BACKGROUND: Sarcoidosis is an immune-mediated systemic disease with unknown etiology affecting the lung predominantly. The clinical manifestation of sarcoidosis is rather diverse ranging from Löfgren's syndrome to fibrotic disease. Also, it differs among patients with distinct geographical and ethnic origins, consistent with environmental and genetic factors' role in its pathogenesis. Of those, the polymorphic genes of the HLA system have been previously implicated in sarcoidosis. Therefore, we have performed an association study in a well-defined cohort of Czech patients aiming to define how variation in HLA genes, may contribute to disease origin and development. MATERIALS AND METHODS: Total of the 301 Czech unrelated sarcoidosis patients were diagnosed according to international guidelines. In those, HLA typing was performed using next-generation sequencing. The allele frequencies at six HLA loci (HLA-A,-B,-C,-DRB1,-DQA1, and -DQB1) observed in the patients were compared with HLA allele distribution determined in 309 unrelated healthy Czech subjects; sub-analyses of relationships between HLA and distinct sarcoidosis clinical phenotypes were performed. Associations were assessed by two-tailed Fischer's exact test with correction for multiple comparisons. RESULTS: We report two variants, HLA-DQB1*06:02, and HLA-DQB1*06:04, as risk factors for sarcoidosis, and three variants, HLA-DRB1*01:01, HLA-DQA1*03:01, and HLA-DQB1*03:02 as protective factors. HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, HLA-DQA1*05:01, and HLA-DQB1*02:01 variants associated with Löfgren's syndrome, a more benign phenotype. HLA- DRB1*03:01 and HLA-DQA1*05:01 alleles were connected with better prognosis-chest X-ray (CXR) stage 1, disease remission, and non-requirement of corticosteroid treatment. The alleles HLA-DRB1*11:01 and HLA-DQA1*05:05 are associated with more advanced disease represented by the CXR stages 2-4. HLA-DQB1*05:03 associated with sarcoidosis extrapulmonary manifestation. CONCLUSION: In our Czech cohort, we document some associations between sarcoidosis and HLA previously described in other populations. Further, we suggest novel susceptibility factors for sarcoidosis, such as HLA-DQB1*06:04, and characterize associations between HLA and sarcoidosis clinical phenotypes in Czech patients. Our study also extends the role of the 8.1 ancestral haplotype (HLA-A*01:01∼HLA-B*08:01∼HLA-C*07:01∼HLA-DRB1*03:01∼HLA-DQA1*05:01∼HLA-DQB1*02:01), already implicated in autoimmune diseases, as a possible predictor of better prognosis in sarcoidosis. The general translational application of our newly reported findings for personalized patient care should be validated by an independent study from another, international referral center.

Department of Pathological Physiology Faculty of Medicine and Dentistry Palacký University Olomouc Olomouc Czechia

Department of Pulmonary Diseases and Tuberculosis Faculty of Medicine of Masaryk University University Hospital Brno Brno Czechia

Histocompatibility and Immunogenetics Laboratory Stanford Blood Center Palo Alto CA United States

Histocompatibility Immunogenetics and Disease Profiling Laboratory Department of Pathology Stanford Blood Center Stanford University School Medicine Palo Alto CA United States

Laboratory of Cardiogenomics Experimental Medicine University Hospital Olomouc Olomouc Czechia

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

Arkema EV, Cozier YC. Sarcoidosis epidemiology: Recent estimates of incidence, prevalence and risk factors. Curr Opin Pulm Med. (2020) 26:527–34. 10.1097/MCP.0000000000000715 PubMed DOI PMC

Kolek V. Epidemiological study on sarcoidosis in Moravia and Silesia. Sarcoidosis. (1994) 11:110–2. PubMed

Zurkova M, Kolek V, Tomankova T, Kriegova E. Extrapulmonary involvement in patients with sarcoidosis and comparison of routine laboratory and clinical data to pulmonary involvement. Biomed. Papers. (2014) 158:613–20. 10.5507/bp.2014.026 PubMed DOI

Doubková M, Pospíšil Z, Skřičková J, Doubek M. Prognostic markers of sarcoidosis: An analysis of patients from everyday pneumological practice. Clin Respir J. (2015) 9:443–9. 10.1111/crj.12160 PubMed DOI

