Allergy Asthma Immunol Res.  2011 Oct;3(4):236-244. 10.4168/aair.2011.3.4.236.

The Search for Genetic Variants and Epigenetics Related to Asthma

  • 1Genome Research Center for Allergy and Respiratory Disease, Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Bucheon, Korea.


For the past two decades, a huge number of genetic studies have been conducted to identify the genetic variants responsible for asthma risk. Several types of genetic and genomic approaches, including linkage analysis, candidate gene single nucleotide polymorphism studies, and whole genome-wide association studies have been applied. In this review article, the results of these approaches are summarized, and their limitations are discussed. Additionally, perspectives for applying upcoming new epigenetic or genomic technologies, such as copy number variation, are introduced to increase our understanding of new omic approaches to asthma genetics.


Asthma; epigenetics; gene; genome; linkage; polymorphism; variants

MeSH Terms

Coat Protein Complex I
Genetic Association Studies
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Coat Protein Complex I


  • Fig. 1 Odd ratios of single nucleotide polymorphisms (SNPs) associated with asthma and asthma phenotypes including IgE and eosinophils counts (2003-2010, SCH Genome Research Center). IgE, immunoglobulin E; RSV, respiratory syncytial virus; NO2, nitrogen dioxide; FcRI and FcRII, high-affinity IgE receptor isoforms; TLR, toll-like receptor; M-CSF, macrophage colony-stimulating factor; NFAT, nuclear factor of activated T-cells; API, activator protein 1; GATA, GATA-binding factor; NFκB, nuclear factor kappa B; IκB, inhibitor of NFκB; OR, odd ratios; ADAM33,15 disintegrin and metalloproteinase domain-containing protein 33; CXCR3,16 chemokine receptor 3; IL17Rβ,17 interleukin 17 receptor β; CD40,18 cluster of differentiation 40; RUNX119; runt-related transcription factor 1; ITK,20 IL2-inducible T-cell kinase; CTNNα3,21 catenin α 3; CSF1R,22 colony-stimulation factor 1 receptor; MCP3,23 monocyte chemotactic protein 3; PPAR,24 peroxisome proliferator-activated receptors; DCNP1,25 dendritic cell nuclear protein 1; IL5Rα,26 interleukin 5 receptor α; STAT4,27 signal transducer and activator of transcription 4; CCR3,28 C-C chemokine receptor type 3; MYLK,29 myosin light chain kinase; eotaxin.30

  • Fig. 2 DNA methylation pattern of nasal polyps from patients with aspirin-exacerbated respiratory disease and those with aspirin tolerant asthma. (A) Volcano plot of differential methylation level between aspirin intolerant asthma (AIA) and aspirin tolerant asthma (ATA) in nasal polyp tissues (A-1) and buffy coat samples (A-2). Red dots, Delta Beta ≥0.5 and P value ≤0.01; blue dots, Delta Beta ≤-0.5 and P value ≤0.01; grey dots, -0.5≤ Delta Beta ≤0.5 and P value >0.01. Delta Beta: difference in DNA methylation level (subtracting the DNA methylation level of ATA from AIA). -log (P): log-transformed t-test P values. (B) Distribution of the DNA methylation level of AIA and ATA in buffy coat and nasal polyps. Average Beta: DNA methylation level (0 to 1). (C) Heat map of 490 differentially methylated CpGs between AIA and ATA in buffy coat and nasal polyps.

Cited by  1 articles

Clinical Implications of Single Nucleotide Polymorphisms in Diagnosis of Asthma and its Subtypes
Jong-Sook Park, Ji-Hye Son, Choon-Sik Park, Hun Soo Chang
Yonsei Med J. 2019;60(1):1-9.    doi: 10.3349/ymj.2019.60.1.1.


1. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989. 320:271–277.
2. Burrows B, Sears MR, Flannery EM, Herbison GP, Holdaway MD, Silva PA. Relation of the course of bronchial responsiveness from age 9 to age 15 to allergy. Am J Respir Crit Care Med. 1995. 152:1302–1308.
3. Bousquet J, Chanez P, Vignola AM, Lacoste JY, Michel FB. Eosinophil inflammation in asthma. Am J Respir Crit Care Med. 1994. 150:S33–S38.
4. Edfors-Lubs ML. Allergy in 7000 twin pairs. Acta Allergol. 1971. 26:249–285.
5. Ho SM. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol. 2010. 126:453–465.
6. Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet. 1995. 29:777–807.
7. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA). Nat Genet. 1997. 15:389–392.
8. Moffatt MF, Cookson WO. Gene identification in asthma and aller gy. Int Arch Allergy Immunol. 1998. 116:247–252.
9. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002. 418:426–430.
10. Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting CP, Bhattacharyya S, Tinsley J, Zhang Y, Holt R, Jones EY, Lench N, Carey A, Jones H, Dickens NJ, Dimon C, Nicholls R, Baker C, Xue L, Townsend E, Kabesch M, Weiland SK, Carr D, von Mutius E, Adcock IM, Barnes PJ, Lathrop GM, Edwards M, Moffatt MF, Cookson WO. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet. 2003. 35:258–263.
11. Zhang Y, Leaves NI, Anderson GG, Ponting CP, Broxholme J, Holt R, Edser P, Bhattacharyya S, Dunham A, Adcock IM, Pulleyn L, Barnes PJ, Harper JI, Abecasis G, Cardon L, White M, Burton J, Matthews L, Mott R, Ross M, Cox R, Moffatt MF, Cookson WO. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet. 2003. 34:181–186.
12. Laitinen T, Polvi A, Rydman P, Vendelin J, Pulkkinen V, Salmikangas P, Makela S, Rehn M, Pirskanen A, Rautanen A, Zucchelli M, Gullsten H, Leino M, Alenius H, Petays T, Haahtela T, Laitinen A, Laprise C, Hudson TJ, Laitinen LA, Kere J. Characterization of a common susceptibility locus for asthma-related traits. Science. 2004. 304:300–304.
13. Oguma T, Palmer LJ, Birben E, Sonna LA, Asano K, Lilly CM. Role of prostanoid DP receptor variants in susceptibility to asthma. N Engl J Med. 2004. 351:1752–1763.
14. Risch NJ. Searching for genetic determinants in the new millennium. Nature. 2000. 405:847–856.
15. Lee JH, Park HS, Park SW, Jang AS, Uh ST, Rhim T, Park CS, Hong SJ, Holgate ST, Holloway JW, Shin HD. ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics. Clin Exp Allergy. 2004. 34:860–865.
16. Cheong HS, Park CS, Kim LH, Park BL, Uh ST, Kim YH, Lym GI, Lee JY, Lee JK, Kim HT, Ryu HJ, Han BG, Kim JW, Park C, Kimm K, Shin HD, Oh B. CXCR3 polymorphisms associated with risk of asthma. Biochem Biophys Res Commun. 2005. 334:1219–1225.
17. Jung JS, Park BL, Cheong HS, Bae JS, Kim JH, Chang HS, Rhim T, Park JS, Jang AS, Lee YM, Kim KU, Uh ST, Na JO, Kim YH, Park CS, Shin HD. Association of IL-17RB gene polymorphism with asthma. Chest. 2009. 135:1173–1180.
18. Park JH, Chang HS, Park CS, Jang AS, Park BL, Rhim TY, Uh ST, Kim YH, Chung IY, Shin HD. Association analysis of CD40 polymorphisms with asthma and the level of serum total IgE. Am J Respir Crit Care Med. 2007. 175:775–782.
