Association of HLA-DRB1*04:05 allele with drug-induced interstitial lung disease in Japanese population


Drug-induced interstitial lung disease (DILD) is a life-threatening adverse reaction. The Japanese population is more susceptible to DILD as compared with other populations, suggesting its pathogenesis could vary depending on ethnic genetic background. We conducted case-control studies to elucidate the association between DILD and HLA alleles in the Japanese. The 177 clinically diagnosed DILD patients and 3002 healthy controls for exploration and 55 DILD patients and 201 healthy controls for validation were genotyped for four HLA genes. HLA-DRB1*04:05 was significantly associated with DILD (corrected p = 0.014); this was also validated in the other set of patients/controls. Chemical drugs other than protein therapeutics showed this association (p = 1.7 × 10−4) . The Japanese population showed a higher HLA-DRB1*04:05 frequency than most other populations. In conclusion, HLA-DRB1*04:05 could be associated with DILD susceptibility in Japanese individuals, and its high general frequency may explain the high reported incidence of DILD in Japanese.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Comparison of HLA-DRB1*04:05 carrier frequency among different countries worldwide.


  1. 1.

    Kubo K, Azuma A, Kanazawa M, Kameda H, Kusumoto M, Genma A, et al. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig. 2013;51:260–77. [Pubmed:24238235]

    Article  PubMed  Google Scholar 

  2. 2.

    Amar RK, Jick SS, Rosenberg D, Maher TM, Meier CR. Drug-/radiation-induced interstitial lung disease in the United Kingdom general population: incidence, all-cause mortality and characteristics at diagnosis. Respirology. 2012;17:861–8. [Pubmed:22563933]

    Article  PubMed  Google Scholar 

  3. 3.

    Nishimura T, Tada H, Nakagawa M, Teramukai S, Matsui S, Fukushima M. Lessons from gefitinib-induced interstitial lung disease in Japan: problems in approval, pharmacovigilance, and regulatory decision-making procedures. Pharm Pr (Granada). 2006;4:168–78. [Pubmed:25214906]

    Article  Google Scholar 

  4. 4.

    min JH, Lee HY, Lim H, Ahn MJ, Park K, Chung MP, et al. Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: a review on current insight. Cancer Chemother Pharm. 2011;68:1099–109. [Pubmed:21913033]

    CAS  Article  Google Scholar 

  5. 5.

    Fricke-Galindo I, LLerena A, López-López M. An update on HLA alleles associated with adverse drug reactions. Drug Metab Pers Ther. 2017;32:73–87. [Pubmed:28315856]

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship Between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149:1025–32. [Pubmed:23884208]

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Phillips E, Mallal S. Successful translation of pharmacogenetics into the clinic: the abacavir example. Mol Diagn Ther. 2009;13:1–9. [Pubmed:19351209]

    Article  PubMed  Google Scholar 

  8. 8.

    Nicoletti P, Aithal GP, Chamberlain TC, Coulthard S, Alshabeeb M, Grove JI, et al. Drug-induced liver injury due to flucloxacillin: relevance of multiple human leukocyte antigen alleles. Clin Pharm Ther. 2019;106:245–53. [Pubmed:30661239]

    CAS  Article  Google Scholar 

  9. 9.

    Furukawa H, Oka S, Shimada K, Tsuchiya N, Tohma S. Genetics of interstitial lung disease: vol de nuit (night flight). Clin Med Insights Circ Respir Pulm Med. 2015;9:1–7. [Pubmed:26056507]

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Nishimura M, Toyoda M, Takenaka K, Imamura Y, Chayahara N, Kiyota N, et al. The combination of HLA-b*15:01 and DRB1*15:01 is associated with gemcitabine plus erlotinib-induced interstitial lung disease in patients with advanced pancreatic cancer. Cancer Chemother Pharm. 2016;77:1165–70. [Pubmed:27100735]

    CAS  Article  Google Scholar 

  11. 11.

    Furukawa H, Oka S, Shimada K, Rheumatoid Arthritis-Interstitial Lung Disease Study Consortium, Tsuchiya N, Tohma S. HLA-A*31:01 and methotrexate-induced interstitial lung disease in Japanese rheumatoid arthritis patients: a multidrug hypersensitivity marker? Ann Rheum Dis. 2013;72:153–5. [Pubmed:22887846]

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Kaniwa N, Saito Y. Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury. J Hum Genet. 2013;58:317–26. [Pubmed:23635947]

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Kamitsuji S, Matsuda T, Nishimura K, Endo S, Wada C, Watanabe K, et al. Japan PGx Data Science Consortium Database: SNPs and HLA genotype data from 2994 Japanese healthy individuals for pharmacogenomics studies. J Hum Genet. 2015;60:319–26. [Pubmed:25855068]

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Gonzalez-Galarza FF, McCabe A, Melo dos Santos EJ, Takeshita L, Ghattaoraya G, Jones AR, et al. Allele frequency net database. Methods Mol Biol. 2018;1802:49–62. [Pubmed:29858801]

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Oka S, Furukawa H, Kawasaki A, Shimada K, Sugii S, Hashimoto A, et al. Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients. PLOS One. 2014;9:e99453 [Pubmed:24911054]

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Di D, Sanchez-Mazas A. Challenging views on the peopling history of East Asia: the story according to HLA markers. Am J Phys Anthropol. 2011;145:81–96. [Pubmed:21484761]

    Article  PubMed  Google Scholar 

  17. 17.

    Seki T, Ota M, Furuta S, Fukushima H, Kondo T, Hino K, et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology. 1992;103:1041–7. [Pubmed:1354193]

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Duarte-Rey C, Pardo AL, Rodríguez-Velosa Y, Mantilla RD, Anaya JM, Rojas-Villarraga A. HLA class II association with autoimmune hepatitis in Latin America: a meta-analysis. Autoimmun Rev. 2009;8:325–31. [Pubmed:19041429]

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, et al. HLA DRB1*0405-DQB1*0401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122:1264–9. [Pubmed:11984513]

    Article  PubMed  Google Scholar 

  20. 20.

    Nakamura Y, Matsushita T, Sato S, Niino M, Fukazawa T, Yoshimura S, et al. Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study. J Neuroinflamm. 2016;13:239 [Pubmed:27599848]

    Article  Google Scholar 

  21. 21.

    Azuma A, Kudoh S. High prevalence of drug-induced pneumonia in Japan. Japan Med Assoc J. 2007; 50: 405–11. (accessed 10 Apr 2019).

  22. 22.

    Koo LC, Clark JA, Quesenberry CP, Higenbottam T, Nyberg F, Wolf MK, et al. National differences in reporting ‘pneumonia’ and ‘pneumonia interstitial’: an analysis of the WHO International Drug Monitoring Database on 15 drugs in nine countries for seven pulmonary conditions. Pharmacoepidemiol Drug Saf. 2005;14:775–87. [Pubmed:15654720]

    Article  PubMed  Google Scholar 

  23. 23.

    Gragert L, Madbouly A, Freeman J, Maiers M. Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. Hum Immunol. 2013;74:1313–20. [Pubmed:23806270]

    CAS  Article  PubMed  Google Scholar 

Download references


This study was supported by AMED under Grant Number 18mk0101085j0002. We are sincerely indebted to all participants of this study. We thank Ms. Mika Suzuki for her invaluable help in carrying out this study.

Author information



Corresponding authors

Correspondence to Yoshiro Saito or Masayuki Hanaoka.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Imatoh, T., Ushiki, A., Ota, M. et al. Association of HLA-DRB1*04:05 allele with drug-induced interstitial lung disease in Japanese population. Pharmacogenomics J (2020).

Download citation