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Low C4A copy numbers and higher HERV gene insertion contributes to increased risk of SLE, with absence of association with disease phenotype and disease activity

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Abstract

Low copy numbers (CNs) of C4 genes are associated with systemic autoimmune disorders and affects autoantibody diversity and disease subgroups. The primary objective of this study was to characterize diversity of complement (C4) and C4-Human Endogenous Retrovirus (HERV) gene copy numbers in SLE. We also sought to assess the association of C4 and C4-HERV CNs with serum complement levels, autoantibodies, disease phenotypes and activity. Finally, we checked the association of C4 and HERV CNs with specific HLA alleles. Genomic DNA from 70 SLE and 90 healthy controls of south Indian Tamil origin were included. Demographic, clinical and serological data was collected in a predetermined proforma. CNs of C4A and C4B genes and the frequency of insertion of 6.4kb HERV within C4 gene (C4AL, C4BL) was determined using droplet digital polymerase chain reaction (ddPCR). A four digit high resolution HLA genotyping was done using next generation sequencing. In our cohort, the total C4 gene copies ranged from 2 to 6. Compared to controls, presence of two or less copies of C4A gene was associated with SLE risk (p = 0.005; OR = 2.79; 95% CI = 1.29–6.22). Higher frequency of HERV insertion in C4A than in C4B increases such risk (p = 0.000; OR = 12.67; 95% CI = 2.80-115.3). AL-AL-AL-BS genotype was significantly higher in controls than SLE (9%vs1%, p = 0.04; OR = 0.15, 95% CI = 0.00-0.16). Distribution of HLA alleles was not different in SLE compared to controls as well as in SLE subjects with ≤ 2 copies and > 2 copies of C4A, but HLA allele distribution was diverse in subjects with C4B ≤ 2 copies and > 2 copies. Finally, there was no correlation between the C4 and the C4-HERV diversity and complement levels, autoantibodies, disease phenotypes and activity. In conclusion, our data show that, low C4A copy number and higher insertion of HERV-K in C4A increases the risk for SLE. C4 and C4-HERV CNs did not correlate with serum complements, autoantibodies, disease phenotypes and activity in SLE. Further validation in a larger homogenous SLE cohort is needed.

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No datasets were generated or analysed during the current study.

References

  1. Carroll MC. The lupus paradox. Nat Genet. 1998;19:3–4. https://doi.org/10.1038/ng0598-3.

    Article  CAS  PubMed  Google Scholar 

  2. Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Rönnblom L, Sturfelt G, Eloranta M-L, Bengtsson AA. C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis Rheum. 2009;60:3081–90. https://doi.org/10.1002/art.24852.

    Article  CAS  PubMed  Google Scholar 

  3. Barilla-LaBarca M-L, Atkinson JP. Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol. 2003;15:55–60. https://doi.org/10.1097/00002281-200301000-00010.

    Article  CAS  PubMed  Google Scholar 

  4. Walport MJ. Complement and systemic lupus erythematosus. Arthritis Res 4 Suppl. 2002;3S279–293. https://doi.org/10.1186/ar586.

  5. Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol. 2000;76:227–324. https://doi.org/10.1016/s0065-2776(01)76021-x.

    Article  CAS  PubMed  Google Scholar 

  6. Truedsson L, Bengtsson AA, Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity. 2007;40:560–6. https://doi.org/10.1080/08916930701510673.

    Article  CAS  PubMed  Google Scholar 

  7. Chu X, Rittner C, Schneider PM. Length polymorphism of the human complement component C4 gene is due to an ancient retroviral integration. Exp Clin Immunogenet. 1995;12:74–81.

    CAS  PubMed  Google Scholar 

  8. Dangel AW, Mendoza AR, Baker BJ, Daniel CM, Carroll MC, Wu LC, Yu CY. The dichotomous size variation of human complement C4 genes is mediated by a novel family of endogenous retroviruses, which also establishes species-specific genomic patterns among Old World primates. Immunogenetics. 1994;40:425–36. https://doi.org/10.1007/BF00177825.