19. Chae SC, Park BL, Park CS, Ryu HJ, Yang YS, Lee SO, Choi YH, Kim EM, Uh ST, Kim YH, Kim KK, Oh B, Chung HT, Kimm K, Shin HD. Putative association of RUNX1 polymorphisms with IgE levels in a Korean population. Exp Mol Med. 2006. 38:583–588.
20. Lee SH, Chang HS, Jang AS, Park SW, Park JS, Uh ST, Kim YH, Oh B, Lee JK, Park BL, Shin HD, Park CS, Kimm K. The association of a single-nucleotide polymorphism of the IL-2 inducible T-cell kinase gene with asthma. Ann Hum Genet. 2011. 75:359–369.
21. Kim SH, Cho BY, Park CS, Shin ES, Cho EY, Yang EM, Kim CW, Hong CS, Lee JE, Park HS. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy. 2009. 39:203–212.
22. Shin EK, Lee SH, Cho SH, Jung S, Yoon SH, Park SW, Park JS, Uh ST, Kim YK, Kim YH, Choi JS, Park BL, Shin HD, Park CS. Association between colony-stimulating factor 1 receptor gene polymorphisms and asthma risk. Hum Genet. 2010. 128:293–302.
23. Park BL, Kim LH, Choi YH, Cheong HS, Park HS, Hong SJ, Choi BW, Lee JH, Uh ST, Park CS, Shin HD. Association analysis of monocyte chemotactic protein-3 (MCP3) polymorphisms with asthmatic phenotypes. J Biochem Mol Biol. 2005. 38:77–81.
24. Oh SH, Park SM, Lee YH, Cha JY, Lee JY, Shin EK, Park JS, Park BL, Shin HD, Park CS. Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms with the development of asthma. Respir Med. 2009. 103:1020–1024.
25. Kim Y, Park CS, Shin HD, Choi JW, Cheong HS, Park BL, Choi YH, Jang AS, Park SW, Lee YM, Lee EJ, Park SG, Lee JY, Lee JK, Han BG, Oh B, Kimm K. A promoter nucleotide variant of the dendritic cell-specific DCNP1 associates with serum IgE levels specific for dust mite allergens among the Korean asthmatics. Genes Immun. 2007. 8:369–378.
26. Cheong HS, Kim LH, Park BL, Choi YH, Park HS, Hong SJ, Choi BW, Park CS, Shin HD. Association analysis of interleukin 5 receptor alpha subunit (IL5RA) polymorphisms and asthma. J Hum Genet. 2005. 50:628–634.
27. Park BL, Cheong HS, Kim LH, Choi YH, Namgoong S, Park HS, Hong SJ, Choi BW, Lee JH, Park CS, Shin HD. Association analysis of signal transducer and activator of transcription 4 (STAT4) polymorphisms with asthma. J Hum Genet. 2005. 50:133–138.
28. Lee JH, Chang HS, Kim JH, Park SM, Lee YM, Uh ST, Rhim T, Chung IY, Kim YH, Park BL, Park CS, Shin HD. Genetic effect of CCR3 and IL5RA gene polymorphisms on eosinophilia in asthmatic patients. J Allergy Clin Immunol. 2007. 120:1110–1117.
29. Lee SO, Cheong HS, Park BL, Bae JS, Sim WC, Chun JY, Isbat M, Uh ST, Kim YH, Jang AS, Park CS, Shin HD. MYLK polymorphism associated with blood eosinophil level among asthmatic patients in a Korean population. Mol Cells. 2009. 27:175–181.
30. Lee JH, Moore JH, Park SW, Jang AS, Uh ST, Kim YH, Park CS, Park BL, Shin HD. Genetic interactions model among Eotaxin gene polymorphisms in asthma. J Hum Genet. 2008. 53:867–875.
31. Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med. 2009. 360:1759–1768.
32. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007. 448:470–473.
33. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, Williams C, Hui J, Beilby J, Warrington NM, James A, Palmer LJ, Koppelman GH, Heinzmann A, Krueger M, Boezen HM, Wheatley A, Altmuller J, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Gislason D, Park CS, Rasmussen LM, Porsbjerg C, Hansen JW, Backer V, Werge T, Janson C, Jonsson UB, Ng MC, Chan J, So WY, Ma R, Shah SH, Granger CB, Quyyumi AA, Levey AI, Vaccarino V, Reilly MP, Rader DJ, Williams MJ, van Rij AM, Jones GT, Trabetti E, Malerba G, Pignatti PF, Boner A, Pescollderungg L, Girelli D, Olivieri O, Martinelli N, Ludviksson BR, Ludviksdottir D, Eyjolfsson GI, Arnar D, Thorgeirsson G, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Gulcher J, Kong A, Jonsdottir I, Thorsteinsdottir U, Stefansson K. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009. 41:342–347.
34. Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, Wilk JB, Willis-Owen SA, Klanderman B, Lasky-Su J, Lazarus R, Murphy AJ, Soto-Quiros ME, Avila L, Beaty T, Mathias RA, Ruczinski I, Barnes KC, Celedon JC, Cookson WO, Gauderman WJ, Gilliland FD, Hakonarson H, Lange C, Moffatt MF, O'Connor GT, Raby BA, Silverman EK, Weiss ST. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet. 2009. 84:581–593.
35. Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, Li H, del Rio-Navarro BE, Willis-Owen SA, Weiss ST, Raby BA, Gao H, Eng C, Chapela R, Burchard EG, Tang H, Sullivan PF, London SJ. Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children. PLoS Genet. 2009. 5:e1000623.
36. Bardy GH, Smith WM, Hood MA, Crozier IG, Melton IC, Jordaens L, Theuns D, Park RE, Wright DJ, Connelly DT, Fynn SP, Murgatroyd FD, Sperzel J, Neuzner J, Spitzer SG, Ardashev AV, Oduro A, Boersma L, Maass AH, Van Gelder IC, Wilde AA, van Dessel PF, Knops RE, Barr CS, Lupo P, Cappato R, Grace AA. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med. 2010. 363:36–44.
37. Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, Bleecker ER. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol. 2010. 125:328–335.e11.
38. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010. 363:1211–1221.
39. Shin HD, Park BL, Kim LH, Jung JH, Kim JY, Yoon JH, Kim YJ, Lee HS. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. Hum Mol Genet. 2003. 12:901–906.
40. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009. 461:747–753.
41. Halapi E, Gudbjartsson DF, Jonsdottir GM, Bjornsdottir US, Thorleifsson G, Helgadottir H, Williams C, Koppelman GH, Heinzmann A, Boezen HM, Jonasdottir A, Blondal T, Gudjonsson SA, Thorlacius T, Henry AP, Altmueller J, Krueger M, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Ludviksson BR, Ludviksdottir D, Gislason D, Park CS, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Kong A, Jonsdottir I, Thorsteinsdottir U, Stefansson K. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet. 2010. 18:902–908.
42. Bouzigon E, Corda E, Aschard H, Dizier MH, Boland A, Bousquet J, Chateigner N, Gormand F, Just J, Le Moual N, Scheinmann P, Siroux V, Vervloet D, Zelenika D, Pin I, Kauffmann F, Lathrop M, Demenais F. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med. 2008. 359:1985–1994.
43. Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, He W, Chen YJ, Makhijani V, Roth GT, Gomes X, Tartaro K, Niazi F, Turcotte CL, Irzyk GP, Lupski JR, Chinault C, Song XZ, Liu Y, Yuan Y, Nazareth L, Qin X, Muzny DM, Margulies M, Weinstock GM, Gibbs RA, Rothberg JM. The complete genome of an individual by massively parallel DNA sequencing. Nature. 2008. 452:872–876.
