Astımda Genetik Faktörler ve Gen-Çevre Etkileşimi

Yıl 2017, Cilt: 9 Sayı: 2, 48 - 62, 15.03.2017

Doç. Ph. Dr. Çağatay Karaaslan

Öz

Öz

Astım genetik faktörlerin, çevresel faktörlerin ve epigenetik faktörlerin etkileşimi sonucu ortaya çıkan hava yollarında daralma ve enflamasyonla karakterize bir hastalıktır.  Astım kompleks hastalıkların tipik özelliklerini taşımaktadır. Yani astım, gelişiminde her birinin etkisi küçük olan birçok gendeki değişimler sonucunda ortaya çıkmaktadır. Astım genetiğinde kullanılan tekniklerin kapasitesi yaygın genetik değişkenlikleri belirlemeyle sınırlıdır. Yaygın genetik değişkenlerin hastalık fenotipine katkıları ise oldukça azdır ve tek gen hastalıklarından elde edilen deneyimin ortaya koyduğu gibi nadir değişkenliklerin hastalık gelişimine olan etkileri oldukça fazladır. Genetik çalışmalarda kullanılan teknolojide gerçekleştirilen büyük ilerlemeler has-talığı daha iyi anlamamızı sağlamıştır. Ancak hala çözüm bekleyen konular vardır.Astım ve alerjik hastalıkların ardında yatan genetik faktörleri belirlemeye yönelik olarak yapılan tüm çalışmalar resmin tam olarak anlaşılabilmesi için çeşitli genler ve değişkenliklerin birbirleri, makro ve mikro çevre ile etkileşimlerinin ve epigenetik faktörlerin belirlenmesi gerekliliğini ortaya koymuştur. Günümüzde, nadir görülen genetik değişkenliklerin, insersiyon ve delesyonların, hatta kopya sayısı değişikliklerinin belirlenmesine olanak sağlayan, tüm genomun veya protein kodlayan gen bölgelerinin tamamının yeniden dizilenmesi tekniği, astım gibi kompleks hastalıkların genetiğinin aydınlatılmasında yeni bir yöntem olarak kullanılmaktadır. Bu teknolojiye  “next generation sequencing” adı verilmektedir. Bu karmaşık etkileşimlerin belirlenmesi için geliştirilen yeni teknikler ve biyoinformatik analiz programları sayesinde, erken tanıya yönelik biyobelirteçlerin bulunması ve bireysel tedavi yöntemlerinin geliştirilmesi mümkün olacaktır.Bu derlemede astımda etkili olan genlerin keşfinde kullanılan yeni ve eski teknikler  ve günümüzde astım genetiğende hangi noktada olduğumuz anlatılacaktır. Ayrıca elde edilen bilgilerin uygulamaya nasıl aktarılacağı ve gelecekte neler yapılması gerektiği tartışılacaktır.

Anahtar Kelimeler

Astım, epigenetik, farmakogenetik, genetik

Kaynakça

• Kaynaklar 1.Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet.2002. 360,1313-1322. 2.Willemsen G, van Beijsterveldt TC, van Baal CG, Postma D, Bo-omsma DI. Heritability of self-reported asthma and allergy: a studyin adult Dutch twins, siblings and parents. Twin Research andHuman Genetics. 2008 11,132–142. 3.Nystad W, Roysamb E, Magnus P, Tambs K, Harris JR. A com-parison of genetic and environmental variance structures for asthma, hay fever and eczema with symptoms of the same diseases:a study of Norwegian twins. International Journal of Epidemio-logy 2005. 34,1302–130 4.van Beijsterveldt CE, Boomsma DI. Genetics of parentally re-ported asthma, eczema and rhinitis in 5-yr-old twins. EuropeanRespiratory Journal. 2007. 29,516–521. 5.Fagnani C, Annesi-Maesano I, Brescianini S, D'Ippolito C, Med-da E, Nisticò L, Patriarca V, et al. . Heritability and shared ge-netic effects of asthma and hay fever: an Italian study of youngtwins. Twin Research and Human Genetics. 2008 11,121–131. 6.Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, John-son CA, et al. Trends in asthma prevalence, health care use, andmortality in the United States, 2001-2010. NCHS Data Brief.2012 May;(94):1-8. 7.Risch N, Merikangas K. The future of genetic studies of complexhuman diseases. Science. 1996, 273,1516-1517. 8.Carlson CS, Eberle MA, Kruglyak L, Nickerson DA. Mappingcomplex disease loci in whole-genome association studies. Na-ture 2004.. 429,446-452. 9.Hoffjan S, Nicolae D, Ober C. Association studies for asthmaand atopic diseases: a comprehensive review of the literature. Res-piratory Research. 