    Article  CAS  PubMed  Google Scholar 

  9. Wu YL, Savelli SL, Yang Y, Zhou B, Rovin BH, Birmingham DJ, Nagaraja HN, Hebert LA, Yu CY. Sensitive and specific real-time polymerase chain reaction assays to accurately determine copy number variations (CNVs) of human complement C4A, C4B, C4-long, C4-short, and RCCX modules: elucidation of C4 CNVs in 50 consanguineous subjects with defined HLA genotypes. J Immunol. 2007;179:3012–25. https://doi.org/10.4049/jimmunol.179.5.3012.

    Article  CAS  PubMed  Google Scholar 

  10. Yang Z, Mendoza AR, Welch TR, Zipf WB, Yu CY. Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. J Biol Chem. 1999;274:12147–56. https://doi.org/10.1074/jbc.274.17.12147.

    Article  CAS  PubMed  Google Scholar 

  11. Griffiths DJ. Endogenous retroviruses in the human genome sequence. Genome Biol. 2001;2:REVIEWS1017. https://doi.org/10.1186/gb-2001-2-6-reviews1017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Blanchong CA, Zhou B, Rupert KL, Chung EK, Jones KN, Sotos JF, Zipf WB, Rennebohm RM, Yung C, Yu. Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. J Exp Med. 2000;191:2183–96. https://doi.org/10.1084/jem.191.12.2183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Song R-H, Gao C-Q, Zhao J, Zhang J-A. An Update Evolving View of Copy Number variations in Autoimmune diseases. Front Genet. 2021;12:794348. https://doi.org/10.3389/fgene.2021.794348.

    Article  CAS  PubMed  Google Scholar 

  14. Yeo NK-W, Lim CK, Yaung KN, Khoo NKH, Arkachaisri T, Albani S, Yeo JG. Genetic interrogation for sequence and copy number variants in systemic lupus erythematosus. Front Genet. 2024;15:1341272. https://doi.org/10.3389/fgene.2024.1341272.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mamtani M, Rovin B, Brey R, Camargo JF, Kulkarni H, Herrera M, Correa P, Holliday S, Anaya J-M, Ahuja SK. CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus. Ann Rheum Dis. 2008;67:1076–83. https://doi.org/10.1136/ard.2007.078048.

    Article  CAS  PubMed  Google Scholar 

  16. Molokhia M, Fanciulli M, Petretto E, Patrick AL, McKeigue P, Roberts AL, Vyse TJ, Aitman TJ. FCGR3B copy number variation is associated with systemic lupus erythematosus risk in afro-caribbeans. Rheumatology (Oxford). 2011;50:1206–10. https://doi.org/10.1093/rheumatology/keq456.

    Article  CAS  PubMed  Google Scholar 

  17. Chen J-Y, Wang C-M, Chang S-W, Cheng C-H, Wu Y-JJ, Lin J-C, Yang B, Ho H-H, Wu J. Association of FCGR3A and FCGR3B copy number variations with systemic lupus erythematosus and rheumatoid arthritis in Taiwanese patients. Arthritis Rheumatol. 2014;66:3113–21. https://doi.org/10.1002/art.38813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang M, Gu Y, Huang S, Lou Q, Xie Q, Xu Z, Chen Y, Pan F, Xu S, Liu S, Tao J, Liu S, Cai J, Chen P, Qian L, Wang C, Liang C, Huang H, Pan H, Su H, Cheng J, Zhang Y, Hu W, Zou Y. Copy number variations and polymorphisms in HSP90AB1 and risk of systemic lupus erythematosus and efficacy of glucocorticoids. J Cell Mol Med. 2019;23:5340–8. https://doi.org/10.1111/jcmm.14410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. García-Ortiz H, Velázquez-Cruz R, Espinosa-Rosales F, Jiménez-Morales S, Baca V, Orozco L. Association of TLR7 copy number variation with susceptibility to childhood-onset systemic lupus erythematosus in Mexican population. Ann Rheum Dis. 2010;69:1861–5. https://doi.org/10.1136/ard.2009.124313.

