Genome-wide association study of aspirin-exacerbated respiratory disease in a Korean population
- 880 Downloads
Aspirin-exacerbated respiratory disease (AERD) is a nonallergic clinical syndrome characterized by a severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. The effects of genetic variants have not fully explained all of the observed individual differences to an aspirin challenge despite previous attempts to identify AERD-related genes. In the present study, we performed genome-wide association study (GWAS) and targeted association study in Korean asthmatics to identify new genetic factors associated with AERD. A total of 685 asthmatic patients without AERD and 117 subjects with AERD were used for the GWAS of the first stage, and 996 asthmatics without AERD and 142 subjects with AERD were used for a follow-up study. A total of 702 SNPs were genotyped using the GoldenGate assay with the VeraCode microbead. GWAS revealed the top-ranked variants in 3′ regions of the HLA-DPB1 gene. To investigate the detailed genetic effects of an associated region with the risk of AERD, a follow-up targeted association study with the 702 single nucleotide polymorphisms (SNPs) of 14 genes was performed on 802 Korean subjects. In a case–control analysis, HLA-DPB1 rs1042151 (Met105Val) shows the most significant association with the susceptibility of AERD (p = 5.11 × 10−7; OR = 2.40). Moreover, rs1042151 also shows a gene dose for the percent decline of FEV1 after an aspirin challenge (p = 2.82 × 10−7). Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the importance of HLA-DPB1 in the genetic etiology of AERD.
KeywordsPercent Decline Aspirin Challenge Nonsynonymous Single Nucleotide Polymorphism Aspirin Hypersensitivity AERD Patient
This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090548 & 010249), and by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (No. 2009-0080157). The DNA samples were generously provided by Soonchunhyang University, Bucheon Hospital Biobank, a member of the National Biobank of Korea, supported by the Ministry of Health, Welfare and Family Affairs, Republic of Korea.
Conflict of interest
The authors declare that they have no conflicts of interest.
- (1995) Global Initiative for Asthma. Global strategy for asthma management and prevention. NHLBI/WHO workshop report. Bethesda. National Institutes of HealthGoogle Scholar
- Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N, Shimizu M, Nakashima K, Cheng L, Doi S, Fujiwara H, Miyatake A, Fujita K, Higashi N, Taniguchi M, Enomoto T, Mao XQ, Nakashima H, Adra CN, Nakamura Y, Tamari M, Shirakawa T (2005) Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet 117:16–26PubMedCrossRefGoogle Scholar
- 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 (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41:342–347PubMedCrossRefGoogle Scholar
- 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 (2009) Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 84:581–593PubMedCrossRefGoogle Scholar
- Hitomi Y, Ebisawa M, Tomikawa M, Imai T, Komata T, Hirota T, Harada M, Sakashita M, Suzuki Y, Shimojo N, Kohno Y, Fujita K, Miyatake A, Doi S, Enomoto T, Taniguchi M, Higashi N, Nakamura Y, Tamari M (2009) Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J Allergy Clin Immunol 124(779-85):e6PubMedGoogle Scholar
- Jinnai N, Sakagami T, Sekigawa T, Kakihara M, Nakajima T, Yoshida K, Goto S, Hasegawa T, Koshino T, Hasegawa Y, Inoue H, Suzuki N, Sano Y, Inoue I (2004) Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet 13:3203–3217PubMedCrossRefGoogle Scholar
- 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 (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448:470–473PubMedCrossRefGoogle Scholar
- Nizankowska-Mogilnicka E, Bochenek G, Mastalerz L, Swierczynska M, Picado C, Scadding G, Kowalski ML, Setkowicz M, Ring J, Brockow K, Bachert C, Wohrl S, Dahlen B, Szczeklik A (2007) EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity. Allergy 62:1111–1118PubMedCrossRefGoogle Scholar
- Oh SH, Park SM, Park JS, Jang AS, Lee YM, Uh ST, Kim YH, Choi IS, Kim MK, Park BL, Shin HD, Park CS (2009) Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with aspirin hypersensitivity in asthmatics. Allergy Asthma Immunol Res 1:30–35PubMedCrossRefGoogle Scholar
- Sturtevant J (1999) NSAID-induced bronchospasm—a common and serious problem. A report from MEDSAFE, the New Zealand Medicines and Medical Devices Safety Authority. NZ Dent J 95:84Google Scholar
- Van der Zwan RE, Tilanus MG (2000) Sequence-based typing for HLA-DPB1 strategy for ABI sequencing equipment. In: Tilanus MGJ, Hansen JA, Heuley CK (eds) IHWG technical manual. International Histocompatibility Working Group, Seattle, TM14A, pp 1–4Google Scholar