Valeyre D, Bernaudin JF, Uzunhan Y, Kambouchner M, Brillet PY, Soussan M, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Respir Crit Care Med. (2014) 35:336–51. 10.1055/s-0034-1381229 PubMed DOI

Rivera NV, Ronninger M, Shchetynsky K, Franke A, Nöthen MM, Müller-Quernheim J, 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) 193:1008–22. 10.1164/rccm.201507-1372OC PubMed DOI PMC

Van Moorsel CHM, Petrek M, Rivera NV. Unravelling the genetic basis of sarcoidosis. In: Bonnella F, Culver DA, Israël-Biet D. editors. Sarcoidosis (ERS Monograph). (Vol. 96), Sheffield: European Respiratory Society; (2022). p. 41–56. 10.1183/2312508x.10031320 DOI

Rossman MD, Thompson B, Frederick M, Maliarik M, Iannuzzi MC, Rybicki BA. HLA-DRB1* 1101: A significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet. (2003) 73:720–35. 10.1086/378097 PubMed DOI PMC

Levin AM, Adrianto I, Datta I, Iannuzzi MC, Trudeau S, Li J, et al. Association of HLA-DRB1 with sarcoidosis susceptibility and progression in African Americans. Am J Respir Cell Mol Biol. (2015) 53:206–16. 10.1165/rcmb.2014-0227OC PubMed DOI PMC

Mrazek F, Holla LI, Hutyrová B, Znojil V, Vasku A, Kolek V, et al. Association of tumour necrosis factor−α, lymphotoxin−α and HLA-DRB1 gene polymorphisms with Löfgren’s syndrome in Czech patients with sarcoidosis. Tissue Antigens. (2005) 65:163–71. 10.1111/j.1399-0039.2005.00370.x PubMed DOI

Statement on sarcoidosis. Joint statement of the American Thoracic Society [ATS], European Respiratory Society [ERS], 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) 160:736–55. 10.1164/ajrccm.160.2.ats4-99 PubMed DOI

Sikorová K, Moon SJ, Yoon HY, Strnad A, Song JW, Petrek M. HLA class II variants defined by next generation sequencing are associated with sarcoidosis in Korean patients. Sci Rep. (2022) 12:9302. 10.1038/s41598-022-13199-w PubMed DOI PMC

Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med. (1997) 156:1601–5. 10.1164/ajrccm.156.5.9704069 PubMed DOI

Voorter CE, Drent M, van den Berg-Loonen EM. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1* 0602–DRB1* 150101. Hum Immunol. (2005) 66:826–35. 10.1016/j.humimm.2005.04.003 PubMed DOI

Sato H, Woodhead FA, Ahmad T, Grutters JC, Spagnolo P, van den Bosch JM, et al. Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum Mol Genet. (2010) 19:4100–11. 10.1093/hmg/ddq325 PubMed DOI PMC

Wennerström A, Pietinalho A, Lasota J, Salli K, Surakka I, Seppänen M, et al. Major histocompatibility complex class II and BTNL2 associations in sarcoidosis. Eur Respir J. (2013) 42:550–3. 10.1183/09031936.00035213 PubMed DOI

Grunewald J. Role of genetics in susceptibility and outcome of sarcoidosis. Semin Respir Crit Care Med. (2010) 31:380–9. 10.1055/s-0030-1262206 PubMed DOI

Sato H, Grutters JC, Pantelidis P, Mizzon AN, Ahmad T, Van Houte AJ. HLA-DQB1* 0201: A marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol. (2002) 27:406–12. 10.1165/rcmb.4782 PubMed DOI

Grutters JC, Sato H, Welsh KI, du Bois RM. The importance of sarcoidosis genotype to lung phenotype. Am J Respir Cell Mol Biol. (2003) 29:S59. PubMed

Naruse TK, Matsuzawa Y, Ota M, Katsuyama Y, Matsumori A, Hara M, et al. HLA-DQB1* 0601 is primarily associated with the susceptibility to cardiac sarcoidosis. Tissue Antigens. (2000) 56:52–7. 10.1034/j.1399-0039.2000.560107.x PubMed DOI

