Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis

Marson, Fernando Augusto Lima; Bertuzzo, Carmen Sílvia; Ribeiro, A.F.; Ribeiro, José Dirceu

doi:10.1186/1471-2466-12-50

Cited by 33 publications

(22 citation statements)

References 28 publications

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“…( 9 , 15 ) The F508del mutation is a class II mutation (causing misprocessed/misfolded CFTR proteins), and it is associated with higher clinical severity of CF. ( 9 ) …”

Section: Introductionmentioning

confidence: 99%

Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis

et al. 2013

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OBJECTIVE: To determine the relevance of screening for the F508del mutation of the cystic fibrosis transmembrane conductance regulator gene as a first step in the genetic diagnosis of cystic fibrosis (CF) by associating the genotype with various clinical variables. METHODS: We evaluated 180 CF patients regarding the F508del mutation. The clinical data were obtained from the medical records of the patients and from interviews with their parents or legal guardians. RESULTS: Of the 180 patients studied, 65 (36.1%) did not carry the F508del mutation (group 0 [G0]), 67 (37.2%) were F508del heterozygous (G1), and 48 (26.7%) were F508del homozygous (G2). All three groups showed associations with the clinical variables. Homozygosis was associated with younger patients, younger age at CF diagnosis, and younger age at the first isolation of Pseudomonas aeruginosa (PA), as well as with higher prevalence of pancreatic insufficiency (PI) and non-mucoid PA (NMPA) colonization. In comparison with G1+G2 patients, G0 patients were older; first experienced clinical symptoms, digestive disease, and pulmonary disease at an older age; were older at CF diagnosis and at first PA isolation; and had a lower prevalence of PI and meconium ileus, as well as of colonization by NMPA, mucoid PA, and Burkholderia cepacia. In G1 patients, values were intermediate for age at CF diagnosis; age at first PA isolation, first pulmonary symptoms, and first clinical manifestations; MPA colonization; and OR for PI. CONCLUSIONS: The identification of F508del in 63.9% of the patients studied showed that this can be a useful tool as a first step in the genetic diagnosis of CF. The F508del genotype was associated with clinical severity of the disease, especially with the variables related to CF onset.

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“…( 9 , 15 ) The F508del mutation is a class II mutation (causing misprocessed/misfolded CFTR proteins), and it is associated with higher clinical severity of CF. ( 9 ) …”

Section: Introductionmentioning

confidence: 99%

Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis

et al. 2013

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“…Other genes were studied in the same CF reference center with same population as previously published [11,13,14]. The GSTM1 and GSTT1 genes were studied in our center considering other CF patients as recent published data showed [12].…”

Section: Methodsmentioning

confidence: 99%

“…In our group, as previously published, multiple genes are associated with CF clinical severity, including Transforming growth factor beta 1 ( TGF - β1 ) [11], Glutathione S-transferase Mu 1 ( GSTM1 ), Glutathione S-transferase Theta 1 ( GSTT1 ) [12], Angiotensin-converting enzyme ( ACE ) [13] and Beta-2-Adrenergic Receptor ( ADBR2 ) [14] genes as possibly modifier genes. In the same population the mannose-binding lectin (protein C) 2 ( MBL2 ) and monocyte differentiation antigen CD14 ( CD14 ) genes were not associated with the CF clinical severity [11].…”

Section: Introductionmentioning

confidence: 99%

Genetic interaction of GSH metabolic pathway genes in cystic fibrosis

et al. 2013

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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.

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“…The severity of disease is also dependent on the CFTR mutations, environmental factors and modifier genes [3][4][5][6][7][8][9][10][11][12][13][14]. Studies to understand the observed variation have been performed, and in the present data the ADIPOR2 gene and its variations was considered.…”

Section: General Aspectsmentioning

confidence: 99%

“…Our group has studied the clinical modulation of CF by candidate modifier genes that influence drug responses, the evolution of the lung and digestive disease in CF, and CF-related comorbidities [6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

ADIPOR2 Polymorphisms in Cystic Fibrosis are Potential Modifiers of Clinical Severity

Marson¹

2014

J Genet Syndr Gene Ther

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Objective: Cystic Fibrosis (CF) severity is determined by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, the environment and modifier genes. The adiponectin receptor 2 (ADIPOR2) gene is one of the potential modifier genes of CF and is responsible for expressing an anti-inflammatory protein. In this context, the 315 base deletion and the 134 base insertion polymorphisms in the ADIPOR2 gene are associated with CF severity.Methodology: A total of 169 CF patients were enrolled, and 27 CF clinical markers were analyzed. Results:The 315 base deletion and haplotypes analyses showed an association with the patient´s age and ethnicity. For the age, the deletion in both alleles was associated with a lower age in the patients without any identified CFTR mutations (OR= 7.257; 95%CI= 1.321-44.83) or disregarding CFTR mutations (OR= 2.394; 95%CI= 1.046-5.721). For the ethnicity, the wild-type allele (315 base no deletion) showed lower risk of occurrence in Caucasians patients with two CFTR mutations identified (OR= 0.052; 95%CI= 0.002-0.382) or no CFTR mutations (OR= 0.154, 95%CI= 0.032-0.592). The same values were observed for the clustered analysis of the 315 base deletions. In the analysis of the haplotype, in the Caucasian group, the patients with two CFTR mutations were identified and demonstrated an OR of 0.076 (95%CI= 0.009-0.432) for wild-type alleles. The 134 base insertions were associated with the SpO 2 [patients without considering the CFTR genotype (p-value= 0.034) and without any identified CFTR mutations (p-value= 0.034)] and the Kanga score (no CFTR mutations identified) (p-value= 0.008). The haplotype was associated with the forced vital capacity (disregarding CFTR genotype) (p-value= 0.028). Conclusion:The 315 base deletions and the insertion of 134 bases in the ADIPOR2 gene are potential modifiers of the severity of CF and should be considered during CFTR mutation screening.

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Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis

Cited by 33 publications

References 28 publications

Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis

Screening for F508del as a first step in the molecular diagnosis of cystic fibrosis

Genetic interaction of GSH metabolic pathway genes in cystic fibrosis

ADIPOR2 Polymorphisms in Cystic Fibrosis are Potential Modifiers of Clinical Severity

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