    Article  CAS  PubMed  Google Scholar 

  20. Kim J-H, Jung S-H, Bae JS, Lee H-S, Yim S-H, Park S-Y, Bang S-Y, Hu H-J, Shin HD, Bae S-C, Chung Y-J. Deletion variants of RABGAP1L, 10q21.3, and C4 are associated with the risk of systemic lupus erythematosus in Korean women. Arthritis Rheum. 2013;65:1055–63. https://doi.org/10.1002/art.37854.

    Article  CAS  PubMed  Google Scholar 

  21. Yokoyama N, Kawasaki A, Matsushita T, Furukawa H, Kondo Y, Hirano F, Sada K-E, Matsumoto I, Kusaoi M, Amano H, Nagaoka S, Setoguchi K, Nagai T, Shimada K, Sugii S, Hashimoto A, Matsui T, Okamoto A, Chiba N, Suematsu E, Ohno S, Katayama M, Migita K, Kono H, Hasegawa M, Kobayashi S, Yamada H, Nagasaka K, Sugihara T, Yamagata K, Ozaki S, Tamura N, Takasaki Y, Hashimoto H, Makino H, Arimura Y, Harigai M, Sato S, Sumida T, Tohma S, Takehara K, Tsuchiya N. Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population. Sci Rep. 2019;9:16366. https://doi.org/10.1038/s41598-019-52920-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brunson T, Wang Q, Chambers I, Song Q. A copy number variation in human NCF1 and its pseudogenes. BMC Genet. 2010;11:13. https://doi.org/10.1186/1471-2156-11-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Linge P, Arve S, Olsson LM, Leonard D, Sjöwall C, Frodlund M, Gunnarsson I, Svenungsson E, Tydén H, Jönsen A, Kahn R, Johansson Å, Rönnblom L, Holmdahl R, Bengtsson A. NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus. Ann Rheum Dis. 2020;79:254–61. https://doi.org/10.1136/annrheumdis-2019-215820.

    Article  CAS  PubMed  Google Scholar 

  24. Yang Y, Chung EK, Wu YL, Savelli SL, Nagaraja HN, Zhou B, Hebert M, Jones KN, Shu Y, Kitzmiller K, Blanchong CA, McBride KL, Higgins GC, Rennebohm RM, Rice RR, Hackshaw KV, Roubey RAS, Grossman JM, Tsao BP, Birmingham DJ, Rovin BH, Hebert LA, Yu CY. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European americans. Am J Hum Genet. 2007;80:1037–54. https://doi.org/10.1086/518257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen JY, Wu YL, Mok MY, Wu Y-JJ, Lintner KE, Wang C-M, Chung EK, Yang Y, Zhou B, Wang H, Yu D, Alhomosh A, Jones K, Spencer CH, Nagaraja HN, Lau YL, Lau C-S, Yu CY. Effects of Complement C4 Gene Copy Number variations, size dichotomy, and C4A Deficiency on genetic risk and clinical presentation of systemic lupus erythematosus in east Asian populations. Arthritis Rheumatol. 2016;68:1442–53. https://doi.org/10.1002/art.39589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang Y, Chung EK, Zhou B, Blanchong CA, Yu CY, Füst G, Kovács M, Vatay A, Szalai C, Karádi I, Varga L. Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index. J Immunol. 2003;171:2734–45. https://doi.org/10.4049/jimmunol.171.5.2734.

    Article  CAS  PubMed  Google Scholar 

  27. Mulvihill E, Ardoin S, Thompson SD, Zhou B, Yu GR, King E, Singer N, Levy DM, Brunner H, Wu YL, Nagaraja HN, Schanberg LE, Yu C-Y. Elevated serum complement levels and higher gene copy number of complement C4B are associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE). Lupus Sci Med. 2019;6:e000333. https://doi.org/10.1136/lupus-2019-000333.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pereira KMC, Faria AGA, Liphaus BL, Jesus AA, Silva CA, Carneiro-Sampaio M, Andrade LEC. Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus. Rheumatology. 2016;55:869–73. https://doi.org/10.1093/rheumatology/kev436.

    Article  CAS  PubMed  Google Scholar 

  29. Alperin JM, Ortiz-Fernández L, Sawalha AH. Monogenic lupus: a developing paradigm of Disease. Front Immunol. 2018;9:2496. https://doi.org/10.3389/fimmu.2018.02496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Demirkaya E, Zhou Q, Smith CK, Ombrello MJ, Deuitch N, Tsai WL, Hoffmann P, Remmers EF, Takeuchi M, Park YH, Chae J, Barut K, Simsek D, Adrovic A, Sahin S, Caliskan S, Chandrasekharappa SC, Hasni SA, Ombrello AK, Gadina M, Kastner DL, Kaplan MJ, Kasapcopur O, Aksentijevich I. Brief report: Deficiency of Complement 1r Subcomponent in early-onset systemic lupus erythematosus: the role of Disease-modifying alleles in a monogenic disease. Arthritis Rheumatol. 2017;69:1832–9. https://doi.org/10.1002/art.40158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lv Y, He S, Zhang Z, Li Y, Hu D, Zhu K, Cheng H, Zhou F, Chen G, Zheng X, Li P, Ren Y, Yin X, Cui Y, Sun L, Yang S, Zhang X. Confirmation of C4 gene copy number variation and the association with systemic lupus erythematosus in Chinese Han population. Rheumatol Int. 2012;32:3047–53. https://doi.org/10.1007/s00296-011-2023-7.

    Article  CAS  PubMed  Google Scholar 

  32. Lundtoft C, Pucholt P, Martin M, Bianchi M, Lundström E, Eloranta M-L, Sandling JK, Sjöwall C, Jönsen A, Gunnarsson I, Rantapää-Dahlqvist S, Bengtsson AA, Leonard D, Baecklund E, Jonsson R, Hammenfors D, Forsblad-d’Elia H, Eriksson P, Mandl T, Magnusson Bucher S, Norheim KB, Auglaend Johnsen SJ, Omdal R, Kvarnström M, Wahren-Herlenius M, Notarnicola A, Andersson H, Molberg Ø, Diederichsen LP, Almlöf J, Syvänen A-C, Kozyrev SV, Lindblad-Toh K, Nilsson B, Blom AM, Lundberg IE, Nordmark G, Diaz-Gallo LM, Svenungsson E, Rönnblom L, ImmunoArray Development Consortium. Complement C4 Copy Number Variation is linked to SSA/Ro and SSB/La Autoantibodies in systemic inflammatory autoimmune diseases. Arthritis Rheumatol. 2022;74:1440–50. https://doi.org/10.1002/art.42122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lundtoft C, Sjöwall C, Rantapää-Dahlqvist S, Bengtsson AA, Jönsen A, Pucholt P, Wu YL, Lundström E, Eloranta M-L, Gunnarsson I, Baecklund E, Jonsson R, Hammenfors D, Forsblad-d’Elia H, Eriksson P, Mandl T, Bucher S, Norheim KB, Auglaend Johnsen SJ, Omdal R, Kvarnström M, Wahren-Herlenius M, Truedsson L, Nilsson B, Kozyrev SV, Bianchi M, Lindblad-Toh K, Yu C-Y, Nordmark G, Sandling JK, Svenungsson E, Leonard D, Rönnblom L, the ImmunoArray consortium. Strong Association of Combined Genetic Deficiencies in the classical complement pathway with risk of systemic Lupus Erythematosus and primary Sjögren’s syndrome. Arthritis Rheumatol. 2022;74:1842–50. https://doi.org/10.1002/art.42270.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zhou D, King EH, Rothwell S, Krystufkova O, Notarnicola A, Coss S, Abdul-Aziz R, Miller KE, Dang A, Yu GR, Drew J, Lundström E, Pachman LM, Mamyrova G, Curiel RV, De Paepe B, De Bleecker JL, Payton A, Ollier W, O’Hanlon TP, Targoff IN, Flegel WA, Sivaraman V, Oberle E, Akoghlanian S, Driest K, Spencer CH, Wu YL, Nagaraja HN, Ardoin SP, Chinoy H, Rider LG, Miller FW, Lundberg IE, Padyukov L, Vencovský J, Lamb JA. C.-Y. Yu, for MYOGEN Investigators, Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies, Ann Rheum Dis 82 (2023) 235–245. https://doi.org/10.1136/ard-2022-222935.

