III mutations, the disease's clinical expression may be very different. Explanations for these broad clinical variations included environmental factors [5], medical management [3], nutrient intake [6], psychological [7], economic situations [3], and classes of mutations and polymorphisms in modifier genes [2-4].Unlike most patients with asthma, the inflammation in CF is predominantly neutrophilic [8], with an intense inflammatory component and lower rate of bronchial hyper responsiveness [9]. In contrast, inhaled bronchodilator (BD) has b
Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis  [PDF]
Mary J. Emond?,Tin Louie?,Julia Emerson?,Jessica X. Chong?,Rasika A. Mathias?,Michael R. Knowles?,Mark J. Rieder?,Holly K. Tabor?,Debbie A. Nickerson?,Kathleen C. Barnes
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005273
Abstract: Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.
AGER -429T/C Is Associated with an Increased Lung Disease Severity in Cystic Fibrosis  [PDF]
Julie Beucher,Pierre-Yves Bo?lle,Pierre-Fran?ois Busson,Céline Muselet-Charlier,Annick Clement,Harriet Corvol
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041913
Abstract: The clinical course of cystic fibrosis (CF) varies between patients bearing identical CFTR mutations, suggesting the involvement of modifier genes. We assessed the association of lung disease severity with the variant AGER -429 T/C, coding for RAGE, a pro-inflammatory protein, in CF patients from the French CF Gene Modifier Study. We analyzed the lung function of 967 CF patients p.Phe508del homozygous. FEV1 was analyzed as CF-specific percentile adjusted on age, height and mortality. AGER -429T/C polymorphism was genotyped and its function was evaluated in vitro by measurement of the luciferase activity. AGER -429 minor allele (C) was associated with poorer lung function (p = 0.03). In vitro, the promoter activity was higher in cells transfected with AGER -429C compared to cells transfected with the AGER -429T allele (p = 0.016 in BEAS-2B cells). AGER seems to be a modifier gene of lung disease severity in CF, and could be an interesting biomarker of CF airway inflammation. The functional promoter AGER -429C variant is associated with an increased RAGE expression that can lead to an increased lung inflammation and a more severe lung disease.
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