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한국인에서 NDFIP2 유전적 다형성과 천식의 상관 연구

Association Study of NDFIP2 Genetic Polymorphism with Asthma in the Korean Population

  • 최은혜 (호서대학교 생명보건대학 임상병리학과) ;
  • 황다현 (호서대학교 생명보건대학 임상병리학과)
  • Choi, Eun Hye (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University) ;
  • Hwang, Dahyun (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University)
  • 투고 : 2021.08.01
  • 심사 : 2021.09.03
  • 발행 : 2021.09.30

초록

천식은 만성 염증성 기도 폐쇄 질환이다. 질병 발생 요인은 다양하며 특히, 유전적 요인과 환경적 요인이 천식 발병에 영향을 미치는 것으로 추정된다. MAPK (mitogen-activated protein kinase)경로는 Th1/Th2의 균형을 조절하며, 천식 발생에 중요한 역할을 하는 것으로 알려져 있다. 본 연구에서는 MAPK 경로를 조절하는 NDFIP2 유전자와 천식 발병과의 상관관계를 분석하였다. 193건의 천식 환자와 3,228건의 정상 대조군의 유전형 데이터를 사용하였다. 그 결과 NDFIP2 안에 있는 4개의 SNP이 천식과 유의한 상관관계와 높은 상대적 위험도를 보였다. 특히 NDFIP2의 rs2783122는 천식과 통계적으로 가장 유의한 연관성을 나타냈다(P-value=9.76×10-6, OR=1.67, 95% CI=1.33~2.10). NDFIP2 유전자에 대한 SNP imputation 결과 16개의 SNP가 추가 발견되었으며, 모두 유의한 상관 관계와 높은 상대적 위험도를 나타냈다. 유전자형 기반 mRNA 발현 분석을 통해 rs1408049가 minor allele을 가질 경우 유전자 발현이 증가됨을 알 수 있었다. 증가된 NDFIP2 발현은 MAPK 경로를 활성화시켜 천식 발병에 영향을 미칠 수 있다. 결론적으로 NDFIP2의 다형성은 천식 발병과 관련이 있으며, 이는 한국 인구의 천식 관리에 대한 새로운 지침을 제공할 수 있다.

Asthma is a chronic inflammatory airway disease. There are many factors including genetic and environmental factors that influence asthma. The mitogen-activated protein kinase (MAPK) pathway is involved in maintaining the T helper cells 1 and 2 (Th1/Th2) balance and plays an important role in the development of asthma. In this study, the correlation between the NDFIP2 gene that regulates the MAPK pathway and asthma was analyzed. The genetic polymorphism of the NDFIP2 gene was analyzed between 193 asthma patients and 3,228 healthy controls in Korea. As a result, 4 single nucleotide polymorphisms (SNPs) showed a significant correlation (P<0.05) and high relative risk with asthma. Among them, rs2783122 of NDFIP2 showed a statistically significant association with asthma (P-value=9.76×10-6, odds ratio (OR)=1.67, 95% confidence interval (CI)=1.33~2.10). In the SNP imputation on the NDFIP2, 16 SNPs were discovered, and all of them showed significant correlation with asthma and high odds ratio. The genotype-based mRNA expression analysis revealed that the group of minor alleles of rs1408049 showed increased mRNA expression. Increased NDFIP2 expression causes the activation of the MAPK pathway, and this may influence the development of asthma. In conclusion, the polymorphisms of NDFIP2 are associated with asthma development and this can provide the basis for new guidelines for the management of asthma in the Korean population.

키워드

과제정보

This study was conducted with bioresources from National Biobank of Korea, the Korea Disease Control and Prevention Agency, Republic of Korea (KBN-2021-023).