44. Thomsen SF, van der Sluis S, Kyvik KO, Skytthe A, Backer V. Estimates of asthma heritability in a large twin sample. Clin Exp Allergy. 2010. 40:1054–1061.
45. Miller RL. Prenatal maternal diet affects asthma risk in offspring. J Clin Invest. 2008. 118:3265–3268.
46. Cheong HS, Park SM, Kim MO, Park JS, Lee JY, Byun JY, Park BL, Shin HD, Park CS. Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics. Allergy. 2011. 66:637–644.
47. Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF, Giannoulatou E, Holmes C, Marchini JL, Stirrups K, Tobin MD, Wain LV, Yau C, Aerts J, Ahmad T, Andrews TD, Arbury H, Attwood A, Auton A, Ball SG, Balmforth AJ, Barrett JC, Barroso I, Barton A, Bennett AJ, Bhaskar S, Blaszczyk K, Bowes J, Brand OJ, Braund PS, Bredin F, Breen G, Brown MJ, Bruce IN, Bull J, Burren OS, Burton J, Byrnes J, Caesar S, Clee CM, Coffey AJ, Connell JM, Cooper JD, Dominiczak AF, Downes K, Drummond HE, Dudakia D, Dunham A, Ebbs B, Eccles D, Edkins S, Edwards C, Elliot A, Emery P, Evans DM, Evans G, Eyre S, Farmer A, Ferrier IN, Feuk L, Fitzgerald T, Flynn E, Forbes A, Forty L, Franklyn JA, Freathy RM, Gibbs P, Gilbert P, Gokumen O, Gordon-Smith K, Gray E, Green E, Groves CJ, Grozeva D, Gwilliam R, Hall A, Hammond N, Hardy M, Harrison P, Hassanali N, Hebaishi H, Hines S, Hinks A, Hitman GA, Hocking L, Howard E, Howard P, Howson JM, Hughes D, Hunt S, Isaacs JD, Jain M, Jewell DP, Johnson T, Jolley JD, Jones IR, Jones LA, Kirov G, Langford CF, Lango-Allen H, Lathrop GM, Lee J, Lee KL, Lees C, Lewis K, Lindgren CM, Maisuria-Armer M, Maller J, Mansfield J, Martin P, Massey DC, McArdle WL, McGuffin P, McLay KE, Mentzer A, Mimmack ML, Morgan AE, Morris AP, Mowat C, Myers S, Newman W, Nimmo ER, O'Donovan MC, Onipinla A, Onyiah I, Ovington NR, Owen MJ, Palin K, Parnell K, Pernet D, Perry JR, Phillips A, Pinto D, Prescott NJ, Prokopenko I, Quail MA, Rafelt S, Rayner NW, Redon R, Reid DM, Renwick , Ring SM, Robertson N, Russell E, St Clair D, Sambrook JG, Sanderson JD, Schuilenburg H, Scott CE, Scott R, Seal S, Shaw-Hawkins S, Shields BM, Simmonds MJ, Smyth DJ, Somaskantharajah E, Spanova K, Steer S, Stephens J, Stevens HE, Stone MA, Su Z, Symmons DP, Thompson JR, Thomson W, Travers ME, Turnbull C, Valsesia A, Walker M, Walker NM, Wallace C, Warren-Perry M, Watkins NA, Webster J, Weedon MN, Wilson AG, Woodburn M, Wordsworth BP, Young AH, Zeggini E, Carter NP, Frayling TM, Lee C, McVean G, Munroe PB, Palotie A, Sawcer SJ, Scherer SW, Strachan DP, Tyler-Smith C, Brown MA, Burton PR, Caulfield MJ, Compston A, Farrall M, Gough SC, Hall AS, Hattersley AT, Hill AV, Mathew CG, Pembrey M, Satsangi J, Stratton MR, Worthington J, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand W, Parkes M, Rahman N, Todd JA, Samani NJ, Donnelly P. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010. 464:713–720.
48. Toft M, Ross OA. Copy number variation in Parkinson's disease. Genome Med. 2010. 2:62.
Full Text Links
  • AAIR
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2022 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: