Abstract
The distribution of complement component 4 (C4) gene copy number (GCN) has been validated in European populations. Meanwhile, C4 gene has been identified as a susceptibility gene for systemic lupus erythematosus (SLE). However, the association and the possible phenotype significance remain to be determined intensely in the Chinese population. This study was designed to validate the distribution of C4 GCNs in Chinese Han and the correlation between C4 GCNs and SLE using quantitative real-time polymerase chain reaction in 924 SLE patients and 1,007 controls. The results presented distribution of C4 GCNs in healthy populations and also showed that lower C4 GCN was a risk factor for SLE and higher C4 GCN was a protective factor against the disease susceptibility, which was similar to the report in the Caucasian population. Furthermore, we found the association between C4A GCN and disease subphenotypes of arthritis with SLE. We conclude that the association of C4 GCN with SLE was replicated in Chinese Han population, which highlighted the importance of C4 in SLE pathogenesis of diverse populations.
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References
Hopkinson ND, Doherty M, Powell RJ (1994) Clinical features and race-specific incidence/prevalence rates of systemic lupus erythematosus in a geographically complete cohort of patients. Ann Rheum Dis 53:675–680
Wang J, Yang S, Chen JJ et al (2007) Systemic lupus erythematosus: a genetic epidemiology study of 695 patients from China. Arch Dermatol Res 298:485–491
Zeng QY, Chen R, Darmawan J et al (2008) Rheumatic diseases in China. Arthritis Res Ther 10:R17
Shen L, LC Wu, Sanlioglu S et al (1994) Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and the C4B genes in the HLA class III region. Molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplication. J Biol Chem 269:8466–8476
Yang Z, Mendoza AR, Welch TR, Zipf WB, Yu CY (1999) 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 274:12147–12156
Yu CY (1991) The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene. J Immunol 146:1057–1066
CY Yu, Belt KT, Giles CM, Campbell RD, Porter RR (1986) Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. EMBO J 5:2873–2881
YL Wu, Yang Y, Chung EK et al (2008) Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus. Cytogenet Genome Res 123:131–141
Yang Y, Chung EK, Wu YL et al (2007) 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 80:1037–1054
Doherty DG, Ireland R, Demaine AG et al (1992) Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese. Arthritis Rheum 35:641–646
Hong GH, Kim HY, Takeuchi F et al (1994) Association of complement C4 and HLA-DR alleles with systemic lupus erythematosus in Koreans. J Rheumatol 21:442–447
Yamada H, Watanabe A, Mimori A et al (1990) Lack of gene deletion for complement C4A deficiency in Japanese patients with systemic lupus erythematosus. J Rheumatol 17:1054–1057
Hochberg MC (1997) Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725
Szilagyi A, Blasko B, Szilassy D et al (2006) Real-time PCR quantification of human complement C4A and C4B genes. BMC Genet 7:1
YL Wu, Savelli SL, Yang Y et al (2007) 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 179:3012–3025
Blanchong CA, Zhou B, Rupert KL et al (2000) 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 191:2183–2196
Chung EK, Yang Y, Rennebohm RM et al (2002) Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. Am J Hum Genet 71:823–837
Schur PH, Sandson J (1968) Immunologic factors and clinical activity in systemic lupus erythematosus. N Engl J Med 278:533–538
Fielder AH, Walport MJ, Batchelor JR et al (1983) Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J (Clin Res Ed) 286:425–428
Kamatani Y, Matsuda K, Ohishi T et al (2008) Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population. J Hum Genet 53:64–73
CY Yu, Campbell RD (1987) Definitive RFLPs to distinguish between the human complement C4A/C4B isotypes and the major Rodgers/Chido determinants: application to the study of C4 null alleles. Immunogenetics 25:383–390
Yang Y, Chung EK, Zhou B et al (2003) 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 171:2734–2745
Leveziel N, Zerbib J, Richard F et al (2008) Genotype-phenotype correlations for exudative age-related macular degeneration associated with homozygous HTRA1 and CFH genotypes. Invest Ophthalmol Vis Sci 49:3090–3094
Thorburn CM, Prokunina-Olsson L, Sterba KA et al (2007) Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun 8:279–287
Zhang Z, Zhu KJ, Xu Q et al (2010) The association of the BLK gene with SLE was replicated in Chinese Han. Arch Dermatol Res 302:619–624
CF He, Liu YS, Cheng YL et al (2010) TNIP1, SLC15A4, ETS1, RasGRP3 and IKZF1 are associated with clinical features of systemic lupus erythematosus in a Chinese Han population. Lupus 19:1181–1186
Dodds AW, Law SK (1990) The complement component C4 of mammals. Biochem J 265:495–502
Martinez OP, Longman-Jacobsen N, Davies R et al (2001) Genetics of human complement component C4 and evolution the central MHC. Front Biosci 6:D904–D913
Asherson RA, Batchelor JR, Krausz T, Hughes GR (1987) Hypocomplementaemic urticarial vasculitis, angio-oedema and ‘lupus-like’ disease: association with C4B null allele. Clin Exp Rheumatol 5:161–164
Odell D, Maciulis A, Cutler A et al (2005) Confirmation of the association of the C4B null allelle in autism. Hum Immunol 66:140–145
Christiansen FT, Dawkins RL, Uko G et al (1983) Complement allotyping in SLE: association with C4A null. Aust N Z J Med 13:483–488
Traustadottir KH, Sigfusson A, Steinsson K, Erlendsson K (2002) C4A deficiency and elevated level of immune complexes: the mechanism behind increased susceptibility to systemic lupus erythematosus. J Rheumatol 29:2359–2366
Welch TR, Brickman C, Bishof N et al (1998) The phenotype of SLE associated with complete deficiency of complement isotype C4A. J Clin Immunol 18:48–51
Gilliam BE, Wolff AE, Moore TL (2007) Partial C4 deficiency in juvenile idiopathic arthritis patients. J Clin Rheumatol 13:256–260
van Zeben D, Giphart MJ, Christiansen FT et al (1992) Properdin factor B and complement factor C4 allotypes in rheumatoid arthritis: results of a follow-up study. Hum Immunol 33:148–151
Acknowledgments
We thank all the volunteers who participated in this work. This work was funded by General Program of National Natural Science Foundation of China (81071940, 30771942, 30800990).
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Lv, Y., He, S., Zhang, Z. et al. Confirmation of C4 gene copy number variation and the association with systemic lupus erythematosus in Chinese Han population. Rheumatol Int 32, 3047–3053 (2012). https://doi.org/10.1007/s00296-011-2023-7
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DOI: https://doi.org/10.1007/s00296-011-2023-7