Genetic polymorphisms and risk of recurrent wheezing in pediatric age

BMC Pulmonary Medicine

Nicola Principi²  Claudio Pelucchi¹  Walter Peves Rios²  Claudia Tagliabue²  Leonardo Terranova²  Alessia Scala²  Cristina Daleno²  Valentina Ierardi²  Susanna Esposito² 

[1] Department of Epidemiology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy;Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy

关键词: Wheezing;    Respiratory viruses;    Recurrent wheezing;    Lower respiratory tract infection;    Genetic polymorphisms;    Asthma;   

Others  :  1091812
DOI  :  10.1186/1471-2466-14-162

 received in 2014-05-07, accepted in 2014-09-22,  发布年份 2014

【 摘 要 】

Background

Wheezing during early life is a very common disorder, but the reasons underlying the different wheezing phenotypes are still unclear. The aims of this study were to analyse the potential correlations between the risk of developing recurrent wheezing and the presence of specific polymorphisms of some genes regulating immune system function, and to study the relative importance of the associations of different viruses and genetic polymorphisms in causing recurrent episodes.

Methods

The study involved 119 otherwise healthy infants admitted to hospital for a first episode of wheezing (74 of whom subsequently experienced recurrent episodes) and 119 age- and sex-matched subjects without any history of respiratory problem randomly selected from those attending our outpatient clinic during the study period. All of the study subjects were followed up for two years, and 47 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped on whole blood using an ABI PRISM 7900 HT Fast Real-time instrument.

Results

IL8-rs4073AT, VEGFA-rs833058CT, MBL2-rs1800450CT and IKBKB-rs3747811AT were associated with a significantly increased risk of developing wheezing (p = 0.02, p = 0.03, p = 0.05 and p = 0.0018), whereas CTLA4-rs3087243AG and NFKBIB-rs3136641TT were associated with a significantly reduced risk (p = 0.05 and p = 0.04). IL8-rs4073AT, VEGFA-rs2146323AA and NFKBIA-rs2233419AG were associated with a significantly increased risk of developing recurrent wheezing (p = 0.04, p = 0.04 and p = 0.03), whereas TLR3-rs3775291TC was associated with a significantly reduced risk (p = 0.03). Interestingly, the study of gene-environment interactions showed that rhinovirus was significantly associated with recurrent wheezing in the presence of IL4Ra-rs1801275GG and G (odds ratio [OR] 6.03, 95% confidence interval [CI]: 1.21-30.10, p = 0.03) and MAP3K1-rs702689AA (OR 4.09, 95% CI: 1.14-14.61, p = 0.03).

Conclusions

This study shows a clear relationship between the risk of wheezing and polymorphisms of some genes involved in the immune response. Although further studies are needed to confirm the results, these findings may be useful for the early identification of children at the highest risk of developing recurrent episodes and possibly subsequent asthma.