  35. Fernando MMA, Boteva L, Morris DL, Zhou B, Wu YL, Lokki M-L, Yu CY, Rioux JD, Hollox EJ, Vyse TJ. Assessment of complement C4 gene copy number using the paralog ratio test. Hum Mutat. 2010;31:866–74. https://doi.org/10.1002/humu.21259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoebeeck J, Speleman F, Vandesompele J. Real-time quantitative PCR as an alternative to Southern blot or fluorescence in situ hybridization for detection of gene copy number changes. Methods Mol Biol. 2007;353:205–26. https://doi.org/10.1385/1-59745-229-7:205.

    Article  PubMed  Google Scholar 

  37. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, Kitano TK, Hodel MR, Petersen JF, Wyatt PW, Steenblock ER, Shah PH, Bousse LJ, Troup CB, Mellen JC, Wittmann DK, Erndt NG, Cauley TH, Koehler RT, So AP, Dube S, Rose KA, Montesclaros L, Wang S, Stumbo DP, Hodges SP, Romine S, Milanovich FP, White HE, Regan JF, Karlin-Neumann GA, Hindson CM, Saxonov S, Colston BW. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem. 2011;83:8604–10. https://doi.org/10.1021/ac202028g.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mazaika E, Homsy J, Digital Droplet PCR. CNV Analysis and other applications. Curr Protoc Hum Genet. 2014;82. 7.24.1–7.24.13.

  39. Whale AS, Huggett JF, Cowen S, Speirs V, Shaw J, Ellison S, Foy CA, Scott DJ. Comparison of microfluidic digital PCR and conventional quantitative PCR for measuring copy number variation. Nucleic Acids Res. 2012;40:e82. https://doi.org/10.1093/nar/gks203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wen T, Zhang X, Lippuner C, Schiff M, Stuber F. Development and evaluation of a Droplet Digital PCR Assay for 8p23 β-Defensin Cluster Copy number determination. Mol Diagn Ther. 2021;25:607–15. https://doi.org/10.1007/s40291-021-00546-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83. https://doi.org/10.1038/nature16549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Boteva L, Morris DL, Cortés-Hernández J, Martin J, Vyse TJ, Fernando MMA. Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Am J Hum Genet. 2012;90:445–56. https://doi.org/10.1016/j.ajhg.2012.01.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kamitaki N, Sekar A, Handsaker RE, de Rivera H, Tooley K, Morris DL, Taylor KE, Whelan CW, Tombleson P, Loohuis LMO, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke M, Kimberly RP, Kaufman KM, Harley JB, Langefeld CD, Seidman CE, Pato MT, Pato CN, Ophoff RA, Graham RR, Criswell LA, Vyse TJ, McCarroll SA. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. 2020;582:577–81. https://doi.org/10.1038/s41586-020-2277-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kerick M, Acosta-Herrera M, Simeón-Aznar CP, Callejas JL, Assassi S, SSc I, Group SM, Proudman M, Nikpour, Australian Scleroderma Interest Group (ASIG), Clinical Consortium PRECISESADS, Hunzelmann N, Moroncini G, de Vries-Bouwstra JK, Orozco G, Barton A, Herrick AL, Terao C, Allanore Y, Fonseca C, Alarcón-Riquelme ME, Radstake TRDJ, Beretta L, Denton CP, Mayes MD, Martin J. Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis. NPJ Genom Med. 2022;7:57. https://doi.org/10.1038/s41525-022-00327-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li N, Zhang J, Liao D, Yang L, Wang Y, Hou S. Association between C4, C4A, and C4B copy number variations and susceptibility to autoimmune diseases: a meta-analysis. Sci Rep. 2017;7:42628. https://doi.org/10.1038/srep42628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Saxena K, Kitzmiller KJ, Wu YL, Zhou B, Esack N, Hiremath L, Chung EK, Yang Y, Yu CY. Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of asian-indian and European American populations. Mol Immunol. 2009;46:1289–303. https://doi.org/10.1016/j.molimm.2008.11.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, French M, Mallal S, Christiansen F. 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. https://doi.org/10.1111/j.1600-065x.1999.tb01398.x.