2003. 4,14. 10.Ober C, Hoffjan S. (2006) Asthma genetics 2006: the long and win-ding road to gene discovery. Genes and Immunity.2006. 7,95-100 11.Kubo, A., K. Nagao, and M. Amagai, Epidermal barrierdysfunction and cutaneous sensitization in atopic diseases. J ClinInvest, 2012. 122(2): p. 440-7. 12.Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K,Simon J, Torrey D, Pandit S, et al Association of the ADAM33gene with asthma and bronchial hyperresponsiveness. Nature.2002. 418,426–430. 13.Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Pon-ting CP, Bhattacharyya S, et al. Positional cloning of a novel geneinfluencing asthma from chromosome 2q14. Nature Genetics.2003. 35,258–263. 14.Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmi-kangas P, et al. Characterization of a common susceptibility lo-cus for asthma-related traits. Science. 2004. 304,300–304. 15.Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, et al. Finemapping and positional candidate studies identify HLA-G as anasthma susceptibility gene on chromosome 6p21. American Jo-urnal of Human Genetics. 2005. 76,349–357. 16.Noguchi E, Yokouchi Y, Zhang J, Shibuya K, Shibuya A, et al. Po-sitional identification of an asthma susceptibility gene on humanchromosome 5q33. American Journal of Respiratory and Criti-cal Care Medicine. 2005. 172,183–188. 17.Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J,Holt R,et al. Positional cloning of a quantitative trait locus onchromosome 13q14 that influences immunoglobulin E levels andasthma. Nature Genetics. 2003. 34,181–186. 18.Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schnei-der R, et al. Allele-specific targeting of microRNAs to HLA-Gand risk of asthma. American Journal of Human Genetics. 2007.81,829-834. 19.Balaci L, Spada MC, Olla N, Sole G, Loddo L, Anedda F, Nait-za S, et al. IRAK-M is involved in the pathogenesis of early-on-set persistent asthma. American Journal of Human Genetics. 2007.80,1103-1114. 20.Vercelli D. Discovering susceptibility genes for asthma and al-lergy. Nature Reviews Immunology. 2008. 8, 169-182. 21.Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, et al. Ge-netic variants regulating ORMDL3 expression contribute to the riskof childhood asthma.Nature. 2007 448,470-473. 22.Halapi E, Gudbjartsson DF, Jonsdottir GM, Bjornsdottir US, Thor-leifsson G, Helgadottir H, et al. A sequence variant on 17q21is associated with age at onset and severity of asthma. Europi-an Journal of Human Genetics. 2010. 18,902–908. 23.Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Lariviè-re M,et al. Allele-specific chromatin remodeling in the ZPBP2⁄ GSDMB ⁄ ORMDL3 locus associated with the risk of asthmaand autoimmune disease. American Journal of Human Genetics.2009 85,377–393. 24.Martinez FD, Vercelli D. Asthma. Lancet. 2013 Oct19;382(9901):1360-72. 25.Mathias RA, Grant AV, Rafaels N, Hand T, Gao L, Vergara C,et al. A genome-wide association study on African-ancestry po-pulations for asthma. Journal of Allergy and Clinical Immuno-logy. 2010. 125,336–346. 26.Sleiman PM, Flory J, Imielinski M et al. Variants of DENND1B as-sociated with asthma in children. N Engl J Med 2010;362:36-44. 27.Moffatt MF, Gut IG, Demenais F et al. A large-scale, consor-tium-based genomewide association study of asthma. N Engl JMed 2010;363:1211-21. 28.Liew FY, Pitman NI, McInnes IB. Disease-associated functi-ons of IL-33: the new kid in the IL-1 family. Nat Rev Immunol2010;10:103-10. 29.Ohno T, Morita H, Arae K, Matsumoto K, Nakae S. Interleukin-33 in allergy. Allergy 2012;67:1203-14. 30.Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gig-noux CR, et al. Meta-analysis of genome-wide association stu-dies of asthma in ethnically diverse North American populations.Nature Genetics. 2011. 43,887-892. 