【 授权许可】

   
2014 Esposito et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Martinez F, Wright A, Taussig L, Holberg CJ, Halonen M, Morgan WJ: Asthma and wheezing in the first six years of life. N Engl J Med 1995, 332:133-138.
• [2]Inoue Y, Shimojo N: Epidemiology of virus-induced wheezing/asthma in children. Front Microbiol 2013, 4:391.
• [3]Jackson DJ: Early-life viral infections and the development of asthma: a target for asthma prevention? Curr Opin Allergy Clin Immunol 2014, 14:131-136.
• [4]Hopp RJ: Recurrent wheezing in infants and young children and bronchial hyperresponsiveness: a perspective. Clin Rev Allergy Immunol 2003, 24:7-18.
• [5]Bloomberg GR: The influence of environment, as represented by diet and air pollution, upon incidence and prevalence of wheezing illnesses in young children. Curr Opin Allergy Clin Immunol 2011, 11:144-149.
• [6]Escobar GJ, Masaquel AS, Li SX, Walsh EM, Kipnis P: Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy. BMC Pediatr 2013, 13:97. BioMed Central Full Text
• [7]Takeyama A, Hashimoto K, Sato M, Sato T, Tomita Y, Maeda R, Ito M, Katayose M, Kawasaki Y, Hosoya M: Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years. Eur J Pediatr 2014, ᅟ:ᅟ. Epub Feb 18
• [8]Halfhide C, Smith RL: Innate immune response and bronchiolitis and preschool recurrent wheezing. Pediatr Resp Rev 2008, 9:251-262.
• [9]Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, Doornbos G, Van’t Slot R, Wijmenga C, Goeman JJ, Kimpen JL, Van Houwelingen HC, Kimman TG, Hoebee B: Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J Infect Dis 2007, 196:826-834.
• [10]Daley D, Park JE, He JQ, Yan J, Akhabir L, Stefanowicz D, Becker AB, Chan-Yeung M, Bossé Y, Kozyrskyj AL, James AL, Musk AW, Laprise C, Hegele RG, Paré PD, Sandford AJ: Associations and interactions of genetic polymorphisms in innate immunity genes with early viral infections and susceptibility to asthma and asthma-related phenotypes. J Allergy Clin Immunol 2012, 130:1284-1293.
• [11]Sharma S, Poon A, Himes BE, Lasky-Su J, Sordillo JE, Belanger K, Milton DK, Bracken MB, Triche EW, Leaderer BP, Gold DR, Litonjua AA: Association of variants in innate immune genes with asthma and eczema. Pediatr Allergy Immunol 2012, 23:315-323.
• [12]Feigin RD, Cherry JD: Textbook of Pediatric Infectious Diseases. 7th edition. Philadelphia, PY: W.B. Saunders Company; 2014.
• [13]Gadsby NJ, Hardie A, Claas EC, Templeton KE: Comparison of the Luminex respiratory virus panel fast assay with in-house real-time PCR for respiratory viral infection diagnosis. J Clin Microbiol 2010, 48:2213-2216.
• [14]Pabbaraju K, Wong S, Tokaryk KL, Fonseca K, Drews SJ: Comparison of the Luminex xTAG respiratory viral panel with xTAG respiratory viral panel fast for diagnosis of respiratory virus infections. J Clin Microbiol 2011, 49:1738-1744.
• [15]Lu X, Holloway B, Dare RK, Kuypers J, Yagi S, Williams JV, Hall CB, Erdman DD: Real-time reverse transcription-PCR assay for comprehensive detection of human rhinoviruses. J Clin Microbiol 2008, 46:533-539.
• [16]Faber TE, Schuurhof A, Vonk A, Koppelman GH, Hennus MP, Kimpen JL, Janssen R, Bont LJ: IL1RL1 gene variants and nasopharyngeal IL1RL-a levels are associated with severe RSV bronchiolitis: a multicenter cohort study. PLoS ONE 2012, 7:e34364.
• [17]De Dooy JJ, Mahieu LM, Van Bever HP: The role of inflammation in the development of chronic lung disease in neonates. Eur J Pediatr 2001, 160:457-463.
• [18]Sharma S, Murphy AJ, Soto-Quiros ME, Avila L, Klanderman BJ, Sylvia JS, Celedón JC, Raby BA, Weiss ST: Association of VEGF polymorphisms with childhood asthma, lung function and airway responsiveness. Eur Respir J 2009, 33:1287-1294.
• [19]Tulic MK, Hurrelbrink RJ, Prêle CM, Laing IA, Upham JW, Le Souef P, Sly PD, Holt PG: TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide. J Immunol 2007, 179:132-140.
• [20]Himes BE, Jiang X, Hu R, Wu AC, Lasky-Su JA, Klanderman BJ, Senter-Sylvia J, Lima JJ, Irvin CG, Peters SP, Meyers DA, Bleecker ER, Kubo M, Tamari M, Nakamura Y, Szefler SJ, Lemanske RF Jr, Zeiger RS, Strunk RC, Martinez FD, Hanrahan JP, Koppelman GH, Postma DS, Nieuwenhuis MA, Vonk JM, Panettieri RA Jr, Markezich A, Israel E, Carey VJ, Tantisira KG, et al.: Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene. PLoS Genet 2012, 8:e1002824.
• [21]Nuolivirta K, He Q, Gröndahl-Yli-Hannuksela K, Koponen P, Korppi M, Helminen M: Mannose-binding lectin gene polymorphisms in infants with bronchiolitis and post-bronchiolitis wheezing. Allergol Int 2012, 61:305-309.
• [22]Goetghebuer T, Isles K, Moore C, Thomson A, Kwiatkowski D, Hull J: Genetic predisposition to wheeze following respiratory syncytial virus bronchiolitis. Clin Exp Allergy 2004, 34:801-803.
• [23]Tadaki H, Arakawa H, Sugiyama M, Ozawa K, Mizuno T, Mochizuki H, Tokuyama K, Morikawa A: Association of cord blood cytokine levels with wheezy infants in the first year of life. Pediatr Allergy Immunol 2009, 20:227-233.
• [24]Hoshino M, Takahashi M, Aoike N: Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol 2001, 107:295-301.
