Evaluation of TRAF6 in a large multiancestral lupus cohort

Bahram Namjou, Chan Bum Choi, Isaac T W Harley, Marta E. Alarcõn-Riquelme, Jennifer A. Kelly, Stuart B. Glenn, Joshua O. Ojwang, Adam Adler, Kwangwoo Kim, Caroline J. Gallant, Susan A. Boackle, Lindsey A. Criswell, Robert P. Kimberly, Elizabeth E. Brown, Jeffrey Edberg, Graciela S. Alarcõn, Anne M. Stevens, Chaim O. Jacob, Gary S. Gilkeson, Diane L. KamenBetty P. Tsao, Juan Manuel Anaya, Eun Mi Kim, So Yeon Park, Yoon Kyoung Sung, Joel M. Guthridge, Joan T. Merrill, Michelle Petri, Rosalind Ramsey-Goldman, Luis M. Vilá, Timothy B. Niewold, Javier Martin, Bernardo A. Pons-Estel, Timothy J. Vyse, Barry I. Freedman, Kathy L. Moser, Patrick M. Gaffney, Adrienne H. Williams, Mary E. Comeau, John D. Reveille, Changwon Kang, Judith A. James, R. Hal Scofield, Carl D. Langefeld, Kenneth M. Kaufman, John B. Harley, Sang Cheol Bae

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10 -5 and P = 4.73 × 10 -5, respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r 2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10 -4, OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10 -6, OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

Original languageEnglish (US)
Pages (from-to)1960-1969
Number of pages10
JournalArthritis and Rheumatism
Volume64
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

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TNF Receptor-Associated Factor 6
Single Nucleotide Polymorphism
Systemic Lupus Erythematosus
Meta-Analysis
Odds Ratio
Confidence Intervals
Thrombocytopenia
Rheumatoid Arthritis
Linkage Disequilibrium
Population Characteristics
Pedigree
Autoimmunity
African Americans
Population
Autoimmune Diseases
Immune System
Immunity
Genes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Namjou, B., Choi, C. B., Harley, I. T. W., Alarcõn-Riquelme, M. E., Kelly, J. A., Glenn, S. B., ... Bae, S. C. (2012). Evaluation of TRAF6 in a large multiancestral lupus cohort. Arthritis and Rheumatism, 64(6), 1960-1969. https://doi.org/10.1002/art.34361

Evaluation of TRAF6 in a large multiancestral lupus cohort. / Namjou, Bahram; Choi, Chan Bum; Harley, Isaac T W; Alarcõn-Riquelme, Marta E.; Kelly, Jennifer A.; Glenn, Stuart B.; Ojwang, Joshua O.; Adler, Adam; Kim, Kwangwoo; Gallant, Caroline J.; Boackle, Susan A.; Criswell, Lindsey A.; Kimberly, Robert P.; Brown, Elizabeth E.; Edberg, Jeffrey; Alarcõn, Graciela S.; Stevens, Anne M.; Jacob, Chaim O.; Gilkeson, Gary S.; Kamen, Diane L.; Tsao, Betty P.; Anaya, Juan Manuel; Kim, Eun Mi; Park, So Yeon; Sung, Yoon Kyoung; Guthridge, Joel M.; Merrill, Joan T.; Petri, Michelle; Ramsey-Goldman, Rosalind; Vilá, Luis M.; Niewold, Timothy B.; Martin, Javier; Pons-Estel, Bernardo A.; Vyse, Timothy J.; Freedman, Barry I.; Moser, Kathy L.; Gaffney, Patrick M.; Williams, Adrienne H.; Comeau, Mary E.; Reveille, John D.; Kang, Changwon; James, Judith A.; Scofield, R. Hal; Langefeld, Carl D.; Kaufman, Kenneth M.; Harley, John B.; Bae, Sang Cheol.

In: Arthritis and Rheumatism, Vol. 64, No. 6, 06.2012, p. 1960-1969.

