The association of CD40 polymorphisms with CD40 serum levels and risk of systemic lupus erythematosus

Jian-Ming Chen, Jing Guo, Chuan-Dong Wei, Chun-Fang Wang, Hong-Cheng Luo, Ye-Sheng Wei, Yan Lan, Jian-Ming Chen, Jing Guo, Chuan-Dong Wei, Chun-Fang Wang, Hong-Cheng Luo, Ye-Sheng Wei, Yan Lan

Abstract

Background: Current evidence shows that the CD40-CD40 ligand (CD40-CD40L) system plays a crucial role in the development, progression and outcome of systemic lupus erythematosus (SLE). The aim of this study was to investigate whether a CD40 gene single nucleotide polymorphism (SNP) is associated with SLE and CD40 expression in the Chinese population. We included controls (n = 220) and patients with either SLE (n =205) in the study.

Methods: The gene polymorphism was measured using Snapshot SNP genotyping assays and confirmed by sequencing. We analyzed three single nucleotide polymorphisms of CD40 gene rs1883832C/T, rs1569723A/C and rs4810485G/T in 205 patients with SLE and 220 age-and sex-matched controls. Soluble CD40 (sCD40) levels were measured by ELISA.

Results: There were significant differences in the genotype and allele frequencies of CD40 gene rs1883832C/T polymorphism between the group of patients with SLE and the control group (P < 0.05). sCD40 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the CD40 rs1883832 C/T variant allele were associated with increased CD40 levels compared to the homozygous wild-type genotype in patients with SLE. The rs1883832C/T polymorphism of CD40 and its sCD40 levels were associated with SLE in the Chinese population.

Conclusions: Our results suggest that CD40 gene may play a role in the development of SLE in the Chinese population.

Figures

Fig. 1
Fig. 1
The levels of CD40 in patients with SLE and normal control subjects. The expression of CD40 was significantly increased in patients with SLE compared to that in control subjects [(mean +/− SD 41.7+/− 13.2 pg/ml, n = 205) vs (mean +/− SD 58.5+/− 22.8 pg/ml, n = 220); P <0.001]
Fig. 2
Fig. 2
Association between the levels of CD40 and the rs1883832 C/T polymorphism of CD40 gene was observed in patients with SLE. Plasma CD40 levels with CC homozygous were significantly lower than that of the TT homozygous or CT heterozygotes, respectively. However, there were no significant differences in the plasma CD40 levels between CT and TT genotypes

