Genetic interaction of GSH metabolic pathway genes in cystic fibrosis

Abstract

BackgroundCystic fibrosis (CF) is a monogenic disease caused by CFTR gene mutations, with clinical expression similar to complex disease, influenced by genetic and environmental factors. Among the possible modifier genes, those associated to metabolic pathways of glutathione (GSH) have been considered as potential modulators of CF clinical severity. In this way it is of pivotal importance investigate gene polymorphisms at Glutamate-Cysteine Ligase, Catalytic Subunit (GCLC), Glutathione S-transferase Mu 1 (GSTM1), Glutathione S-transferase Theta 1 (GSTT1), and Glutathione S-transferase P1 (GSTP1), which have been associated to the GSH metabolic pathway and CF clinical severity.MethodA total of 180 CF’s patients were included in this study, which investigated polymorphisms in GCLC and GST genes (GCLC -129C>T and -3506A>G; GSTM1 and GSTT1 genes deletion, and GSTP1*+313A>G) by PCR and PCR-RFLP associating to clinical variables of CF severity, including variables of sex, clinical scores [Shwachman-Kulczycki, Kanga e Bhalla (BS)], body mass index, patient age, age for diagnosis, first clinical symptoms, first colonization by Pseudomonas aeruginosa, sputum’s microorganisms, hemoglobin oxygen saturation in the blood, spirometry and comorbidities. The CFTR genotype was investigated in all patients, and the genetic interaction was performed using MDR2.0 and MDRPT0.4.7 software.ResultsThe analysis of multiple genes in metabolic pathways in diseases with variable clinical expression, as CF disease, enables understanding of phenotypic diversity. Our data show evidence of interaction between the GSTM1 and GSTT1 genes deletion, and GSTP1*+313A>G polymorphism with CFTR gene mutation classes, and BS (Balance testing accuracy= 0.6824, p= 0.008), which measures the commitment of bronchopulmonary segments by tomography.ConclusionPolymorphisms in genes associated with metabolism of GSH act on the CF’s severity.

Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis

“…In addition, we were a pioneering group in the use of the MDR tool to determine the genetic interaction with CF severity markers. As noted in the aforementioned literature, a study published by Marson et al showed that pulmonary injury in CF, assessed by the Bhalla score, was a result of the following interaction: deletion of GSTM1 (Glutathione S‐transferase Mu 1) and GSTT1 (Glutathione S‐transferase Theta 1) genes, GSTP1 *+313A>G variant and class of mutations in the CFTR gene. In our previous study, it was evidenced that genes belonging to the same metabolic pathway were key factors for the outcome of pulmonary severity evaluated by a tomographic score.…”

“…In this context, our research group has been working to contribute to studies on numerous genes, which can act on drug response, inflammatory processes and the immune response to the pathogens that aggravate, mainly, the pulmonary disease …”

Association of growth and nutritional parameters with pulmonary function in cystic fibrosis: a literature review

“…Pulmonary disease is the most important manifestation in CF and the main factor acting in morbidity and mortality of the disease. The response in pulmonary disease is mediated by abnormal CFTR,2 modifier genes,3 - 8 airway infections and inflammation,9 probably affecting weight and height due to appetite suppression and enhanced energy expenditure.…”

Gene modifiers of cystic fibrosis lung disease: A systematic review

“…Because of its role in protecting the lung from an oxidative lung injury, Glutathione S‐Transferase mu ( GSTM1 ) has been investigated in nine studies, and whereas some smaller studies showed a link between the null genotype and poorer outcomes, the largest study showed no effect. A possible explanation for this discrepancy is that the studies showing an effect used radiological and clinical score outcomes, whereas the large Gene Modifier study used FEV 1 .…”