Polymorphic genes with immune functions, namely those of the human leukocyte antigen (HLA) system, have been implicated in sarcoidosis pathogenesis. As HLA polymorphisms in sarcoidosis have not been yet investigated in the Korean population, we used next-generation sequencing (NGS), allowing detailed characterization of HLA alleles to investigate the role of HLA variation in Korean sarcoidosis patients. We enrolled 103 patients diagnosed by the ATS/ERS/WASOG guidelines at Asan Medical Centre, Seoul, Korea. Among those, genotyping of 7 HLA loci (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1, -DPB1) was performed using Omixon Holotype™ kit and HLATwin software™. HLA allele frequencies were compared with frequency data on healthy Koreans from the allelic frequency databases, and 4-digit characteristics of HLA genotyping were used. Associations were assessed by two-tailed Fischer's exact test with correction for multiple comparisons. Variants previously associated with sarcoidosis risk (HLA-C*03:04, HLA-DRB1*12:01, HLA-DRB1*14:54) and a known protective variant HLA-DPB1*04:01, were associated with sarcoidosis in Koreans. Further, we suggest new HLA variants associated with sarcoidosis risk (e.g., HLA-DQA1*05:08) and novel protective variants HLA-DQB1*03:02 and HLA-DQA1*01:02 in Koreans. This first study of HLA variation in Korean patients with sarcoidosis by precise genotyping methodology reports data that could serve future meta-analyses on HLA variation's role in sarcoidosis.

Department of Pathological Physiology and Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Pathological Physiology Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Pulmonary and Critical Care Medicine Asan Medical Center University of Ulsan College of Medicine Seoul Republic of Korea

Division of Allergy and Respiratory Diseases Soonchunhyang University Seoul Hospital Seoul Republic of Korea

Zobrazit více v PubMed

Calender A, Weichhart T, Valeyre D, Pacheco Y. Current insights in genetics of sarcoidosis: Functional and clinical impacts. J. Clin. Med. 2020;9(8):2633. doi: 10.3390/jcm9082633. PubMed DOI PMC

Arkema EV, Cozier YC. Epidemiology of sarcoidosis: Current findings and future directions. Therap. Adv. Chronic Dis. 2018;9(11):227–240. doi: 10.1177/2040622318790197. PubMed DOI PMC

Judson MA. A sarcoidosis clinician’s perspective of MHC functional elements outside the antigen binding site. Hum. Immunol. 2019;80(1):85–89. doi: 10.1016/j.humimm.2018.05.007. PubMed DOI

Jeon MH, et al. The incidence, comorbidity and mortality of sarcoidosis in Korea, 2008–2015: A nationwide population-based study. Sarcoidosis Vasculitis Diffuse Lung Dis. 2020;37(1):24. PubMed PMC

Yoon HY, Kim HM, Kim YJ, Song JW. Prevalence and incidence of sarcoidosis in Korea: A nationwide population-based study. Respir. Res. 2018;19(1):1–8. doi: 10.1186/s12931-017-0698-3. PubMed DOI PMC

Rossman MD, et al. HLA-DRB1*1101: A significant risk factor for sarcoidosis in blacks and whites. Am. J. Hum. Genet. 2003;73(4):720–735. doi: 10.1086/378097. PubMed DOI PMC

Levin AM, et al. Association of HLA-DRB1 with sarcoidosis susceptibility and progression in African Americans. Am. J. Respir. Cell Mol. Biol. 2015;53(2):206–216. doi: 10.1165/rcmb.2014-0227OC. PubMed DOI PMC

Rivera NV, et al. High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences. Am. J. Respir. Crit. Care Med. 2016;193(9):1008–1022. doi: 10.1164/rccm.201507-1372OC. PubMed DOI PMC

Sato H, et al. Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum. Mol. Genet. 2010;19(20):4100–4111. doi: 10.1093/hmg/ddq325. PubMed DOI PMC

Meguro A, et al. Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis. Commun. Biol. 2020;3(1):1–10. doi: 10.1038/s42003-020-01185-9. PubMed DOI PMC

Ishihara M, et al. Molecular genetic studies of HLA class II alleles in sarcoidosis. Tissue Antigens. 1994;43(4):238–241. doi: 10.1111/j.1399-0039.1994.tb02331.x. PubMed DOI

