A polymorphism in ADRB2 gene is associated with severity of pulmonary phenotype in Cystic Fibrosis patients.
Languages of publication
Background: Cystic Fibrosis (CF) is a common genetic disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein. It is known that modifier genes and environmental factors play a key role in determining the severity of the disease. Methods: We analyzed Single Nucleotide Polymorphisms (SNPs) in three genes, namely TNFA, TGFB1 and ADRB2, as potential modifiers of CF lung phenotype: c.−851C>T, c.−308G>A, c.−238G>A and c.+691G ins/del SNPs in TNFA, p.Leu10Pro (c.869C>T) and p.Arg25Pro (c.915G>C) SNPs in TGFB1 and p.Arg16Gly (c.46G>A), p.Gln27Glu (c.79C>G) and p.Thr164Ile (c.491C>T) in ADRB2. Results: For the c.46G>A SNP of ADRB2 the A allele (Arg16), as well as the AA genotype, were significantly more frequent in CF patients than healthy controls. When stratifying CF patients according to FEV1 (Forced Expiratory Volume in 1 second) phenotype we observed a statistically significant difference (p=0.02) in the allelic and genotype frequencies. The A allele and A/A genotype were more frequent in mild CF patients when compared to severe CF subjects and thus probably associate with a protective effect toward the development of severe pulmonary manifestation in CF patients. Conclusions: Our results are indicative of the involvement of the ADRB2 gene as modifier gene in Cystic Fibrosis pulmonary phenotype.
24 - 02 - 2014
3 - 11 - 2013
5 - 4 - 2013
-  Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996; 154 (5):1229-1256.
-  Kirk K. New paradigms of CFTR chloride channel regulation. Cell Mol Life Sci 2000; 57 (4):623-634.
-  Dequeker E, Stuhrmann M, Morris MA, Casals T, Castellani C, Claustres M, et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations. Eur J Hum Genet 2009; 17 (1):51-65.[PubMed][Crossref]
-  Moskowitz SM, Chmiel JF, Sternen DL, Cheng E, Gibson RL, Marshall SG and Cutting GR. Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders. Genetics in Medicine 2008; 10 (12): 851–868.[Crossref][WoS]
-  Bienvenu T. Molecular basis of phenotype heterogeneity in cystic fibrosis. Ann Biol Clin 1997; 55 (2):113-121.
-  Salvatore F, Scudiero O, Castaldo G. Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes. Am J Med Genet 2002; 111 (1): 88-95.
-  Bonfield TL, Panuska JR, Konstan MW, Hilliard KA, Hilliard JB, Ghnaim H et al. Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med 1995; 152 (6 Pt.1): 2111-2118.
-  Ignotz RA, Massague J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 1986; 261 (9): 4337-4345.
-  Taylor DR, Kennedy MA. Genetic variation of the beta(2)-adrenoceptor: its functional and clinical importance in bronchial asthma. Am J Pharmacogenomics 2001; 1 (3): 165-174.
-  Büscher R, Eilmes KJ, Grasemann H, Torres B, Knauer N, Sroka K et al. Beta2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetic 2002; 12 (5): 347-353.[Crossref]
-  Steagall WK, Barrow BJ, Glasgow CG, Mendoza JW, Ehrmantraut M, Lin JP, et al. Beta-2-adrenergic receptor polymorphisms in cystic fibrosis. Pharmacogenet Genomics 2007; 17 (6): 425-430.[WoS][PubMed]
-  Hart MA, Konstan MW, Darrah RJ, Schluchter MD, Storfer-Isser A, Xue L. et al. Beta 2 adrenergic receptor polymorphisms in cystic fibrosis. Pediatric Pulmonology 2005; 39 (6): 544-550.[PubMed]
-  Buranawuti K, Boyle MP, Cheng S, Steiner LL, McDougal K, Fallin MD et al. Variants in mannose-binding lectin and tumour necrosis factor alpha affect survival in cystic fibrosis. J Med Genet 2007; 44 (3): 209-214. [PubMed][WoS]
-  Hajeer AH, Hutchinson IV. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hum Immunol 2001; 62 (11): 1191-1199.
-  Yarden J, Radojkovic D, De Boeck K, Macek M Jr, Zemkova D, Vavrova V, et al. Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. Thorax 2005; 60 (4): 320-325.
-  Xaubet A, Marin-Arguedas A, Lario S, Ancochea J, Morell F, Ruiz-Manzano J, et al. Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168 (4): 431-435.
-  Collaco JM, Cutting GR. Update on gene modifiers in cystic fibrosis. Curr Opin Pulm Med 2008; 14 (6): 559-566.[Crossref][PubMed][WoS]
-  Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9419.
-  Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 1959; 23: 545– 549.
-  Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353(14): 1443-1453
-  Excoffier, L., Laval, C. & Schneider, S. Arlequin ver 3.0: an integrated software package for population genetics data analysis. Evolutionary Bioinformatics Online 2005; 1: 47-50.
-  Chen XJ, Eaton DC, Jain L. Alveolar epithelial ion and fluid transport. beta-Adrenergic regulation of amiloride-sensitive lung sodium channels. Am J Physiol Lung Cell Mol Physiol 2002; 282: L609–L620.
Publication order reference