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

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Abstract

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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References

  1. 1

    Crispín JC, Kyttaris V, Juang YT, Tsokos GC . Systemic lupus erythematosus: new molecular targets (review). Ann Rheum Dis 2007; 66: 65–69.

  2. 2

    Crispín JC, Liossis SN, Kis-Toth K, Lieberman LA, Kyttaris VC, Juang YT et al. Pathogenesis of human systemic lupus erythematosus: recent advances (review). Trends Mol Med 2010; 16: 47–57.

  3. 3

    Guerra SG, Vyse TJ, Cunninghame Graham DS . The genetics of lupus: a functional perspective (review). Arthritis Res Ther 2012; 14: 211–222.

  4. 4

    Löfgren SE, Frostegård J, Truedsson L, Pons-Estel BA, D'Alfonso Witte ST, Lauwerys BR et al. Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun 2012; 13: 268–274.

  5. 5

    Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 2010; 142: 914–929.

  6. 6

    Liossis SN, Ding XZ, Dennis GJ, Tsokos GC . 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 Invest 1998; 101: 1448–1457.

  7. 7

    Nambiar MP, Fisher CU, Warke VG, Krishnan S, Mitchell JP, Delaney N et al. Reconstitution of deficient T cell receptor zeta chain restores T cell signaling and augments T cell Receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus. Arthritis Rheum 2003; 48: 1948–1955.

  8. 8

    Enyedy EJ, Nambiar MP, Liossis SN, Dennis G, Kammer GM, Tsokos GC . Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum 2001; 44: 1114–1121.

  9. 9

    Gorman CL, Russell AI, Zhang Z, Cunninghame Graham D, Cope AP, Vyse TJ . Polymorphisms in the CD3Z gene influence TCRz expression in systemic lupus erythematosus patients and healthy controls. J Immunol 2008; 180: 1060–1070.

  10. 10

    Warchoł T, Piotrowski P, Lianeri M, Cieślak D, Wudarski M, Hrycaj P et al. The CD3Z 844 T&gt;A polymorphism within the 3′-UTR of CD3Z confers increased risk of incidence of systemic lupus erythematosus. Tissue Antigens 2009; 74: 68–72.

  11. 11

    Li R, Yang W, Zhang J, Hirankarn N, Pan HF, Mok CC et al. Association of CD247 with systemic lupus erythematosus in Asian populations. Lupus 2012; 21: 75–83.

  12. 12

    Hopkinson ND, Doherty M, Powell RJ . Clinical features and race-specific incidence/prevalence rates of systemic lupus erythematosus in a geographically complete cohort of patients. Ann Rheum Dis 1994; 53: 675–680.

  13. 13

    Danchenko N, Satia JA, Anthony MS . Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden (review). Lupus 2006; 15: 308–318.

  14. 14

    International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) Harley JB International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) Alarcón-Riquelme ME International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) Criswell LA International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) Jacob CO International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) Kimberly RP et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM PXK KIAA1542 and other loci. Nat Genet 2008; 40: 204–210.

  15. 15

    Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 211–216.

  16. 16

    Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1059–1061.

  17. 17

    Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X et al. A large-scale replication study identifies TNIP1 PRDM1 JAZF1 UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1228–1233.

  18. 18

    Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 2009; 41: 1234–1237.

  19. 19

    Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 2010; 6: e1000841.

  20. 20

    Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 2010; 42: 426–429.

  21. 21

    Gorlova O, Martin JE, Rueda B, Koeleman BP, Ying J, Teruel M et al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet 2011; 7: e1002178.

  22. 22

    Dieudé P, Boileau C, Guedj M, Avouac J, Ruiz B, Hachulla E et al. Independent replication establishes CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis 2011; 70: 1695–1696.

  23. 23

    Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet 2011; 7: e1002004.

  24. 24

    Wang K, Zhang H, Kugathasan S, Annese V, Bradfield JP, Russell RK et al. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn disease. Am J Hum Genet 2009; 84: 399–405.

  25. 25

    Hinks A, Cobb J, Sudman M, Eyre S, Martin P, Flynn E et al. Investigation of rheumatoid arthritis susceptibility loci in juvenile idiopathic arthritis confirms high degree of overlap. Ann Rheum Dis 2012; 71: 1117–1121.

  26. 26

    Moulton VR, Tsokos GC . Abnormalities of T cell signaling in systemic lupus erythematosus (review). Arthritis Res Ther 2011; 13: 207.

  27. 27

    Call ME, Wucherpfennig KW . Molecular mechanisms for the assembly of the T cell receptor-CD3 complex (review). Mol Immunol 2004; 40: 1295–1305.

  28. 28

    Pang M, Setoyama Y, Tsuzaka K, Yoshimoto K, Amano K, Abe T et al. Defective expression and tyrosine phosphorylation of the T cell receptor zeta chain in peripheral blood T cells from systemic lupus erythematosus patients. Clin Exp Immunol 2002; 129: 160–168.

  29. 29

    Berg L, Rönnelid J, Klareskog L, Bucht A . Down-regulation of the T cell receptor CD3 zeta chain in rheumatoid arthritis (RA) and its influence on T cell responsiveness. Clin Exp Immunol 2000; 120: 174–182.

  30. 30

    Romagnoli P, Strahan D, Pelosi M, Cantagrel A, van Meerwijk JP . A potential role for protein tyrosine kinase p56(lck) in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness. Int Immunol 2001; 13: 305–312.

  31. 31

    Baniyash M . TCR zeta-chain downregularion: curtailing an excessive inflammatory immune response (review). Nat Rev Immunol 2004; 4: 675–687.

  32. 32

    Krishnan S, Juang YT, Chowdhury B, Magilavy A, Fisher CU, Nguyen H et al. Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells. J Immunol 2008; 181: 8145–8152.

  33. 33

    Tenbrock K, Juang YT, Kyttaris VC, Tsokos GC . Altered signal transduction in SLE T cells (review). Rheumatology 2007; 46: 1525–1530.

  34. 34

    Takeuchi T, Suzuki K, Kondo T, Yoshimoto K, Tsuzaka K . CD3 ζ defects in systemic lupus erythematosus (review). Ann Rheum Dis 2012; 71: i78–i81.

  35. 35

    Deng Y, Tsao B . Genetic susceptibility to systemic lupus erythematosus in the genomic era (review). Nat Rev Rheumatol 2010; 6: 683–692.

  36. 36

    Lessard CJ, Adrianto I, Ice JA, Wiley GB, Kelly JA, Glenn SB et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet 2012; 90: 648–660.

  37. 37

    Lessard CJ, Adrianto I, Kelly JA, Kaufman KM, Grundahl KM, Adler A et al. Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study. Am J Hum Genet 2011; 88: 83–91.

  38. 38

    Hochberg MC . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus (letter). Arthritis Rheum 1997; 40: 1725.

  39. 39

    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

  40. 40

    Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

  41. 41

    Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A et al. A high-density admixture map for disease gene discovery in African Americans. Am J Hum Genet 2004; 74: 1001–1013.

  42. 42

    Halder I, Shriver M, Thomas M, Fernandez JR, Frudakis T . A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: utility and applications. Hum Mutat 2008; 29: 648–658.

  43. 43

    Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

  44. 44

    Whitlock MC . Combining probability from independent tests: The weighted Z-method is superior to Fisher’s approach. J Evol Biol 2005; 18: 1368–1373.

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Acknowledgements

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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