31.Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Doi S, etal. Genome-wide association study identifies three new suscep-tibility loci for adult asthma in the Japanese population. Natu-re Genetics. 2011. 43,893–6. 32.Fang Q, Zhao H, Wang A, Gong Y, Liu Q. Association of gene-tic variants in chromosome 17q21 and adultonset asthma in a Chi-nese Han population. BMC Medical Genetics. 2011. 12,133. 33.Dolan CM, Fraher KE, Bleecker ER, Borish L, Chipps B, Hay-den ML. et al. TENOR Study Group. Design and baseline cha-racteristics of the epidemiology and natural history of asthma:Outcomes and Treatment Regimens (TENOR) study: a large co-hort of patients with severe or difficult-to-treat asthma. Annalsof Allergy, Asthma & Immunology. 2004. 92,32–39. 34.Haselkorn T, Fish JE, Zeiger RS, Szefler SJ, Miller DP, et al. .Consistently very poorly controlled asthma, as defined by the im-pairment domain of the Expert Panel Report 3 guidelines, increa-ses risk for future severe asthma exacerbations in The Epidemio-logy and Natural History of Asthma: Outcomes and TreatmentRegimens (TENOR) study. Journal of Allergy and Clinical Im-munology. 2009. 124,895–902. 35.Costa GN, Dudbridge F, Fiaccone RL, da Silva TM, ConceiçãoJS, Strina A et al. Agenome-wide association study of asthma symptoms in Latin Ame-rican children. BMC Genet. 2015 Dec 3;16:141 36.Barreto-Luis A, Pino-Yanes M, Corrales A, Campo P, CalleroA, Acosta-HerreraM, Cumplido J et. al. Genome-wide association study in Spanish iden-tifies ADAM metallopeptidase with thrombospondin type 1 mo-tif, 9 (ADAMTS9), as a novel asthma susceptibility gene. J AllergyClin Immunol. 2016 Mar;137(3):964-6. 37.Wang L, Murk W, DeWan AT. Genome-Wide Gene by Environ-ment Interaction Analysis Identifies Common SNPs at 17q21.2that Are Associated with Increased Body Mass Index Only amongAsthmatics. PLoS One. 2015 Dec 16;10(12):e0144114 38.Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, etal. . (2010) Meta-analyses of genome-wide association studies iden-tify multiple loci associated with pulmonary function. Nature Ge-netics. 42,45–52. 39.Repapi E, Sayers I, Wain LV, Burton PR, Johnson T, Obeidat M,etal. Genome-wide association study identifies five loci associa-ted with lung function. Nature Genetics. 2010.42,36–44. 40.Slager RE, Hawkins GA, Li X, Postma DS, Meyers DA, Bleec-ker ER. Genetics of asthma susceptibility and severity. Clinics inChest Medicine. 2012. 33,431-443. 41.Liang S, Wei X, Gong C, Wei J, Chen Z, Deng J. A disintegrinand metalloprotease 33 (ADAM33) gene polymorphisms and therisk of asthma: a meta-analysis. Hum Immunol. 2013May;74(5):648-57. 42.Huang H, Nie W, Qian J, Zang Y, Chen J, Lai G, Ye T, Xiu Q.Effects of TNF-αpolymorphisms on asthma risk: a systematic re-view and meta-analysis. J Investig Allergol Clin Immunol.2014;24(6):406-17 43.Zheng XY, Guan WJ, Mao C, Chen HF, Ding H, Zheng JP, HuTT, Luo MH, Huang YH, Chen Q. Interleukin-10 promoter 1082/-819/-592 polymorphisms are associated with asthma suscepti-bility in Asians and atopic asthma: a meta-analysis. Lung. 2014Feb;192(1):65-73. 44.Tizaoui K, Berraies A, Hamdi B, Kaabachi W, Hamzaoui K, Ham-zaoui A. Association of vitamin D receptor gene polymorphismswith asthma risk: systematic review and updated meta-analysisof case-control studies. Lung. 2014 Dec;192(6):955-65. 45.Xie ZK, Zhao H, Huang J, Xie ZF. The regulated upon activati-on normal T-cell expressed and secreted (RANTES) -28C/G and-403G/A polymorphisms and asthma risk: a meta-analysis. MolDiagn Ther. 2014 Oct;18(5):523-31 46.Cheng D, Hao Y, Zhou W, Ma Y. The relationship between in-terleukin-18 polymorphisms and allergic disease: a meta-analy-sis. Biomed Res Int. 2014;2014:290687. 47.Liang S, Wei X, Gong C, Wei J, Chen Z, Chen X, Wang Z, DengJ. Significant association between asthma risk and the GSTM1and GSTT1 deletion polymorphisms:an updated meta-analysis of case-control studies. Respirology.2013 Jul;18(5):774-83. 