참고문헌

  1. Do HY, Yu CH, Kang SW, Kim KI, Lee BJ, Jung HJ. A comparative analysis of deficiency-excess pattern identification with sputum cytokines and the characteristics of asthma patients. Korean J Orient Int Med. 2019;40:582-596. https://doi.org/10.22246/jikm.2019.40.4.582
  2. Ahn YS, Koh DH, Moon KT. The etiologic fraction of isocyanate-related asthma in isocyanate-exposed workers. Korean J Occup Environ Med. 2007;19:276-284. https://doi.org/10.35371/kjoem.2007.19.4.276
  3. Park IS, Yun HK. Asthma worsening factors of adolescent asthma patients in Korea-asscociated with intake of antioxidant food. J Digit Converg. 2017;15:297-304. https://doi.org/10.14400/JDC.2017.15.6.297
  4. Kim JH. Diagnosis of severe asthma: definition and identification. Korean J Med. 2018;93:153-158. https://doi.org/10.3904/kjm.2018.93.2.153
  5. Braun CM, Huang SK, Bashian GG, Kagey-Sobotka A, Lichtenstein LM, Essayan DM. Corticosteroid modulation of human, antigen-specific Th1 and Th2 responses. J Allergy Clin Immunol. 1997;100:400-407. https://doi.org/10.1016/S0091-6749(97)70255-0
  6. Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J. 1998;12: 1209-1218. https://doi.org/10.1183/09031936.98.12051209
  7. Lee JH, Park YM. Proper use of topical corticosteroids. J Korean Med Assoc. 2018;632-636. https://doi.org/10.5124/jkma.2018.61.10.632
  8. Yu SR, Jeong SY, Jung JH, Kim JJ, Jung SK. Association study of glutathione-s-transferase M1/T1 gene polymorphism with deficiency-excess differentiation-syndrome in Korean bronchial asthmatics. Korean J Orient Int Med. 2007;28:453-463.
  9. Hwang WS, Jeong SY, Kim JJ, Jung DY, Jung SK. Analysis of monocyte chemoattractant protein 1(MCP-1) polymorphism in Korean patients with asthma. Korean J Orient Int Med. 2008;29: 32-41.
  10. Cho SG, Lee ER, Kim JY, Ahn JY. Protein phosphorylation as a regulatory mechanism of various cellular function. J Cancer Prev. 2006;11:1-8.
  11. Kim SH, Kim HJ, Park YN, Cho SH. The expression of extracellular signal regulated kinase (ERK) in non-small cell lung carcinoma. Korean J Pathol. 2001;35:361.
  12. Atsaves V, Lekakis L, Drakos E, Leventaki V, Ghaderi M, Baltatzis GE, et al. The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK plus anaplastic large cell lymphoma. Br J Haematol. 2014;167:514-523. https://doi.org/10.1111/bjh.13079
  13. Li B, Tournier C, Davis RJ, Flavell RA. Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation. EMBO J. 1999;18:420-432. https://doi.org/10.1093/emboj/18.2.420
  14. Mo JH. T cell differentiation and Th17. Korean J Otorhinolaryngol-Head Neck Surg. 2008;51:688-693. https://doi.org/10.3342/kjorl-hns.2008.51.8.688
  15. Wuyts WA, Vanaudenaerde BM, Dupont LJ, Demedts MG, Verleden GM. Involvement of p38 MAPK, JNK, p42/p44 ERK and NF-κB in IL-1β-induced chemokine release in human airway smooth muscle cells. Respir Med. 2003;97:811-817. https://doi.org/10.1016/S0954-6111(03)00036-2
  16. Poreau B, Lin S, Bosson C, Dieterich K, Satre V, Devillard F, et al. 13q31.1 microdeletion: a prenatal case report with macrocephaly and macroglossia. Eur J Hum Genet. 2015;58:526-530. https://doi.org/10.1016/j.ejmg.2015.09.003
  17. Yoon SC, Min JG, Young JK, Jee YH, Ji HO, Ban HJ, et al. A large-scale genome-wide association study of asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527-534. https://doi.org/10.1038/ng.357
  18. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010;34:816-834. https://doi.org/10.1002/gepi.20533
  19. Gibbs RA, Belmont JW, Hardenbol P, Willis TD, Yu FL, Yang HM. The international HapMap project. Nature. 2003:426:789-796. https://doi.org/10.1038/nature02168
  20. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. BMC Bioinform. 2010;26:2336-2337. https://doi.org/10.1093/bioinformatics/btq419
  21. Yun MJ. Factors related to asthma in Korean adults: a secondary data analysis of the Korea national health and nutrition examination survey from 2016. Korean J Adult Nurs. 2019;31:259-268. https://doi.org/10.7475/kjan.2019.31.3.259
  22. Park CS. Genetics of branchal asthma. Tuberc Respir Dis. 2006; 60:391-396. https://doi.org/10.4046/trd.2006.60.4.391
  23. Sohn MH. Overview and challenges of current genetic research on allergic diseases in Korean children. Allergy Asthma Respir Dis. 2018;6(Suppl 1):77-84. https://doi.org/10.4168/aard.2018.6.S1.S77
  24. Lund RJ, Loytomaki M, Naumanen T, Dixon C, Chen Z, Ahlfors H, et al. Genome-wide identification of novel genes involved in early Th1 and Th2 cell differentiation. J Immunol. 2007;178:3648-3660. https://doi.org/10.4049/jimmunol.178.6.3648
  25. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12:9-18. https://doi.org/10.1038/sj.cr.7290105
  26. Alam R, Gorska MM. Mitogen-activated protein kinase signalling and ERK1/2 bistability in asthma. Clin Exp Allergy. 2011; 41:149-159. https://doi.org/10.1111/j.1365-2222.2010.03658.x
  27. Koizumi S, Sasaki D, Hsieh T, Taira N, Arakaki N, Yamasaki S, et al. JunB regulates homeostasis and suppressive functions of effector regulatory T cells. Nat Commun. 2018;9:1-14. https://doi.org/10.1038/s41467-018-07735-4
  28. Chen S, Yun F, Yao Y, Cao M, Zhang Y, Wang J, et al. USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein. J Exp Med. 2018;215:2850-2867. https://doi.org/10.1084/jem.20172026