References

    1. Okamura T, Morita K, Fujio K, Yamamoto K. Regulatory T cells in systemic lupus erythematosus. Nihon Rinsho Meneki Gakkai Kaishi. 2015;38:69–77. doi: 10.2177/jsci.38.69.
    1. Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65:2161–2171. doi: 10.1002/art.38008.
    1. O’Neill S, Cervera R. Systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2010;24:841–855. doi: 10.1016/j.berh.2010.10.006.
    1. Hawro T, Bogucki A, Krupińska-Kun M, Maurer M, Woźniacka A. Intractable Headaches, Ischemic Stroke, and Seizures Are Linked to the Presence of Anti-β2GPI Antibodies in Patients with Systemic Lupus Erythematosus. PLoS One. 2015;10:e0119911. doi: 10.1371/journal.pone.0119911.
    1. Finno CJ, Aleman M, Higgins RJ, Madigan JE, Bannasch DL. Risk of false positive genetic associations in complex traits with underlying population structure: a case study. Vet J. 2014;202:543–549. doi: 10.1016/j.tvjl.2014.09.013.
    1. Ciccacci C, Perricone C, Ceccarelli F, Rufini S, Di Fusco D, Alessandri C, et al. A multilocus genetic study in a cohort of Italian SLE patients confirms the association with STAT4 gene and describes a new association with HCP5 gene. PLoS One. 2014;9:e111991. doi: 10.1371/journal.pone.0111991.
    1. Mak A, Tay SH. Environmental factors, toxicants and systemic lupus erythematosus. Int J Mol Sci. 2014;15:16043–16056. doi: 10.3390/ijms150916043.
    1. Marks SD, Tullus K. Autoantibodies in systemic lupus erythematosus. Pediatr Nephrol. 2012;27:1855–1868. doi: 10.1007/s00467-011-2078-4.
    1. Belot A, Cochat P. Monogenic systemic lupus erythematosus. Nephrol Ther. 2012;8:1–4. doi: 10.1016/j.nephro.2011.05.003.
    1. Gandhi KS, McKay FC, Cox M, Riveros C, Armstrong N, Heard RN, et al. The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis. Hum Mol Genet. 2010;19:2134–2143. doi: 10.1093/hmg/ddq090.
    1. Norbert D, Kathrin P, Martin H, Harrer T, Schuster P, Ries M, et al. Chronic Immune Activation in HIV-1 Infection Contributes to Reduced Interferon Alpha Production via Enhanced CD40:CD40 Ligand Interaction. PLoS One. 2012;7:e33925. doi: 10.1371/journal.pone.0033925.
    1. Karimi MH, Marzban S, Hajiyan MR, Geramizadeh B, Pourfathollah AA, Rajabiyan MH, et al. Effect of CD40 silenced dendritic cells by RNA interference on mice skin allograft rejection. Immunotherapy. 2015;7:111–118. doi: 10.2217/imt.14.112.
    1. Gao Y, Kazama H, Yonehara S. Bim regulates B-cell receptor-mediated apoptosis in the presence of CD40 signaling in CD40-pre-activated splenic B cells differentiating into plasma cells. Int Immunol. 2012;24:283–292. doi: 10.1093/intimm/dxr127.
    1. Gorbacheva V, Fan R, Wang X, Baldwin WM, 3rd, Fairchild RL, Valujskikh A. IFN-γ production by memory helper T cells is required for CD40-independent alloantibody responses. J Immunol. 2015;194:1347–1356. doi: 10.4049/jimmunol.1401573.
    1. Rabant M, Gorbacheva V, Fan R, Yu H, Valujskikh A. CD40-independent help by memory CD4 T cells induces pathogenic alloantibody but does not lead to long-lasting humoral immunity. Am J Transplant. 2013;13:2831–2841. doi: 10.1111/ajt.12432.
    1. Portillo JA, Greene JA, Schwartz I, Subauste MC, Subauste CS. Blockade of CD40-TRAF2,3 or CD40-TRAF6 is sufficient to inhibit pro-inflammatory responses in non-haematopoietic cells. Immunology. 2015;144:21–33. doi: 10.1111/imm.12361.
    1. Yuan M, Ohishi M, Wang L, Raguki H, Wang H, Tao L, Ren J. Association between serum levels of soluble CD40/CD40 ligand and organ damage in hypertensive patients. Clin Exp Pharmacol Physiol. 2010;37:848–851. doi: 10.1111/j.1440-1681.2010.05368.x.
    1. Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation-tipping the balance in atherosclerosis. Thromb Haemost. 2011;106:804–813. doi: 10.1160/TH11-09-0605.
    1. Wu T, Guo R, Zhang B. Developments in the study of CD40/ CD40L gene and its polymorphism in atherosclerosis. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2012;37:413–418.
    1. Wagner M, Wisniewski A, Bilinska M, Pokryszko-Dragan A, Cyrul M, Kusnierczyk P, et al. Investigation of gene-gene interactions between CD40 and CD40L in Polish multiple sclerosis patients. Hum Immunol. 2014;75:796–801. doi: 10.1016/j.humimm.2014.05.013.
    1. Huber AK, Finkelman FD, Li CW, Concepcion E, Smith E, Jacobson E, et al. Genetically driven target tissue over expression of CD40:a novel mechanism in autoimmune disease. J Immunol. 2012;189:3043–3053. doi: 10.4049/jimmunol.1200311.
    1. Li G, Diogo D, Wu D, Spoonamore J, Dancik V, Franke L, et al. Human genetics in rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway. PLoS Genet. 2013;9:e1003487. doi: 10.1371/journal.pgen.1003487.
    1. Wang DM, Tang S, Li Z, Cheng X, Gao SQ, Deng ZH. High through-put genomic DNA isolation technique and its application in HLA genotyping for samples from bone marrow donor program. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009;17:1265–1268.
    1. ShiYY HL. SHEsis, a powerful software platform for analyses of inkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15:97–98. doi: 10.1038/sj.cr.7290272.
    1. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978–989. doi: 10.1086/319501.
    1. Comte D, Karampetsou MP, Tsokos GC. T cells as a therapeutic target in SLE. Lupus. 2015;24:351–363. doi: 10.1177/0961203314556139.
    1. Bankert KC, Oxley KL, Smith SM, Graham JP, de Boer M, Thewissen M, et al. Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40. J Immunol. 2015;194:4319–4327. doi: 10.4049/jimmunol.1402903.
    1. Zhang B, Wu T, Song C, Chen M, Li H, Guo R. Association of CD40-1 C/T polymorphism with cerebral infarction susceptibility and its effect on sCD40L in Chinese population. Int Immunophar-macol. 2013;16:461–465. doi: 10.1016/j.intimp.2013.04.028.
    1. Joo YB, Park BL, Shin HD, Park SY, Kim I, Bae SC. Association of genetic polymorphisms in CD40 with susceptibility to SLE in the Korean population. Rheumatology (Oxford) 2013;52:623–630. doi: 10.1093/rheumatology/kes339.
    1. Pau E, Chang NH, Loh C, Lajoie G, Wither JE. Abrogation of pathogenic IgG autoantibody production in CD40L gene-deleted lupus-prone New Zealand Black mice. Clin Immunol. 2011;139:215–227. doi: 10.1016/j.clim.2011.02.005.
    1. Vazgiourakis VM, Zervou MI, Choulaki C, Bertsias G, Melissourgaki M, Yilmaz N, et al. A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with alteredCD40 expression: implications for the pathogenesis. Ann Rheum Dis. 2011;70:2184–2190. doi: 10.1136/ard.2010.146530.
    1. Piotrowski P, Lianeri M, Wudarski M, Olesinska M, Jagodzinski PP. Single nucleotide polymorphism of CD40 region and the risk of systemic lupus erythematosus. Lupus. 2013;22:233–237. doi: 10.1177/0961203312470184.

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