48.He Y, Peng S, Xiong W, Xu Y, Liu J. Association between poly-morphism of interleukin-1 beta and interleukin-1 receptor anta-gonist gene and asthma risk: a meta-analysis. ScientificWorld-Journal. 2015;2015:685684. 49.Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bous-quet J, Chateigner N, Gormand F, Just J, Le Moual N, ve ark.Effect of 17q21 variants and smoking exposure in early-onset asth-ma. New England Journal of Medicine. 2008 359,1985-1994. 50.Woo JG, Assa'ad A, Heizer AB, Bernstein JA, Hershey GK. The-159 C-->T polymorphism of CD14 is associated with nonato-pic asthma and food allergy. Journal of Allergy and Clinical Im-munology. 2003. 112,438-444. 51.Vercelli D. (2004) Genetics, epigenetics, and the environment:switching, buffering, releasing. Journal of Allergy and ClinicalImmunology. 2004. 113,381-386. 52.Keskin O, Birben E, Saçkesen C, Soyer OU, Alyamaç E, Kara-aslan C, Tokol N, Ercan H, Kalayci O. (2006) The effect of CD14-C159T genotype on the cytokine response to endotoxin byPBMC from asthmatic children. Annals of Allergy, Asthma & Im-munology.2006; 97,321-328. 53.Kabesch M, Schedel M, Carr D, Woitsch B, Fritzsch C, WeilandSK, von Mutius E. (2006) IL-4/IL-13 pathway genetics stronglyinfluence serum IgE levels and childhood asthma. Journal of Al-lergy and Clinical Immunology. 117,269-274. 54.Namkung JH, Lee JE, Kim E, Park GT, Yang HS, Jang HY, ShinES, Cho EY, Yang JM. An association between IL-9 and IL-9 re-ceptor gene polymorphisms and atopic dermatitis in a Korean po-pulation. J Dermatol Sci. 2011 Apr;62(1):16-21 55.Bottema RW, Kerkhof M, Reijmerink NE, Thijs C, Smit HA, vanSchayck CP, et al. . Gene-gene interaction in regulatory T-cell func-tion in atopy and asthma development in childhood. J Allergy ClinImmunol. 2010 Aug;126(2):338-46, 346.e1-10. 56.Via M, De Giacomo A, Corvol H, Eng C, Seibold MA, Gillett C,et al. Genetics of Asthma in Latino Americans (GALA) Study.. Therole of LTA4H and ALOX5AP genes in the risk for asthma in La-tinos. Clin Exp Allergy. 2010 Apr;40(4):582-9. 57.Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Ad-cock IM. Expression and activity of histone deacetylases in hu-man asthmatic airways. Am J Respir Crit Care Med. 2002 Aug1;166(3):392-6. 58.Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, SuhHH, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J. (2009) Ra-pid DNA methylation changes after exposure to traffic particles.American Journal of Respiratory and Critical Care Medicine.2009. 179,572-8. 59.Liu J, Ballaney M, Al-alem U, Quan C, Jin X, Perera F, Chen LC,Miller RL. Combined inhaled diesel exhaust particles and aller-gen exposure alter methylation of T helper genes and IgE pro-duction in vivo. Toxicological Sciences. 2008. 102,76–81. 60.Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM.Cigarette smoking reduces histone deacetylase 2 expression, en-hances cytokine expression, and inhibits glucocorticoid actionsin alveolar macrophages. FASEB J. 2001 Apr;15(6):1110-2. 61.Schaub B, Liu J, Höppler S, Schleich I, Huehn J, Olek S, Wiec-zorek G, Illi S, von Mutius E. Maternal farm exposure modula-tes neonatal immune mechanisms through regulatory T cells. JAllergy Clin Immunol. 2009 Apr;123(4):774-82.e5. 62.Munthe-Kaas MC, Torjussen TM, Gervin K, Lødrup Carlsen KC,Carlsen KH, Granum B, Hjorthaug HS, Undlien D, Lyle R. CD14 polymorphisms and serum CD14 levels through childhood: a rolefor gene methylation? J Allergy Clin Immunol. 2010Jun;125(6):1361-8. 63.Tsitsiou E, Williams AE, Moschos SA, Patel K, Rossios C, JiangX, Adams OD, Macedo P, Booton R, Gibeon D, Chung KF, Lind-say MA. Transcriptome analysis shows activation of circulatingCD8+ T cells in patients with severe asthma. J Allergy Clin Im-munol. 