Abstract
BackgroundCystic fibrosis (CF) clinically manifests with various levels of severity, which are thought to be modulated by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), modifier genes, and the environment. This study verified whether polymorphisms in modifier genes associated with glutathione (GSH) metabolism influence CF severity.MethodsA cross-sectional study of 180 CF patients was carried out from 2011 to 2012. We analyzed CFTR mutations, polymorphisms (GSTM1 and GSTT1 deletions, GSTP1 + 313A > G, GCLC-129C > T, and GCLC-3506A > G) in modifier genes and CF clinical severity as assessed by 28 clinical and laboratory variables.ResultsSignificant associations were found between modifier gene polymorphisms and particular phenotypes or genotype changes. These included GCLC-129C > T with a higher frequency of the Pseudomonas aeruginosa mucoid to CC genotype (p = 0.044), and GCLC-3506A > G with a higher frequency of the no-mucoid P. aeruginosa (NMPA) to AA genotype (p = 0.012). The GSTT1 deletion was associated with a higher frequency of the NMPA to homozygous deletion (p = 0.008), GSTP1 + 313A > G with a minor risk of osteoporosis (p = 0.036), and patient age ≤ 154 months (p = 0.044) with the AA genotype. The Bhalla score was associated with GCLC-3506A > G (p = 0.044) and GSTM1/GSTT1 deletion polymorphisms (p = 0.02), while transcutaneous hemoglobin oxygen saturation levels were associated with GSTT1 deletions (p = 0.048).ConclusionCF severity is associated with polymorphisms in GSH pathways and CFTR mutations.
Highlights
Cystic fibrosis (CF) clinically manifests with various levels of severity, which are thought to be modulated by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), modifier genes, and the environment
At our CF center, all patients receive free medication provided by the state, have a similar socioeconomic status, share similar Class I, II and/or III mutations, receive support from the Cystic Fibrosis Association, and there are no severe cases of malnutrition
Variations in CF severity can be associated with a modifier gene, such as those associated with oxidative stress [19,20,21,26,30] that are related to chronic obstructive pulmonary disease (COPD) [18]
Summary
Cystic fibrosis (CF) clinically manifests with various levels of severity, which are thought to be modulated by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR), modifier genes, and the environment. Cystic fibrosis (CF) presents with broad phenotypic variability, even in patients with identical mutations in the causative gene, cystic fibrosis transmembrane conductance regulator (CFTR) [1]. Explanations for this include environmental factors [2], medical management [3], nutritional status [4], emotional maladjustments [5], socioeconomic status [3], CFTR mutations [1], and modifier genes [1,3,6]. As polymorphisms can alter the GSH metabolic pathway, genetic variations of this pathway have previously been studied in association with CF [19,20,21]
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