Polymorphisms in the glutathione pathway modulate cystic fibrosis severity: a cross-sectional study

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.

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“…Additionally, variants in other bystander/modifier genes significantly affect disease severity in other CF organs. A few examples of such genes include CLCA4 (Chloride channel accessory 4/Ca++ activated chloride channel 4, promoting intestinal disease); A1AT (Alpha 1 Anti‐Trypsin, promoting CF Liver Disease [CFLD]); GSTP1 (glutathione‐S‐transferase pi 1; promoting increased osteoporosis), TCF7L2 (transcription factor 7‐like 2; promoting increased incidence of CF related diabetes [CFRD]), and SLC26A9 (solute carrier family 26 member 9; promoting pancreatic damage, CF related diabetes, [CFRD], and meconium ileus). Thus if iPSC‐dependent therapies were directed exclusively to the lung, they might render effects of lung‐centric bystander/modifier genes moot.…”

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“…33,37,38 A cross-sectional study focusing on polymorphisms in the glutathione pathways and modulation in cystic fibrosis severity found that the polymorphisms in glutathione pathways are associated with the severity of cystic fibrosis. 39 The study was conducted between 2011 and 2012 and included 180 patients with cystic fibrosis. Polymerase chain reaction (PCR) was used to identify polymorphisms.…”

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“…of outpatient visits* 5 (3-9) 7 (4-10) Participants, n (% of total clinic population) 36 (64) 15 (30) 20 (35) (19)(20)(21)(22)(23)(24) No. of outpatient visits* 4 (3-6) 4 (3-9) 9 (4-12) 4 (2)(3)(4)(5)(6) No.…”

“…glutathione pathways), ion transporters (e.g. solute carrier family genes) and pancreatic β-cell function (transcription factor 7-like 2 gene) have been implicated in modifying CF phenotype (18,20,(22)(23)(24).…”

“…In part, this variability may reflect different environmental exposures and quality of clinical care provided, however, the influence of non-CFTR gene modifiers has also been postulated (18,25). Genes that encode immune mediators, anti-oxidants, ion transporters and pancreatic β-cell function have each been implicated in modifying CF phenotype (18,20,(22)(23)(24).…”