Objective: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. Methods: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. Results: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10−7; rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. Conclusion: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.
DanchenkoNSatiaJAAnthonyMS.Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus2006; 15: 308–318.
2.
ArnettFCShulmanLE.Studies in familial systemic lupus erythematosus. Medicine (Baltimore)1976; 55: 313–322.
3.
Ramos-NiembroFAlarcon-SegoviaD.Familial aspects of mixed connective tissue disease (MCTD). I. Occurrence of systemic lupus erythematosus in another member in two families and aggregation of MCTD in another family. J Rheumatol1978; 5: 433–440.
4.
SestakALShaverTSMoserKLNeasBRHarleyJB.Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree. J Rheumatol1999; 26: 1495–1499.
5.
Pons-EstelGJAlarconGSScofieldLReinlibLCooperGS.Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum2010; 39: 257–268.
6.
MokCCLauCS.Lupus in Hong Kong Chinese. Lupus2003; 12: 717–722.
7.
WongSNTseKCLeeTL. Lupus nephritis in Chinese children–a territory-wide cohort study in Hong Kong. Pediatr Nephrol2006; 21: 1104–1112.
8.
HomGGrahamRRModrekB. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med2008; 358: 900–909.
9.
RemmersEFPlengeRMLeeAT. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med2007; 357: 977–986.
10.
GrahamRRCotsapasCDaviesL. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet2008; 40: 1059–1061.
11.
HarleyJBAlarcon-RiquelmeMECriswellLA. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet2008; 40: 204–210.
12.
YangWNgPZhaoM. Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun2009; 10: 219–226.
13.
YangWZhaoMHirankarnN. ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum Mol Genet2009; 18: 2063–2070.
14.
WebbRMerrillJTKellyJA. A polymorphism within IL21R confers risk for systemic lupus erythematosus. Arthritis Rheum2009; 60: 2402–2407.
15.
JacobCOZhuJArmstrongDL. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A2009; 106: 6256–6261.
16.
WuZMZhangSZLiuXJLanLYangWYHanDY.[Analysis of clinical features of concomitant vertigo in idiopathic sudden deafness]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi2010; 45: 916–918.
17.
GatevaVSandlingJKHomG. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet2009; 41: 1228–1233.
18.
O'MalleySSuHZhangTNgCGeHTangCK.TOB suppresses breast cancer tumorigenesis. Int J Cancer2009; 125: 1805–1813.
LiossisSNDingXZDennisGJTsokosGC.Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain. J Clin Invest1998; 101: 1448–1457.
21.
TsokosGCWongHKEnyedyEJNambiarMP.Immune cell signaling in lupus. Curr Opin Rheumatol2000; 12: 355–363.
22.
GormanCLRussellAIZhangZCunninghame GrahamDCopeAPVyseTJ.Polymorphisms in the CD3Z gene influence TCRzeta expression in systemic lupus erythematosus patients and healthy controls. J Immunol2008; 180: 1060–1070.
23.
WarcholTPiotrowskiPLianeriM. The CD3Z 844 T>A polymorphism within the 3'-UTR of CD3Z confers increased risk of incidence of systemic lupus erythematosus. Tissue Antigens2009; 74: 68–72.
24.
HochbergMC.Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1725.
25.
PurcellSNealeBTodd-BrownK. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet2007; 81: 559–575.
26.
PriceALPattersonNJPlengeRMWeinblattMEShadickNAReichD.Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet2006; 38: 904–909.
27.
BarrettJCFryBMallerJDalyMJ.Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics2005; 21: 263–265.
28.
YangJYangWHirankarnN. ELF1 is associated with systemic lupus erythematosus in Asian populations. Hum Mol Genet2011; 20: 601–607.
29.
TsokosGCNambiarMPJuangYT.Activation of the Ets transcription factor Elf-1 requires phosphorylation and glycosylation: defective expression of activated Elf-1 is involved in the decreased TCR zeta chain gene expression in patients with systemic lupus erythematosus. Ann N Y Acad Sci2003; 987: 240–245.
30.
RadstakeTRGorlovaORuedaB. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet2010; 42: 426–429.
31.
WangKZhangHKugathasanS. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. Am J Hum Genet2009; 84: 399–405.