    Article  CAS  PubMed  Google Scholar 

  48. Zhou D, Rudnicki M, Chua GT, Lawrance SK, Zhou B, Drew JL, Barbar-Smiley F, Armstrong TK, Hilt ME, Birmingham DJ, Passler W, Auletta JJ, Bowden SA, Hoffman RP, Wu YL, Jarjour WN, Mok CC, Ardoin SP, Lau YL, Yu CY. Human complement C4B allotypes and deficiencies in selected cases with Autoimmune diseases. Front Immunol. 2021;12:739430. https://doi.org/10.3389/fimmu.2021.739430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Candore G, Modica MA, Lio D, Colonna-Romano G, Listì F, Grimaldi MP, Russo M, Triolo G, Accardo-Palumbo A, Cuccia MC, Caruso C. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype. Biomed Pharmacother. 2003;57:274–7. https://doi.org/10.1016/s0753-3322(03)00079-9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Céline Manier is acknowledged for technical assistance.

Funding

This work was supported by Indo-French Centre for the Promotion of Advanced Research (IFCPAR/CEFIPRA-5103-1-Negi/Tamouza) and by Agence Nationale de la Recherche (I-GIVE ANR-13-SAMA-0004-01 and ERANET Neuron-ANR-18-0008-01), INSERM (Institut National de la Santé et de la Recherche Médicale) and Fondation FondaMental. CMM was a postdoctoral fellow of CEFIPRA 5103-1.

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Author notes

  1. Ryad Tamouza and Vir Singh Negi are senior co-authors.

Authors and Affiliations

  1. Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605 006, India

    Christina Mary Mariaselvam, Gaurav Seth, Chengappa Kavadichanda, Molly Mary Thabah & Vir Singh Negi

  2. AP-HP, DMU IMPACT, FHU ADAPT, Fondation FondaMental, IMRB, Translational Neuropsychiatry, INSERM UMR 955, Univ Paris Est Créteil, Créteil, F-94010, France

    Christina Mary Mariaselvam, Wahid Boukouaci, Ching-Lien Wu, Rajagopal Krishnamoorthy, Marion Leboyer & Ryad Tamouza

  3. IMRB, INSERM U955, Univ Paris Est Créteil, Créteil, F-94010, France

    Bruno Costes

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  1. Christina Mary Mariaselvam
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Contributions

RK, ML, VSN and RT contributed to conceptualization, supervision, review and editing. GS, CK, MMT and VSN were involved in the recruitment of subjects, collection, and interpretation of clinical data. CK and MMT reviewed the article. CMM performed the experiments, analysed the data, and wrote the manuscript. BC, WB and CW were involved in experiments and data analysis. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Christina Mary Mariaselvam.

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Mariaselvam, C.M., Seth, G., Kavadichanda, C. et al. Low C4A copy numbers and higher HERV gene insertion contributes to increased risk of SLE, with absence of association with disease phenotype and disease activity. Immunol Res (2024). https://doi.org/10.1007/s12026-024-09475-8

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