• [25]McColley SA, Stellmach V, Boas SR, Jain M, Crawford SE: Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation. Am J Respir Crit Care Med 2000, 161:1877-1880.
• [26]Kanazawa H, Asai K, Nomura S: Vascular endothelial growth factor as a non-invasive marker of pulmonary vascular remodeling in patients with bronchitis-type of COPD. Respir Res 2007, 8:22. BioMed Central Full Text
• [27]Nishigaki Y, Fujiuchi S, Yamazaki Y, Matsumoto H, Takeda A, Fujita Y, Okamoto K, Fujikane T, Shimizu T, Kikuchi K: Increased vascular endothelial growth factor in acute eosinophilic pneumonia. Eur Respir J 2003, 21:774-778.
• [28]Choi IS, Byeon JH, Yoo Y, Lee KC, Choung JT: Increased serum interleukin-5 and vascular endothelial growth factor in children with acute mycoplasma pneumonia and wheeze. Pediatr Pulmonol 2009, 44:423-428.
• [29]Leung TF, Tang NL, Sung YM, Li CY, Ma SL, Lam CW, Wong GW: Genetic association study between mbl2 and asthma phenotypes in Chinese children. Pediatr Allergy Immunol 2006, 17:501-507.
• [30]Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, Janda A, Hese K, Schlesier M, Holzmann K, Borte S, Laux C, Rump EM, Rosenberg A, Zelinski T, Schrezenmeier H, Wirth T, Ehl S, Schroeder ML, Schwarz K: Deficiency of innate and acquired immunity caused by an IKBKB mutation. N Engl J Med 2013, 369:2504-2514.
• [31]Bulek K, Liu C, Swaidani S, Wang L, Page RC, Gulen MF, Herjan T, Abbadi A, Qian W, Sun D, Lauer M, Hascall V, Misra S, Chance MR, Aronica M, Hamilton T, Li X: The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat Immunol 2011, 12:844-852.
• [32]Bazzi MD, Sultan MA, Al Tassan N, Alanazi M, Al-Amri A, Al-Hajjaj MS, Al-Muhsen S, Alba-Concepcion K, Warsy A: Interleukin 17A and F and asthma in Saudi Arabia: gene polymorphisms and protein levels. J Investig Allergol Clin Immunol 2011, 21:551-555.
• [33]Sheikh A, Smeeth L, Hubbard R: There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: lack of support for the hygiene hypothesis. J Allergy Clin Immunol 2003, 111:131-135.
• [34]Borrego LM, Arroz MJ, Videira P, Martins C, Guimarães H, Nunes G, Papoila AL, Trindade H: Regulatory cells, cytokine pattern and clinical risk factors for asthma in infants and young children with recurrent wheeze. Clin Exp Allergy 2009, 39:1160-1169.
• [35]Ermers MJ, Janssen R, Onland-Moret NC, Hodemaekers HM, Rovers MM, Houben ML, Kimpen JL, Bont LJ: IL10 family member genes IL19 and IL20 are associated with recurrent wheeze after respiratory syncytial virus bronchiolitis. Pediatr Res 2011, 70:518-523.
• [36]Torres D, Dieudonné A, Ryffel B, Lassalle P, Trottein F, Gosset P: Double-stranded RNA exacerbates pulmonary allergic reaction through TLR3: implication of airway epithelium and dendritic cells. J Immunol 2010, 185:451-459.
• [37]Wang Q, Miller DJ, Bowman ER, Nagarkar DR, Schneider D, Zhao Y, Linn MJ, Goldsmith AM, Bentley JK, Sajjan US, Hershenson MB: MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness. PLoS Pathog 2011, 7:e1002070.
• [38]Nuolivirta K, He Q, Vuononvirta J, Koponen P, Helminen M, Korppi M: Toll-like receptor 3 L412F polymorphisms in infants with bronchiolitis and postbronchiolitis wheezing. Pediatr Infect Dis J 2012, 31:920-923.
• [39]Ermers MJ, Hoebee B, Hodemaekers HM, Kimman TG, Kimpen JL, Bont L: IL-13 genetic polymorphism identifies children with late wheezing after respiratory syncytial virus infection. J Allergy Clin Immunol 2007, 119:1086-1091.
• [40]Beghé B, Barton S, Rorke S, Peng Q, Sayers I, Gaunt T, Keith TP, Clough JB, Holgate ST, Holloway JW: Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 2003, 33:1111-1117.
• [41]Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O’Toole S, Myint SH, Tyrrell DA: Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. BMJ 1995, 310:1225-1229.
• [42]Kennedy JL, Heymann PW, Platts-Mills TA: The role of allergy in severe asthma. Clin Exp Allergy 2012, 42:659-669.
• [43]Turchiarelli V, Schinkel J, Molenkamp R, Foschino Barbaro MP, Carpagnano GE, Spanevello A, Lutter R, Bel EH, Sterk PJ: Repeated virus identification in the airways of patients with mild and severe asthma during prospective follow-up. Allergy 2011, 66:1099-1106.
• [44]Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, Holgate ST, Davies DE: Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med 2005, 201:937-947.
• [45]Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, Kebadze T, Mallia P, Stanciu LA, Parker HL, Slater L, Lewis-Antes A, Kon OM, Holgate ST, Davies DE, Kotenko SV, Papi A, Johnston SL: Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med 2006, 12:1023-1026.
• [46]Subrata LS, Bizzintino J, Mamessier E, Bosco A, McKenna KL, Wikström ME, Goldblatt J, Sly PD, Hales BJ, Thomas WR, Laing IA, LeSouëf PN, Holt PG: Interactions between innate antiviral and atopic immunoinflammatory pathways precipitate and sustain asthma exacerbations in children. J Immunol 2009, 183:2793-2800.
• [47]Szczepankiewicz A, Sobkowiak P, Rachel M, Bręborowicz A, Schoneich N, Bruce K, Kycler Z, Wojsyk-Banaszak I, Dmitrzak-Węglarz M: Multilocus analysis of candidate genes involved in neurogenic inflammation in pediatric asthma and related phenotypes: a case–control study. J Asthma 2012, 49:329-335.