Kockum I, Sanjeevi CB, Eastman S, Landin-Olsson M, Dahlquist G, Lernmark Å. Complex interaction between HLA DR and DQ in conferring risk for childhood type 1 diabetes. Eur J Immunogenet. (1999) 26:361–72. 10.1046/j.1365-2370.1999.00173.x PubMed DOI

Gambino CM, Aiello A, Accardi G, Caruso C, Candore G. Autoimmune diseases and 8.1 ancestral haplotype: An update. HLA. (2018) 92:137–43. 10.1111/tan.13305 PubMed DOI

Price P, Witt C, Allock R, Sayer D, Garlepp M, Kok CC, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. (1999) 167:257–74. 10.1111/j.1600-065x.1999.tb01398.x PubMed DOI

Candore G, Lio D, Romano GC, Caruso C. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: Effect of multiple gene interactions. Autoimmun Rev. (2002) 1:29–35. 10.1016/s1568-9972(01)00004-0 PubMed DOI

Grubić Z, Žunec R, Peroš-Golubičič T, Tekavec-Trkanjec J, Martinez N, Alilović M, et al. HLA class I and class II frequencies in patients with sarcoidosis from Croatia: Role of HLA-B8,- DRB1* 0301, and- DQB1* 0201 haplotype in clinical variations of the disease. Tissue Antigens. (2007) 70:301–6. 10.1111/j.1399-0039.2007.00904.x PubMed DOI

Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients. Am J Respir Crit Care Med. (2004) 169:696–702. 10.1164/rccm.200303-459OC PubMed DOI

Yanardag H, Tetikkurt C, Bilir M, Yilmaz E. Association of HLA antigens with the clinical course of sarcoidosis and familial disease. Monaldi Arch. Chest Dis. (2017) 87:835. 10.4081/monaldi.2017.835 PubMed DOI

Wu JS, Qiu W, Castley A, James I, Joseph J, Christiansen FT, et al. Presence of CSF oligoclonal bands (OCB) is associated with the HLA-DRB1 genotype in a West Australian multiple sclerosis cohort. J neurol sci. (2010) 288:63–7. 10.1016/j.jns.2009.10.005 PubMed DOI

Fischer A, Ellinghaus D, Nutsua M, Hofmann S, Montgomery CG, Iannuzzi MC, et al. Identification of immune-relevant factors conferring sarcoidosis genetic risk. Am J Respir Crit Care Med. (2015) 192:727–36. 10.1164/rccm.201503-0418OC PubMed DOI PMC

Ishihara M, Ohno S, Ishida T, Ando H, Naruse T, Nose Y, et al. Molecular genetic studies of HLA class II alleles in sarcoidosis. Tissue Antigens. (1994) 43:238–41. 10.1111/j.1399-0039.1994.tb02331.x PubMed DOI

Darlington P, Gabrielsen A, Sörensson P, Tallstedt L, Padyukov L, Eklund A, et al. HLA-alleles associated with increased risk for extra-pulmonary involvement in sarcoidosis. Tissue Antigens. (2014) 83:267–72. 10.1111/tan.12326 PubMed DOI

Ozyilmaz E, Goruroglu Ozturk O, Yunsel D, Deniz A, Hanta I, Kuleci S. Could HLA-DRB1*11 allele be a clue for predicting extra-pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. (2014) 31:154–62. PubMed

Sharma SK, Balamurugan A, Pandey RM, Saha PK, Mehra NK. Human leukocyte antigen-DR alleles influence the clinical course of pulmonary sarcoidosis in Asian Indians. Am J Respir Cell Mol Biol. (2003) 29:225–31. 10.1165/rcmb.2003-0007OC PubMed DOI

Petrek M, Drabek J, Kolek V, Zlamal J, Welsh KI, Bunce M, et al. CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis. Am J Respir Crit Care Med. (2000) 162:1000–3. 10.1164/ajrccm.162.3.2001022 PubMed DOI

Baughman RP, Valeyre D, Korsten P, Mathioudakis AG, Wuyts WA, Wells A, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. (2021) 58:2004079. 10.1183/13993003.04079-2020 PubMed DOI