Whole Exome Sequencing Identified Two Single Nucleotide Polymorphisms
of Human Leukocyte Antigen-DRB5 in Familial Sarcoidosis in
China

Qian      Zhang; Zuojun      Xu; Hui      Huang; Meijun      Zhang

Abstract

Background: Sarcoidosis is a multisystem granulomatous disorder whose etiology is related to genetic and immunological factors. Familial aggregation and ethnic prevalence suggest a genetic predisposition and inherited susceptibility to sarcoidosis.

Objective: This study aimed to identify suspected risk loci for familial sarcoidosis patients.

Methods: We conducted whole exome sequencing on two sarcoidosis patients and five healthy family members in a Chinese family for a case-control study. The two sarcoidosis patients were siblings who showed chronic disease.

Results: The Gene Ontology results showed single nucleotide polymorphisms in three genes, including human leukocyte antigen (HLA)-DRB1, HLA-DRB5, and KIR2DL4, associated with both ‘antigen processing and presentation’ and ‘regulation of immune response.’ Sanger sequencing verified two nonsynonymous mutations in HLA-DRB5 (rs696318 and rs115817940) located on 6p21.3 in the major histocompatibility complex (MHC) class II beta 1 region. The structural model simulated on Prot- Param protein analysis by the Expert Protein Analysis System predicted that the hydropathy index changed at two mutation sites (rs696318: p.F96L, -1.844 to -1.656 and rs115817940: p.T106N, -0.322 to -0.633), which indicated the probability of changes in peptide-binding selectivity.

Conclusion: Our results indicated that two nonsynonymous mutations of HLA-DRB5 have been identified in two sarcoidosis siblings, while their healthy family members do not have the mutations. The two HLA-DRB5 alleles may influence genetic susceptibility and chronic disease progression through peptide mutations on the MHC class II molecule among the two affected family members.

[1]
Sindhu RK, Rahman MH, Madaan P, Chandel P, Akter R, Adilakshmi G. Therapeutic approaches for the management of autoimmune disorders via gene therapy: Prospects, challenges and opportunities. Curr Gene Ther  2022; 22(3): 245-61.
 [http://dx.doi.org/10.2174/1566523221666210916113609] [PMID: 34530709]

[2]
Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med  2001; 164(11): 2085-91.
 [http://dx.doi.org/10.1164/ajrccm.164.11.2106001] [PMID: 11739139]

[3]
Islam MA, Kundu S, Hassan R. Gene therapy approaches in an autoimmune demyelinating disease: Multiple sclerosis. Curr Gene Ther  2020; 19(6): 376-85.
 [http://dx.doi.org/10.2174/1566523220666200306092556] [PMID: 32141417]

[4]
Martin WJ II, Iannuzzi MC, Gail DB, Peavy HH. Future directions in sarcoidosis research: summary of an NHLBI working group. Am J Respir Crit Care Med  2004; 170(5): 567-71.
 [http://dx.doi.org/10.1164/rccm.200308-1073WS] [PMID: 15142870]

[5]
McGrath DS, Daniil Z, Foley P, et al. Epidemiology of familial sarcoidosis in the UK. Thorax  2000; 55(9): 751-4.
 [http://dx.doi.org/10.1136/thorax.55.9.751] [PMID: 10950893]

[6]
Brennan NJ, Crean P, Long JP, Fitzgerald MX. High prevalence of familial sarcoidosis in an Irish population. Thorax  1984; 39(1): 14-8.
 [http://dx.doi.org/10.1136/thx.39.1.14] [PMID: 6695348]

[7]
Papadopoulos KI, Melander O, Orho-Melander M, Groop LC, Carlsson M, Hallengren B. Angiotensin converting enzyme (ACE) gene polymorphism in sarcoidosis in relation to associated autoimmune diseases. J Intern Med  2000; 247(1): 71-7.
 [http://dx.doi.org/10.1046/j.1365-2796.2000.00575.x] [PMID: 10672133]

