Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study

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A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247–SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10−4<P<4.15 × 10−2), where we further identified a five-marker haplotype (rs12141731–rs2949655–rs16859085–rs12144621–rs858554; G-G-A-G-A; Phap=2.12 × 10−5) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls=13%; P=4.99 × 10−4, odds ratio=1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P<0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10−3<P<3.97 × 10−2), with one (rs704848) remaining significant after Bonferroni correction (Pmeta=2.66 × 10−2). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

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We thank the SLE patients and healthy controls for their collaboration in this study. We also thank the entire OMRF team for organizing this study. We thank all the authors of the ‘Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus’ (Yang et al. 2010) paper for sharing the data information on the GWAS results on the CD247 region. We also thank the University of Alabama Birmingham Center for Clinical and Translational Science (CCTS). This study was supported by the: National Institutes of Health grants (UL1RR025741) to RRG, Northwestern University Feinberg School of Medicine (K24AR002138, P602AR30692, P01AR49084) to RPK, GSA and EEB, University of Alabama Birmingham to LMP, National Institute of Arthritis and Musculoskeletal and Skin Diseases to RRG, UL1TR000165 and P01AI083194 to RPK, RO1AR43814 to BPT, University of California Los Angeles (P60AR053308, UL1TR000004) to LC, University of California San Francisco (AR43727) to MAP, Johns Hopkins University (R21AI070304) to SAB, University of Colorado School of Medicine (RO1AR057172) to COJ, University of Southern California (UL1RR025014 and R01AR051545-03) to AMS, Seattle Children’s Research Institute Arthritis Foundation (UL1RR029882 and P60AR062755) to GSG and DLK, Medical University of South Carolina (P30AR53483, U19AI082714, P30GM103510, U01AI101934) to JAJ and JMG, AI063274, AR056360 and AI083194 to PMG, Oklahoma Medical Research Foundation (R37AI024717, P01083194, P01AR049084) to JH, Cincinnati Children’s Hospital Medical Center; the US Departments of Defense (PR094002) to JH and Veterans Affairs to JH; the Alliance for Lupus Research to LC and BPT; a Kirkland Scholar Award to LC; Korea Healthcare technology R & D project (A121983) funded by the Ministry for Health and Welfare, Republic of Korea to SCB; the Swedish Research Council and Instituto de Salud Carlos III grant (PS09/00129) cofinanced by FEDER funds of the European Union to MEAR; Fundação para a Ciência e Tecnologia (FCT, Portugal) fellowships (SFRH/BPD/29354/2006) to M Martins and (SFRH/BPD/34648/2007) to CF.

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Correspondence to M Martins.

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Martins, M., Williams, A., Comeau, M. et al. Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. Genes Immun 16, 142–150 (2015) doi:10.1038/gene.2014.73

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