2012 Jan;129(1):95-103. 64.Maccani MA, Avissar-Whiting M, Banister CE, McGonnigal B,Padbury JF, Marsit CJ. Maternal cigarette smoking during preg-nancy is associated with downregulation of miR-16, miR-21, andmiR-146a in the placenta. Epigenetics. 2010 Oct 1;5(7):583-9. 65.Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Cra-ig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, ve ark. Use of re-gularly scheduled albuterol treatment in asthma: genotype-stra-tified, randomised, placebo-controlled cross-over trial. Lancet.2004. 364,1505-1512. 66.Zuurhout MJ, Vijverberg SJ, Raaijmakers JA, Koenderman L,Postma DS, Koppelman GH, Maitland-van der Zee AH. Arg16ADRB2 genotype increases the risk of asthma exacerbation inchildren with a reported use of long-acting β2-agonists: resultsof the PACMAN cohort. Pharmacogenomics. 2013Dec;14(16):1965-71. 67.Israel E, Lasky-Su J, Markezich A, Damask A, Szefler SJ, Schue-mann B et al. Genome-wide association study of short-acting β2-agonists. A novel genome-wide significant locus on chromoso-me 2 near ASB3. Am J Respir Crit Care Med. 2015 Mar1;191(5):530-7. 68.Padhukasahasram B, Yang JJ, Levin AM, Yang M, Burchard EG,Kumar R Gene-based association identifies SPATA13-AS1 as apharmacogenomic predictor of inhaled short-acting beta-agonistresponse in multiple population groups. Pharmacogenomics J.2014 Aug;14(4):365-71. 69.Drake KA, Torgerson DG, Gignoux CR, Galanter JM, Roth LA,Huntsman S et al. A genome-wide association study of broncho-dilator response in Latinos implicates rare variants. J Allergy ClinImmunol. 2014 Feb;133(2):370-8 70.Davis JS, Weiss ST, Tantisira KG. Asthma Pharmacogenomics:2015 Update. Curr Allergy Asthma Rep. 2015 Jul;15(7):42. 71.Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Sil-verman EK et al. Corticosteroid pharmacogenetics: associationof sequence variants in CRHR1 with improved lung function inasthmatics treated with inhaled corticosteroids. Hum Mol Genet.2004 Jul 1;13(13):1353-9. 72.Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA,Himes BE, Lange C, Lazarus R, Sylvia J, Klanderman B, ve ark.(2011) Genomewide association betweenGLCCI1 and response to glucocorticoid therapy in asthma. New En-gland Journal of Medicine. 365, 1173–1183. 73.Asano K, Shiomi T, Hasegawa N, Nakamura H, Kudo H, Mat-suzaki T, et al. Leukotriene C4 synthase gene A(-444)C polymorp-hism and clinical response to a CYS-LT(1) antagonist, pranlu-kast, in Japanese patients with moderate asthma. Pharmacoge-netics. 2002 Oct;12(7):565-70. 74.Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H et.al. Influence of leukotriene pathway polymorphisms on respon-se to montelukast in asthma. Am J Respir Crit Care Med. 2006Feb 15;173(4):379-85. 75.Klotsman M, York TP, Pillai SG, Vargas-Irwin C, Sharma SS, vanden Oord EJ, Anderson WH. Pharmacogenetics of the 5-lipoxy-genase biosynthetic pathway and variable clinical response to mon-telukast. Pharmacogenet Genomics. 2007 Mar;17(3):189-96. 76.Telleria JJ, Blanco-Quiros A, Varillas D, Armentia A, Fernan-dez-Carvajal I, Jesus Alonso M, et al. ALOX5 promoter genoty-pe and response to montelukast in moderate persistent asthma.Respir Med. 2008 Jun;102(6):857-61. 77.Kang MJ, Kwon JW, Kim BJ, Yu J, Choi WA, Shin YJ, Hong SJ.Polymorphisms of the PTGDR and LTC4S influence responsive-ness to leukotriene receptor antagonists in Korean children withasthma. J Hum Genet. 2011 Apr;56(4):284-9. 78.Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ. Absorption ofmontelukast is transporter mediated: a common variant of OATP2B1is associated with reduced plasma concentrations and poor respon-se. Pharmacogenet Genomics. 2009 Feb;19(2):129-38. 79.Qiu W, Rogers AJ, Damask A, Raby BA, Klanderman BJ, DuanQL et al. Pharmacogenomics: novel loci identification via integ-rating gene differential analysis and eQTL analysis. Hum Mol Ge-net. 2014 Sep 15;23(18):5017-24. 