[8]
Spagnolo P, Renzoni EA, Wells AU, et al. C-C chemokine receptor 2 and sarcoidosis: association with Lofgren’s syndrome. Am J Respir Crit Care Med  2003; 168(10): 1162-6.
 [http://dx.doi.org/10.1164/rccm.200303-456OC] [PMID: 12882757]

[9]
Petřek M, Drábek J, Kolek V, et al. CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis. Am J Respir Crit Care Med  2000; 162(3): 1000-3.
 [http://dx.doi.org/10.1164/ajrccm.162.3.2001022] [PMID: 10988120]

[10]
Hattori N, Niimi T, Sato S, et al. Cytotoxic T-lymphocyte antigen 4 gene polymorphisms in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis  2005; 22(1): 27-32.
 [PMID: 15881277] [PMID: 15881277]

[11]
Rasmussen SL, Nielsen SL, Amtorp O, Folke K, Frit-Hansen P. 201- Thallium imaging as an indicator of graft patency after coronary artery bypass surgery. Eur Heart J  1984; 5(6): 494-9.
 [http://dx.doi.org/10.1093/oxfordjournals.eurheartj.a061696] [PMID: 6611259]

[12]
Grutters JC, Sato H, Pantelidis P, et al. Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis  2003; 20(1): 20-7.
 [PMID: 12737276] [PMID: 12737276]

[13]
Hill MR, Papafili A, Booth H, et al. Functional prostaglandin-endoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis. Am J Respir Crit Care Med  2006; 174(8): 915-22.
 [http://dx.doi.org/10.1164/rccm.200512-1839OC] [PMID: 16840740]

[14]
Pabst S, Baumgarten G, Stremmel A, et al. Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis. Clin Exp Immunol  2006; 143(3): 420-6.
 [http://dx.doi.org/10.1111/j.1365-2249.2006.03008.x] [PMID: 16487240]

[15]
Grutters JC, Sato H, Pantelidis P, et al. Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med  2002; 165(8): 1119-24.
 [http://dx.doi.org/10.1164/ajrccm.165.8.200110-0320] [PMID: 11956055]

[16]
Yang J, Huang T, Song W, et al. Discover the network mechanisms underlying the connections between aging and age-related diseases. Sci Rep  2016; 6(1): 32566.
 [http://dx.doi.org/10.1038/srep32566] [PMID: 27582315]

[17]
Yang J, Peng S, Zhang B, et al. Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases. Geroscience  2020; 42(1): 353-72.
 [http://dx.doi.org/10.1007/s11357-019-00106-x] [PMID: 31637571]

[18]
Design of a case control etiologic study of sarcoidosis (ACCESS). J Clin Epidemiol  1999; 52(12): 1173-86.
 [http://dx.doi.org/10.1016/S0895-4356(99)00142-0] [PMID: 10580780]

[19]
Karp DR, Marthandan N, Marsh SGE, et al. Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis. Hum Mol Genet  2010; 19(4): 707-19.
 [http://dx.doi.org/10.1093/hmg/ddp521] [PMID: 19933168]

[20]
de Jesus MB. Gene therapy & cell therapy. Curr Gene Ther  2021; 21(5): 361.
 [http://dx.doi.org/10.2174/156652322105211223141951] [PMID: 34983337]

[21]
Szklarczyk D, Gable AL, Lyon D, et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res  2019; 47(D1): D607-13.
 [http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]

[22]
Straiton J, Free T, Sawyer A, Martin J. From Sanger sequencing to genome databases and beyond. Biotechniques  2019; 66(2): 60-3.
 [http://dx.doi.org/10.2144/btn-2019-0011] [PMID: 30744413]

[23]
Waterhouse A, Bertoni M, Bienert S, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res  2018; 46(W1): W296-303.
 [http://dx.doi.org/10.1093/nar/gky427] [PMID: 29788355]

[24]
Wilkins MR, Gasteiger E, Bairoch A, et al. Protein identification and analysis tools in the ExPASy server Methods Mol Biol  1999; 112: 531-52.
 [http://dx.doi.org/10.1385/1-59259-584-7:531] [PMID: 10027275]

[25]
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 by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med  1999; 160(2): 736-55.
 [http://dx.doi.org/10.1164/ajrccm.160.2.ats4-99] [PMID: 10430755]

[26]
Martusewicz-Boros M, Piotrowski W. Diagnosis of sarcoidosis - the updated ATS 2020 recommendations through the prism of everyday clinical practice. Adv Respir Med  2020; 88(4): 293-6.
 [http://dx.doi.org/10.5603/ARM.2020.0134] [PMID: 32869261]

[27]
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; 87(3): 835.
 [http://dx.doi.org/10.4081/monaldi.2017.835] [PMID: 29424190]

[28]
Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA. Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med  2003; 167(9): 1225-31.
 [http://dx.doi.org/10.1164/rccm.200209-1097OC] [PMID: 12615619]

[29]
Schürmann M, Bein G, Kirsten D, Schlaak M, Müller-Quernheim J, Schwinger E. HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med  1998; 92(4): 649-52.
 [http://dx.doi.org/10.1016/S0954-6111(98)90512-1] [PMID: 9659531]

[30]
Raphael SA, Blau EB, Zhang WH, Hsu SH. Analysis of a large kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis Am J Dis Child  1993; 147(8): 842-.
 [http://dx.doi.org/10.1001/archpedi.1993.02160320044017] [PMID: 394645] [PMID: 8394645]

[31]
Rybicki BA, Maliarik MJ, Poisson LM, et al. The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans. Am J Respir Crit Care Med  2003; 167(3): 444-9.
 [http://dx.doi.org/10.1164/rccm.2112060] [PMID: 12554629]

[32]
Perng RP, Chou KT, Chu H, Chung YM. Familial Sarcoidosis in Taiwan. J Formos Med Assoc  2007; 106(6): 499-503.
 [http://dx.doi.org/10.1016/S0929-6646(09)60301-6] [PMID: 17588845]

[33]
Nowack D, Goebel KM. Genetic aspects of sarcoidosis. Class II histocompatibility antigens and a family study. Arch Intern Med  1987; 147(3): 481-3.
 [http://dx.doi.org/10.1001/archinte.1987.00370030085016] [PMID: 3827423]

[34]
Wolin A, Lahtela EL, Anttila V, et al. SNP variants in major histocompatibility complex are associated with sarcoidosis susceptibility-A joint analysis in four european populations. Front Immunol  2017; 8: 422.
 [http://dx.doi.org/10.3389/fimmu.2017.00422] [PMID: 28469621]

[35]
Huan P, Hachulla E, Delaporte E, Piette F, Hatron PY, Devulder B. [Familial sarcoidosis: 3 cases in the same family Rev Med Interne  1995; 16(4): 280-2.
 [http://dx.doi.org/10.1016/0248-8663(96)80708-9] [PMID: 7746968]

[36]
Hiraga Y. [An epidemiological study of clustering of sarcoidosis cases. Jpn J Clin Med  1994; 52(6): 1438-42. An epidemiological study of clustering of sarcoidosis cases
 [PMID: 8046820] [PMID: 8046820]

[37]
Goljan A. Puścińska E, Podobińska I, Zieliński J. [Histocompatibility class I antigens loci A and B in familial sarcoidosis in Poland. Pneumonol Alergol Pol  2000; 68(11-12): 523-32. [Histocompatibility class I antigens loci A and B in familial sarcoidosis in Poland.
 [PMID: 1320563]

[38]
Schürmann M, Lympany PA, Reichel P, et al. Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med  2000; 162(3): 861-4.
 [http://dx.doi.org/10.1164/ajrccm.162.3.9901099] [PMID: 10988096]

[39]
Elford J, Fitch P, Kaminski E, McGavin C, Wells IP. Five cases of sarcoidosis in one family: a new immunological link? Thorax  2000; 55(4): 343-4.
 [http://dx.doi.org/10.1136/thorax.55.4.343] [PMID: 10722776]

[40]
Nakamura H, Hashimoto T, Yagyuu H, et al. (Sarcoidosis in a man and his identical twin sons). Nihon Kokyuki Gakkai Zasshi  2000; 38(6): 452-5.
 [PMID: 10979283]

[41]
Grönhagenriska C, Fyhrquist F, Hortling L, Koskimies S. Familial occurrence of sarcoidosis and Crohn’s disease. Lancet  1983; 321(8336): 1287-8.
 [http://dx.doi.org/10.1016/S0140-6736(83)92748-4] [PMID: 6134089]

[42]
Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet  2005; 37(4): 357-64.
 [http://dx.doi.org/10.1038/ng1519] [PMID: 15735647]

[43]
Cozier YC, Ruiz-Narvaez EA, McKinnon CJ, Berman JS, Rosenberg L, Palmer JR. Fine-mapping in African-American women confirms the importance of the 10p12 locus to sarcoidosis. Genes Immun  2012; 13(7): 573-8.
 [http://dx.doi.org/10.1038/gene.2012.42] [PMID: 22972473]

[44]
Hofmann S, Fischer A, Nothnagel M, et al. Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis. Eur Respir J  2013; 41(4): 888-900.
 [http://dx.doi.org/10.1183/09031936.00033812] [PMID: 22936702]

[45]
Zhang Z, Cui F, Zhou M, Wu S, Zou Q, Gao B. Single-cell RNA sequencing analysis identifies key genes in brain metastasis from lung adenocarcinoma. Curr Gene Ther  2021; 21(4): 338-48.
 [http://dx.doi.org/10.2174/1566523221666210319104752] [PMID: 33745433]

[46]
Liu J, Lan Y, Tian G, Yang J. A systematic framework for identifying prognostic genes in the tumor microenvironment of colon cancer. Front Oncol  2022; 12: 899156.
 [http://dx.doi.org/10.3389/fonc.2022.899156] [PMID: 35664768]

[47]
Andersson G. Evolution of the human HLA-DR region. Front Biosci  1998; 3(4): A317.
 [http://dx.doi.org/10.2741/A317] [PMID: 9675159]

[48]
Sibener LV, Fernandes RA, Kolawole EM, et al. Isolation of a structural mechanism for uncoupling T cell receptor signaling from peptide-MHC binding. Cell  2018; 174(3): 672-687.e27.
 [http://dx.doi.org/10.1016/j.cell.2018.06.017] [PMID: 30053426]

[49]
Chelvanayagam G. A roadmap for HLA-DR peptide binding specificities. Hum Immunol  1997; 58(2): 61-9.
 [http://dx.doi.org/10.1016/S0198-8859(97)00185-7] [PMID: 9475335]

[50]
Broos CE, van Nimwegen M, Hoogsteden HC, Hendriks RW, Kool M, van den Blink B. Granuloma formation in pulmonary sarcoidosis. Front Immunol  2013; 4: 437.
 [http://dx.doi.org/10.3389/fimmu.2013.00437] [PMID: 24339826]

[51]
Martinez-Bravo MJ, Wahlund CJE, Qazi KR, et al. Pulmonary sarcoidosis is associated with exosomal vitamin D-binding protein and inflammatory molecules. J Allergy Clin Immunol  2017; 139(4): 1186-94.
 [http://dx.doi.org/10.1016/j.jaci.2016.05.051] [PMID: 27566455]

[52]
Rossides M, Grunewald J, Eklund A, et al. Familial aggregation and heritability of sarcoidosis: a Swedish nested case-control study. Eur Respir J  2018; 52(2): 1800385.
 [http://dx.doi.org/10.1183/13993003.00385-2018] [PMID: 29946010]