Lahtela E, Kankainen M, Sinisalo J, Selroos O, Lokki ML. Exome sequencing identifies susceptibility loci for sarcoidosis prognosis. Front. Immunol. 2019;10:2964. doi: 10.3389/fimmu.2019.02964. PubMed DOI PMC

Lahtela E, Wolin A, Pietinalho A, Lokki ML, Selroos O. Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients. Respir. Med. 2017;132:92–94. doi: 10.1016/j.rmed.2017.09.014. PubMed DOI

Grunewald J, et al. T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis. Eur. Respir. J. 2016;47(3):898–909. doi: 10.1183/13993003.01209-2015. PubMed DOI

Yanardag H, Tetikkurt C, Bilir M, Yılmaz E. Association of HLA antigens with the clinical course of sarcoidosis and familial disease. Monaldi Arch. Chest Dis. 2017 doi: 10.4081/monaldi.2017.835. PubMed DOI

Esendagli D, Ozmen F, Koksal D, Onder S, Emri S. Association of class II human leukocyte antigen (HLA) alleles with pulmonary sarcoidosis. Sarcoidosis Vasculitis Diffuse Lung Dis. 2018;35(2):143. PubMed PMC

Rallon N, et al. Human leucocyte antigen (HLA)-DQB 1*03:02 and HLA-A*02:01 have opposite patterns in their effects on susceptibility to HIV infection. HIV Med. 2017;18(8):587–594. doi: 10.1111/hiv.12494. PubMed DOI

Hadley D, et al. HLA-DPB1*04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study. Am. J. Gastroenterol. 2015;110(6):915. doi: 10.1038/ajg.2015.150. PubMed DOI PMC

Takahashi M, Yasunami M, Kubota S, Tamai H, Kimura A. HLA-DPB1* 0202 is associated with a predictor of good prognosis of Graves’ disease in the Japanese. Hum. Immunol. 2006;67(1–2):47–52. doi: 10.1016/j.humimm.2006.02.023. PubMed DOI

Rybicki BA, Iannuzzi MC. Sarcoidosis and human leukocyte antigen class I and II genes: It takes two to tango? Am. J. Respir. Crit. Care Med. 2004;169(6):665–666. doi: 10.1164/rccm.2401005. PubMed DOI

Tarasidis A, Arce S. Immune response biomarkers as indicators of sarcoidosis presence, prognosis, and possible treatment: An immunopathogenic perspective. Autoimmun. Rev. 2020;19(3):102462. doi: 10.1016/j.autrev.2020.102462. PubMed DOI

Lee KW, Oh DH, Lee C, Yang SY. Allelic and haplotypic diversity of HLA-A,-B,-C,-DRB1, and-DQB1 genes in the Korean population. Tissue Antigens. 2005;65(5):437–447. doi: 10.1111/j.1399-0039.2005.00386.x. PubMed DOI

Gonzalez-Galarza FF, et al. Allele frequency net database. Methods Mol. Biol. 2018;1802:49–62. doi: 10.1007/978-1-4939-8546-3_4. PubMed DOI

New World Encyclopedia Contributors. Demographics of South Korea. New World Encyclopedia.https://www.newworldencyclopedia.org/p/index.php?title=Demographics_of_South_Korea&oldid=1038227 (2020). (accessed date 20.4.2022)

Karakaya B, et al. Bronchoalveolar lavage characteristics correlate with HLA tag SNPs in patients with Löfgren’s syndrome and other sarcoidosis. Clin. Exp. Immunol. 2019;196(2):249–258. doi: 10.1111/cei.13257. PubMed DOI PMC

van Moorsel CH, Petrek M, Rivera NV. Unravelling the genetic basis of sarcoidosis. In: Bonella F, editor. Sarcoidosis (ERS Monograph) European Respiratory Society; 2022. pp. 41–56.

Statement on Sarcoidosis Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and ERS. Am. J. Respir. Crit. Care Med. 1999;160:736–755. doi: 10.1164/ajrccm.160.2.ats4-99. PubMed DOI

Kim HJ, Kim HM, Song JW. Clinical characteristics and outcomes of Korean patients with sarcoidosis. Sci. Rep. 2021;11(1):1–8. doi: 10.1038/s41598-020-79139-8. PubMed DOI PMC

Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment