ABSTRACT
The clinical course of cystic fibrosis (CF) varies considerably among patients carrying the same CF-causing gene mutation. Additional genetic modifiers may contribute to this variability. As airway inflammation is a key component of CF pathophysiology, we investigated whether major cytokine variants represent such modifiers in young CF patients. We tested 13 polymorphisms in 8 genes that play a key role in the inflammatory response: tumor necrosis factor, lymphotoxin alpha, interleukin (IL) 1B, IL1 receptor antagonist, IL6, IL8, IL10 and transforming growth factor beta 1 (TGFB1), for an association with lung disease progression and nutritional status in 329 CF patients. Variants in the TGFB1 gene at position +869T/C demonstrated a significant association with lung function decline. A less pronounced rate of decline in forced expiratory volume in 1 sec (FEV(1)) and forced vital capacity (FVC) were observed in patients heterozygous for TGFB1 +869 (+869CT), when compared to patients carrying either TGFB1 +869TT or +869CC genotypes. These findings support the concept that TGFB1 gene variants appear to be important genetic modifiers of lung disease progression in CF.
Subject(s)
Cystic Fibrosis/genetics , Inflammation Mediators/metabolism , Adolescent , Child , Disease Progression , Female , Genetic Variation , Humans , Interleukin-1/genetics , Interleukin-10/genetics , Interleukin-6/genetics , Interleukin-8/genetics , Lymphotoxin-alpha/genetics , Male , Transforming Growth Factor beta1/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
It is well accepted that control of airway inflammation is crucial for overall asthma control. Hence, efficient anti-inflammatory therapy is important for disease control. Therefore, we studied the effect of a treatment with montelukast on subjective and objective measures in preschool asthmatic children with insufficient control of airway inflammation, illustrated by increased fractional exhaled nitric oxide (FeNO). Thirty-one preschool children (2.5-5 years) were included in this study. Children with FeNO > or = 10 ppb at the first visit received montelukast 4 mg as a first line therapy or an add-on therapy to their baseline treatment (group 1). Therapy was not changed at first visit in children with FeNO < 10 ppb (group 2). Symptom scores, FeNO, lung function (forced oscillation, Rrs8Hz) and airway responsiveness to adenosine 5'-monophosphate (AMP) were assessed at visits 1 and 2 eight weeks apart. There was a significant decrease in FeNO (median [interquartile range]; 12.9 [3.7] vs. 7.6 [6.85] ppb, P = 0.011), Rrs8Hz (mean +/- SD; 10.03 +/- 3.1 vs. 8.72 +/- 2.43 hPa.s/L; P = 0.047) and symptom scores (2[2] vs. 1.5[2], P = 0.034) and a significant increase in the provocative AMP dose (2.65 +/- 2.1 vs. 4.54 +/- 1.05; P = 0.015) in group 1 but not in group 2. First line or add-on treatment of oral montelukast in preschool children with mild to moderate asthma and elevated FeNO, decreased levels of FeNO, improved airway responsiveness to AMP, lung function and symptom scores.
Subject(s)
Acetates/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Asthma/physiopathology , Leukotriene Antagonists/therapeutic use , Nitric Oxide/metabolism , Quinolines/therapeutic use , Adenosine Monophosphate/metabolism , Asthma/metabolism , Child, Preschool , Cyclopropanes , Exhalation , Female , Forced Expiratory Volume , Humans , Infant , Male , Prospective Studies , Respiratory Function Tests , Severity of Illness Index , Spirometry , Sulfides , Treatment Outcome , Vital CapacityABSTRACT
Recent evidence suggests that genetic polymorphisms that affect the production of interleukin (IL)-10 may play a role in the response to pathogens in cystic fibrosis (CF). The present study was designed to investigate a possible association between alleles carried at position -1082 in the promoter region of the IL-10 gene and clinical data on 378 patients with CF. After adjustment for potential confounding variables, a significant relationship was found between the -1082GG genotype and both colonization with Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. In addition, higher serum levels of IL-10 were observed in patients colonized with A. fumigatus. These results suggest that polymorphisms in the promoter region of the IL-10 gene may influence the host response to A. fumigatus in the context of CF.
Subject(s)
Aspergillosis/immunology , Aspergillus fumigatus , Cystic Fibrosis/immunology , Interleukin-10/genetics , Lung Diseases, Fungal/immunology , Polymorphism, Genetic/immunology , Adolescent , Child , Child, Preschool , Cystic Fibrosis/genetics , Cystic Fibrosis/microbiology , HumansABSTRACT
Variants in the genes encoding for the nitric oxide synthases may act as disease modifier loci in cystic fibrosis, affecting both an individual's nitric oxide level and pulmonary function. In this study, the 894G/T variant in exon 7 of the endothelial nitric oxide synthase gene was related to exhaled nitric oxide and pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.9 years (mean +/- SD), with a FEV1 of 69.4 +/- 24.8% predicted. Although there was no association between endothelial nitric oxide synthase genotypes and exhaled nitric oxide in males, nitric oxide levels were significantly higher in female cystic fibrosis patients with an 894T mutant allele, compared with female patients homozygous for the 894G wild-type allele (7.0 +/- 4.4 versus 3.6 +/- 1.9 parts per billion, p = 0.02). Furthermore, in female patients, colonization of airways with Pseudomonas aeruginosa was significantly (p < 0.05) less frequent when carrying an 894T mutant allele as compared with wild type. These data suggest that the 894T variant in the endothelial nitric oxide synthase gene is associated with increased airway nitric oxide formation in female cystic fibrosis patients, possibly affecting colonization of airways with P. aeruginosa.
Subject(s)
Cystic Fibrosis/enzymology , Cystic Fibrosis/microbiology , Nitric Oxide Synthase/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , Mutation , Nitric Oxide Synthase Type III , Pseudomonas aeruginosa/isolation & purification , Sex FactorsABSTRACT
The cystic fibrosis membrane conductance regulator can be activated through beta2-adrenoceptor (beta2AR) stimulation. We tested the hypothesis that coding sequence polymorphisms in the beta2AR gene contribute to the disease state in patients with cystic fibrosis. The Arg16Gly, Gln27Glu, and Thr164Ile beta2AR polymorphisms were studied by specific polymerase chain reaction and restriction fragment length polymorphism analysis in 126 cystic fibrosis patients. Forced expiratory volume in 1 s was significantly (P < 0.05) reduced in cystic fibrosis patients carrying the Gly16 allele in either homozygous or heterozygous form (Gly16Gly + Arg16Gly) compared to patients homozygous for the Arg16 allele (60.3 +/- 3.5% versus 75.7 +/- 4.9% predicted). Similarly, forced vital capacity and flows at lower lung volumes were significantly (P < 0.05 and P < 0.01) lower in cystic fibrosis patients carrying the Gly16 allele. In addition, the Gly16 allele was associated with a greater 5 year decline in pulmonary function (P < 0.01). Bronchodilator responses to albuterol were not significantly different between the groups. The Thr164Ile variant was found in four patients; these patients had markedly reduced pulmonary function. Isoproterenol-stimulated cyclic AMP formation was significantly blunted in cystic fibrosis patients carrying either the Gly16 allele or Thr164Ile genotype compared to cystic fibrosis patients homozygous for the respective Arg16 alleles. These data provide the first evidence suggesting that polymorphisms of the beta2AR gene contribute to clinical severity and disease progression in cystic fibrosis.