80.Fryer AA, Bianco A, Hepple M, Jones PW, Strange RC, Spite-ri MA. (2000) Polymorphism at the glutathione S-transferaseGSTP1 locus. A new marker for bronchial hyperresponsivenessand asthma. American Journal of Respiratory and Critical CareMedicine. 161,1437-1442. 81.Ercan H, Birben E, Dizdar EA, Keskin O, Karaaslan C, Soyer OU,Dut R, Sackesen C, Besler T, Kalayci O.(2006) Oxidative stressand genetic and epidemiologic determinants of oxidant injury inchildhood asthma. Journal of Allergy and Clinical Immunology.1118,1097-1104. 82.Dut R, Dizdar EA, Birben E, Sackesen C, Soyer OU, Besler T,Kalayci O. (2008) Oxidative stress and its determinants in the air-ways of children with asthma. Allergy. 63,1605-1609. 83.Leung TF, Sy HY, Ng MC, Chan IH, Wong GW, Tang NL et al.Asthma and atopy are associated with chromosome 17q21 mar-kers in Chinese children. Allergy. 2009 Apr;64(4):621-8. 84.Bisgaard H, Bønnelykke K, Sleiman PM, Brasholt M, Chawes B,Kreiner-Møller E, et al. Chromosome 17q21 gene variants are as-sociated with asthma and exacerbations but not atopy in early child-hood. Am J Respir Crit Care Med. 2009 Feb 1;179(3):179-85. 85.Faber TE, Schuurhof A, Vonk A, Koppelman GH, Hennus MP,Kimpen JL et al. IL1RL1 gene variants and nasopharyngealIL1RL-a levels are associated with severe RSV bronchiolitis: amulticenter cohort study. PLoS One. 2012;7(5):e34364. 86.Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Merca-der JM, Belgrave D, et al. A genome-wide association study iden-tifies CDHR3 as a susceptibility locus for early childhood asth-ma with severe exacerbations. Nat Genet. 2014 Jan;46(1):51-5. 87.Che Z, Zhu X, Yao C, Liu Y, Chen Y, Cao J et al. The associa-tion between the C-509T and T869C polymorphisms of TGF-β1gene and the risk of asthma: a meta-analysis. Hum Immunol. 2014Feb;75(2):141-50. 88.Hobbs K, Negri J, Klinnert M, Rosenwasser LJ, Borish L. Inter-leukin-10 and transforming growth factor-beta promoter poly-morphisms in allergies and asthma. Am J Respir Crit Care Med.1998 Dec;158(6):1958-62. 89.Meng J, Thongngarm T, Nakajima M, Yamashita N, Ohta K, BatesCA et al. Association of transforming growth factor-beta1 single nuc-leotide polymorphism C-509T with allergy and immunological ac-tivities. Int Arch Allergy Immunol. 2005 Oct;138(2):151-60. 90.Chiang CH, Chuang CH, Liu SL, Shen HD. Genetic polymorp-hism of transforming growth factor β1 and tumor necrosis fac-tor αis associated with asthma and modulates the severity of asth-ma. Respir Care. 2013 Aug;58(8):1343-50. 91.Jones BL, Rosenwasser LJ. Linkage and Genetic Association inSevere Asthma. Immunol Allergy Clin North Am. 2016Aug;36(3):439-47. 92.Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R et al. Effectof variation in CHI3L1 on serum YKL-40 level, risk of asthma, andlung function. N Engl J Med. 2008 Apr 17;358(16):1682-91 93.Tsai Y, Ko Y, Huang M, Lin M, Wu C, Wang C et al. CHI3L1 poly-morphisms associate with asthma in a Taiwanese population. BMCMed Genet. 2014 Jul 23;15:86. 94.Cortes A, Brown MA. Promise and pitfalls of the Immunochip.Arthritis Res Ther. 2011 Feb 1;13(1):101. 95.Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A,Bakker SF et al. Dense genotyping identifies and localizes mul-tiple common and rare variant association signals in celiac di-sease. Nat Genet. 2011 Nov 6;43(12):1193-201. 96.Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, GibbsRA, Hurles ME, McVean GA. 1000 Genomes Project Consortium.,A map of human genome variation from population-scale sequen-cing. Nature. 2010 Oct 28;467(7319):1061-73. 97.Benoist C, Lanier L, Merad M, Mathis D; Immunological Geno-me Project. Consortium biology in immunology: the perspecti-ve from the Immunological Genome Project. Nat Rev Immunol.2012 Oct;12(10):734-40.