Análise de genes modificadores relacionados à gravidade clínica da fibrose cística / Analysis of modifier genes related to the clinical severity in cystic fibrosis

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

25/08/2011

RESUMO

Introduction: Cystic fibrosis (CF) is clinically manifested in various forms of gravity, modulated by different genotypes and environment. While the classes of mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene are well defined as modulators of severity in CF, polymorphisms remain controversial. Objective: To determine whether polymorphisms in modifier genes are associated with the severity in the CF. Method: Cross-sectional study, between 2009 to 2010. All patients were subjected to analysis of major mutations in CFTR gene, presence of polymorphisms (using different molecular techniques - Nested PCR, enzyme digestion, multiplex PCR, genotyping in automatic sequencer and ARMS PCR) and clinical severity in CF. Results: Mutations were identified in CFTR gene associated with variables that describe the onset of the disease, acting as a protective factor for the clinical severity [age (p?0.0001), first clinical manifestation (1CM) (p?0.0001), diagnosis (p?0.0001) , onset of pulmonary symptoms (OPS) (p?0.0001) and digestive (ODS) (p?0.0001), 1st isolated bacterium Pseudomonas aeruginosa (1PA) (p?0.0001), pancreatic insufficiency (PI) ( p?0.0001), P. aeruginosa mucoid (PAM) (p?0.0001) and P. aeruginosa no mucoid (PANM) (p?0.0001)]. ACE gene was associated with 1CM (p:0.038), Bhalla score (BS) (p:0.049) and presence of Bulkolderia cepacia (BC) (p:0.038). Polymorphism GCLC129C>T was associated with PAM (p:0.037). Polymorphism GCLC350 was associated with 1PA (p:0.049), Achromobacter xylosoxidans (p:0.044) and Staphylococcus aureus (SA) (p:0.037). GSTM1 gene was associated with diagnosis (p:0.014), body mass index (BMI) (0.045), Kanga score (KS) (p:0.046), forced vital capacity [FVC(%)] (p:0.004) and forced expiratory volume in one second [FEV1(%)] (p:0.004). GSTT1 gene was associated with ODS (p:0033), osteoporosis (p:0.021), BS (p:0.026), Shwachman-Kulczycki score (SS) (p:0.009), FVC(%) (p:0.015) , FEV1(%) (p:0.005), ratio between FEV1 and FVC [TIF(%)] (p:0.033), forced expiratory flow between 25 and 75% of FVC [FEF25-75%(%)] (p:0.005) and PAM (p:0.038). The genotypic groupings of genes GSTM1 and GSTT1 was associated with diagnosis (p:0.014), BC (p:0.042) and SA (p:0.032). GSTP1 gene was associated with the OPS (p:0.026), PI (p:0.011), BS (p:0.015), KS (p:0.028), SS (p:0.039), FVC(%) (p:0.021 ), FEV1(%) (p:0.021), FEF25-75% (p:0.02) and 1PA (p:0.022). Allele 1 for AAT repeat polymorphism in NOS-1 gene was associated with age (p:0.009) and ODS (p:0.001). Allele 2 with OPS (p:0.031), ODS (p:0.001) and BS (p:0.046). Allele 1 for repeat polymorphism GT-1 in NOS-1 gene was not associated with clinical variables. Allele 2 was associated with transcutaneous oxygen saturation (p:0.012), BS (p:0.013), FVC(%) (p:0.038), FEV1(%) (p:0.007), TIF(%) (p:0.036) and FEF25-75(%) (p:0.007). The allele 1 for repeat polymorphism GT-2 in NOS1 gene was associated with FVC(%) (p:0.032). The allele 2 was associated with the TIF(%) (p:0.009). Polymorphism Arg>Gly in ADRB2R gene was associated with PI (p:0.009), BS (p:0.039), FEV1(%) (p:0.003), FEF25-75(%) (p:0.008), 1PA ( p:0.012), PAM (p:0.023) and PANM (p:0.024). Polymorphism Gln>Glu in ADRB2R gene was associated with BS (p:0.019) and TIF(%) (p:0.047). The response to inhaled bronchodilator in the spirometry test presented association for the markers of clinical severity FEV1(%) (p:0.011) and FEF25-75(%) (p:0.019) only for the polymorphism Arg>Gly in ADRB2R gene. Conclusion: There was association between the polymorphisms studied and CFTR mutations with the clinical severity in CF.

ASSUNTO(S)

modulação genica variabilidade genetica fenótipo polimorfismo (genética) genetic modulation variability phenotype genotype genótipo polymorphism

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