title: Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study.
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; P(hap) = 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 (P(meta) = 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.
authors.affiliation: 1] Instituto de Medicina Molecular, Lisboa, Portugal [2] Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: M
authors.identifier: 0000000183606806
authors.initials: M
authors.lastname: Martins
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Williams
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Comeau
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Marion
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Ziegler
authors.affiliation: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: B I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Merrill
authors.affiliation: Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Glenn
authors.affiliation: Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Sivils
authors.affiliation: 1] Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA [2] Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: James
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: 1] Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA [2] Centro de Genómica e Investigaciones Oncológicas (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain.
authors.forename: M E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: S-C
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.affiliation: Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, Colombia.
authors.forename: J-M
authors.initials: JM
authors.lastname: Anaya
authors.affiliation: Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Boackle
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Kimberly
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Alarcón
authors.affiliation: Departments of Medicine and Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Brown
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: L M
authors.initials: LM
authors.lastname: Vilá
authors.affiliation: Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Petri
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.affiliation: Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: T B
authors.initials: TB
authors.lastname: Niewold
authors.affiliation: Division of Rheumatology, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Gilkeson
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Kamen
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: C O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute Arthritis Foundation, Seattle, WA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Stevens
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: 1] Division of Rheumatology and the Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA [2] US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Fesel
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D017252:CD3 Complex / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000276:immunology; D044465:White People / Q000235:genetics
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain