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

M. Martins, A. H. Williams, M. Comeau, M. Marion, J. T. Ziegler, B. I. Freedman, J. T. Merrill, S. B. Glenn, J. A. Kelly, K. M. Sivils, J. A. James, J. M. Guthridge, M. E. Alarcón-Riquelme, S. C. Bae, J. H. Kim, D. Kim, J. M. Anaya, S. A. Boackle, L. A. Criswell, R. P. KimberlyG. S. Alarcón, E. E. Brown, L. M. Vilá, M. A. Petri, R. Ramsey-Goldman, T. B. Niewold, B. P. Tsao, G. S. Gilkeson, D. L. Kamen, C. O. Jacob, A. M. Stevens, P. M. Gaffney, J. B. Harley, C. D. Langefeld, C. Fesel

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 -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-3-2), 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.

Original languageEnglish (US)
Pages (from-to)142-150
Number of pages9
JournalGenes and Immunity
Volume16
Issue number2
DOIs
StatePublished - Mar 1 2015

Fingerprint

Systemic Lupus Erythematosus
Single Nucleotide Polymorphism
Population
T-Lymphocytes
T-Cell Antigen Receptor
Gene Frequency
Introns
Haplotypes
Down-Regulation
Odds Ratio
Phenotype

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics

Cite this

Martins, M., Williams, A. H., Comeau, M., Marion, M., Ziegler, J. T., Freedman, B. I., ... Fesel, C. (2015). Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. Genes and Immunity, 16(2), 142-150. https://doi.org/10.1038/gene.2014.73

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. / Martins, M.; Williams, A. H.; Comeau, M.; Marion, M.; Ziegler, J. T.; Freedman, B. I.; Merrill, J. T.; Glenn, S. B.; Kelly, J. A.; Sivils, K. M.; James, J. A.; Guthridge, J. M.; Alarcón-Riquelme, M. E.; Bae, S. C.; Kim, J. H.; Kim, D.; Anaya, J. M.; Boackle, S. A.; Criswell, L. A.; Kimberly, R. P.; Alarcón, G. S.; Brown, E. E.; Vilá, L. M.; Petri, M. A.; Ramsey-Goldman, R.; Niewold, T. B.; Tsao, B. P.; Gilkeson, G. S.; Kamen, D. L.; Jacob, C. O.; Stevens, A. M.; Gaffney, P. M.; Harley, J. B.; Langefeld, C. D.; Fesel, C.

In: Genes and Immunity, Vol. 16, No. 2, 01.03.2015, p. 142-150.

Research output: Contribution to journalArticle

Martins, M, Williams, AH, Comeau, M, Marion, M, Ziegler, JT, Freedman, BI, Merrill, JT, Glenn, SB, Kelly, JA, Sivils, KM, James, JA, Guthridge, JM, Alarcón-Riquelme, ME, Bae, SC, Kim, JH, Kim, D, Anaya, JM, Boackle, SA, Criswell, LA, Kimberly, RP, Alarcón, GS, Brown, EE, Vilá, LM, Petri, MA, Ramsey-Goldman, R, Niewold, TB, Tsao, BP, Gilkeson, GS, Kamen, DL, Jacob, CO, Stevens, AM, Gaffney, PM, Harley, JB, Langefeld, CD & Fesel, C 2015, 'Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study', Genes and Immunity, vol. 16, no. 2, pp. 142-150. https://doi.org/10.1038/gene.2014.73
Martins M, Williams AH, Comeau M, Marion M, Ziegler JT, Freedman BI et al. Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. Genes and Immunity. 2015 Mar 1;16(2):142-150. https://doi.org/10.1038/gene.2014.73
Martins, M. ; Williams, A. H. ; Comeau, M. ; Marion, M. ; Ziegler, J. T. ; Freedman, B. I. ; Merrill, J. T. ; Glenn, S. B. ; Kelly, J. A. ; Sivils, K. M. ; James, J. A. ; Guthridge, J. M. ; Alarcón-Riquelme, M. E. ; Bae, S. C. ; Kim, J. H. ; Kim, D. ; Anaya, J. M. ; Boackle, S. A. ; Criswell, L. A. ; Kimberly, R. P. ; Alarcón, G. S. ; Brown, E. E. ; Vilá, L. M. ; Petri, M. A. ; Ramsey-Goldman, R. ; Niewold, T. B. ; Tsao, B. P. ; Gilkeson, G. S. ; Kamen, D. L. ; Jacob, C. O. ; Stevens, A. M. ; Gaffney, P. M. ; Harley, J. B. ; Langefeld, C. D. ; Fesel, C. / Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study. In: Genes and Immunity. 2015 ; Vol. 16, No. 2. pp. 142-150.
@article{3a4d084e755c45439d3d82a6ee11b154,
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 -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-3-2), 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.",
author = "M. Martins and Williams, {A. H.} and M. Comeau and M. Marion and Ziegler, {J. T.} and Freedman, {B. I.} and Merrill, {J. T.} and Glenn, {S. B.} and Kelly, {J. A.} and Sivils, {K. M.} and James, {J. A.} and Guthridge, {J. M.} and Alarc{\'o}n-Riquelme, {M. E.} and Bae, {S. C.} and Kim, {J. H.} and D. Kim and Anaya, {J. M.} and Boackle, {S. A.} and Criswell, {L. A.} and Kimberly, {R. P.} and Alarc{\'o}n, {G. S.} and Brown, {E. E.} and Vil{\'a}, {L. M.} and Petri, {M. A.} and R. Ramsey-Goldman and Niewold, {T. B.} and Tsao, {B. P.} and Gilkeson, {G. S.} and Kamen, {D. L.} and Jacob, {C. O.} and Stevens, {A. M.} and Gaffney, {P. M.} and Harley, {J. B.} and Langefeld, {C. D.} and C. Fesel",
year = "2015",
month = "3",
day = "1",
doi = "10.1038/gene.2014.73",
language = "English (US)",
volume = "16",
pages = "142--150",
journal = "Genes and Immunity",
issn = "1466-4879",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study

AU - Martins, M.

AU - Williams, A. H.

AU - Comeau, M.

AU - Marion, M.

AU - Ziegler, J. T.

AU - Freedman, B. I.

AU - Merrill, J. T.

AU - Glenn, S. B.

AU - Kelly, J. A.

AU - Sivils, K. M.

AU - James, J. A.

AU - Guthridge, J. M.

AU - Alarcón-Riquelme, M. E.

AU - Bae, S. C.

AU - Kim, J. H.

AU - Kim, D.

AU - Anaya, J. M.

AU - Boackle, S. A.

AU - Criswell, L. A.

AU - Kimberly, R. P.

AU - Alarcón, G. S.

AU - Brown, E. E.

AU - Vilá, L. M.

AU - Petri, M. A.

AU - Ramsey-Goldman, R.

AU - Niewold, T. B.

AU - Tsao, B. P.

AU - Gilkeson, G. S.

AU - Kamen, D. L.

AU - Jacob, C. O.

AU - Stevens, A. M.

AU - Gaffney, P. M.

AU - Harley, J. B.

AU - Langefeld, C. D.

AU - Fesel, C.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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 -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-3-2), 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.

AB - 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 -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-3-2), 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.

UR - http://www.scopus.com/inward/record.url?scp=84938552405&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938552405&partnerID=8YFLogxK

U2 - 10.1038/gene.2014.73

DO - 10.1038/gene.2014.73

M3 - Article

C2 - 25569266

AN - SCOPUS:84938552405

VL - 16

SP - 142

EP - 150

JO - Genes and Immunity

JF - Genes and Immunity

SN - 1466-4879

IS - 2

ER -