[53]
Facco M, Cabrelle A, Teramo A, et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax  2011; 66(2): 144-50.
 [http://dx.doi.org/10.1136/thx.2010.140319] [PMID: 21139119]

[54]
Ramstein J, Broos CE, Simpson LJ, et al. IFN-γ–producing T-Helper 17.1 Cells Are increased in sarcoidosis and are more prevalent than T-helper type 1 cells. Am J Respir Crit Care Med  2016; 193(11): 1281-91.
 [http://dx.doi.org/10.1164/rccm.201507-1499OC] [PMID: 26649486]

[55]
Prasse A, Zissel G, Lützen N, et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med  2010; 182(4): 540-8.
 [http://dx.doi.org/10.1164/rccm.200909-1451OC] [PMID: 20442436]

[56]
Dai S, Murphy GA, Crawford F, et al. Crystal structure of HLA-DP2 and implications for chronic beryllium disease. Proc Natl Acad Sci USA  2010; 107(16): 7425-30.
 [http://dx.doi.org/10.1073/pnas.1001772107] [PMID: 20356827]

[57]
Coordinators NR. Database resources of the national center for biotechnology information. Nucleic Acids Res  2016; 44(D1): D7-D19.
 [http://dx.doi.org/10.1093/nar/gkv1290] [PMID: 26615191]

[58]
Galperin M, Farenc C, Mukhopadhyay M, et al. CD4 + T cell–mediated HLA class II cross-restriction in HIV controllers. Sci Immunol  2018; 3(24): eaat0687.
 [http://dx.doi.org/10.1126/sciimmunol.aat0687] [PMID: 29884618]

[59]
Abelin JG, Harjanto D, Malloy M, et al. Defining HLA-II ligand processing and binding rules with mass spectrometry enhances cancer epitope prediction. Immunity  2019; 51(4): 766-779.e17.
 [http://dx.doi.org/10.1016/j.immuni.2019.08.012] [PMID: 31495665]

[60]
Rossman MD, Thompson B, Frederick M, et al. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet  2003; 73(4): 720-35.
 [http://dx.doi.org/10.1086/378097] [PMID: 14508706]

[61]
Wennerström A, Pietinalho A, Vauhkonen H, et al. HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis. Hum Immunol  2012; 73(1): 93-100.
 [http://dx.doi.org/10.1016/j.humimm.2011.10.016] [PMID: 22074998]

[62]
Foley PJ, McGrath DS, Puscinska E, et al. Human leukocyte antigen-DRB1 position 11 residues are a common protective marker for sarcoidosis. Am J Respir Cell Mol Biol  2001; 25(3): 272-7.
 [http://dx.doi.org/10.1165/ajrcmb.25.3.4261] [PMID: 11588003]

[63]
Sato H, Woodhead FA, Ahmad T, et al. Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum Mol Genet  2010; 19(20): 4100-11.
 [http://dx.doi.org/10.1093/hmg/ddq325] [PMID: 20685690]

[64]
Reche PA, Reinherz EL. Sequence variability analysis of human class I and class II MHC molecules: functional and structural correlates of amino acid polymorphisms. J Mol Biol  2003; 331(3): 623-41.
 [http://dx.doi.org/10.1016/S0022-2836(03)00750-2] [PMID: 12899833]

[65]
Rajagopalan S, Long EO. KIR2DL4 (CD158d): An activation receptor for HLA-G. Front Immunol  2012; 3: 258.
 [http://dx.doi.org/10.3389/fimmu.2012.00258] [PMID: 22934097]

[66]
Mizuki M, Eklund A, Grunewald J. Altered expression of natural killer cell inhibitory receptors (KIRs) on T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis  2000; 17(1): 54-9.
 [PMID: 10746261]

Cite As

Current Gene Therapy

Whole Exome Sequencing Identified Two Single Nucleotide Polymorphisms of Human Leukocyte Antigen-DRB5 in Familial Sarcoidosis in China

Abstract