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

BMC Genetics

Yan Lan¹  Ye-Sheng Wei²  Hong-Cheng Luo²  Chun-Fang Wang²  Chuan-Dong Wei²  Jing Guo¹  Jian-Ming Chen² 

[1] Department of Dermatology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China;Department of Laboratory Medicine, Affiliated hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China

关键词: SLE;    Polymorphism;    Gene;    CD40;   

Others  :  1228881
DOI  :  10.1186/s12863-015-0279-8

 received in 2015-05-27, accepted in 2015-10-09,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Chen et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [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.
• [2]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.
• [3]O’Neill S, Cervera R. Systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2010; 24:841-855.
• [4]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.
• [5]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.
• [6]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.
• [7]Mak A, Tay SH. Environmental factors, toxicants and systemic lupus erythematosus. Int J Mol Sci. 2014; 15:16043-16056.
• [8]Marks SD, Tullus K. Autoantibodies in systemic lupus erythematosus. Pediatr Nephrol. 2012; 27:1855-1868.
• [9]Belot A, Cochat P. Monogenic systemic lupus erythematosus. Nephrol Ther. 2012; 8:1-4.
• [10]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.
• [11]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.
• [12]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.
• [13]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.
• [14]Gorbacheva V, Fan R, Wang X, Baldwin WM, 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.
• [15]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.
• [16]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.
• [17]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.
• [18]Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation-tipping the balance in atherosclerosis. Thromb Haemost. 2011; 106:804-813.
• [19]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.
• [20]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.
• [21]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.
• [22]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.
• [23]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.
• [24]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.
• [25]Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 68:978-989.
• [26]Comte D, Karampetsou MP, Tsokos GC. T cells as a therapeutic target in SLE. Lupus. 2015; 24:351-363.
• [27]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.
• [28]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.
• [29]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.
• [30]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.
• [31]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.
• [32]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.