Research output: Contribution to journalArticle

Namjou, B, Choi, CB, Harley, ITW, Alarcõn-Riquelme, ME, Kelly, JA, Glenn, SB, Ojwang, JO, Adler, A, Kim, K, Gallant, CJ, Boackle, SA, Criswell, LA, Kimberly, RP, Brown, EE, Edberg, J, Alarcõn, GS, Stevens, AM, Jacob, CO, Gilkeson, GS, Kamen, DL, Tsao, BP, Anaya, JM, Kim, EM, Park, SY, Sung, YK, Guthridge, JM, Merrill, JT, Petri, M, Ramsey-Goldman, R, Vilá, LM, Niewold, TB, Martin, J, Pons-Estel, BA, Vyse, TJ, Freedman, BI, Moser, KL, Gaffney, PM, Williams, AH, Comeau, ME, Reveille, JD, Kang, C, James, JA, Scofield, RH, Langefeld, CD, Kaufman, KM, Harley, JB & Bae, SC 2012, 'Evaluation of TRAF6 in a large multiancestral lupus cohort', Arthritis and Rheumatism, vol. 64, no. 6, pp. 1960-1969. https://doi.org/10.1002/art.34361
Namjou B, Choi CB, Harley ITW, Alarcõn-Riquelme ME, Kelly JA, Glenn SB et al. Evaluation of TRAF6 in a large multiancestral lupus cohort. Arthritis and Rheumatism. 2012 Jun;64(6):1960-1969. https://doi.org/10.1002/art.34361
Namjou, Bahram ; Choi, Chan Bum ; Harley, Isaac T W ; Alarcõn-Riquelme, Marta E. ; Kelly, Jennifer A. ; Glenn, Stuart B. ; Ojwang, Joshua O. ; Adler, Adam ; Kim, Kwangwoo ; Gallant, Caroline J. ; Boackle, Susan A. ; Criswell, Lindsey A. ; Kimberly, Robert P. ; Brown, Elizabeth E. ; Edberg, Jeffrey ; Alarcõn, Graciela S. ; Stevens, Anne M. ; Jacob, Chaim O. ; Gilkeson, Gary S. ; Kamen, Diane L. ; Tsao, Betty P. ; Anaya, Juan Manuel ; Kim, Eun Mi ; Park, So Yeon ; Sung, Yoon Kyoung ; Guthridge, Joel M. ; Merrill, Joan T. ; Petri, Michelle ; Ramsey-Goldman, Rosalind ; Vilá, Luis M. ; Niewold, Timothy B. ; Martin, Javier ; Pons-Estel, Bernardo A. ; Vyse, Timothy J. ; Freedman, Barry I. ; Moser, Kathy L. ; Gaffney, Patrick M. ; Williams, Adrienne H. ; Comeau, Mary E. ; Reveille, John D. ; Kang, Changwon ; James, Judith A. ; Scofield, R. Hal ; Langefeld, Carl D. ; Kaufman, Kenneth M. ; Harley, John B. ; Bae, Sang Cheol. / Evaluation of TRAF6 in a large multiancestral lupus cohort. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 6. pp. 1960-1969.
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title = "Evaluation of TRAF6 in a large multiancestral lupus cohort",
abstract = "Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95{\%} confidence intervals (95{\%} CIs) were calculated. Results Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10 -5 and P = 4.73 × 10 -5, respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r 2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10 -4, OR 0.89 [95{\%} CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10 -6, OR 0.57 [95{\%} CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.",
author = "Bahram Namjou and Choi, {Chan Bum} and Harley, {Isaac T W} and Alarc{\~o}n-Riquelme, {Marta E.} and Kelly, {Jennifer A.} and Glenn, {Stuart B.} and Ojwang, {Joshua O.} and Adam Adler and Kwangwoo Kim and Gallant, {Caroline J.} and Boackle, {Susan A.} and Criswell, {Lindsey A.} and Kimberly, {Robert P.} and Brown, {Elizabeth E.} and Jeffrey Edberg and Alarc{\~o}n, {Graciela S.} and Stevens, {Anne M.} and Jacob, {Chaim O.} and Gilkeson, {Gary S.} and Kamen, {Diane L.} and Tsao, {Betty P.} and Anaya, {Juan Manuel} and Kim, {Eun Mi} and Park, {So Yeon} and Sung, {Yoon Kyoung} and Guthridge, {Joel M.} and Merrill, {Joan T.} and Michelle Petri and Rosalind Ramsey-Goldman and Vil{\'a}, {Luis M.} and Niewold, {Timothy B.} and Javier Martin and Pons-Estel, {Bernardo A.} and Vyse, {Timothy J.} and Freedman, {Barry I.} and Moser, {Kathy L.} and Gaffney, {Patrick M.} and Williams, {Adrienne H.} and Comeau, {Mary E.} and Reveille, {John D.} and Changwon Kang and James, {Judith A.} and Scofield, {R. Hal} and Langefeld, {Carl D.} and Kaufman, {Kenneth M.} and Harley, {John B.} and Bae, {Sang Cheol}",
year = "2012",
month = "6",
doi = "10.1002/art.34361",
language = "English (US)",
volume = "64",
pages = "1960--1969",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
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TY - JOUR

T1 - Evaluation of TRAF6 in a large multiancestral lupus cohort

AU - Namjou, Bahram

AU - Choi, Chan Bum

AU - Harley, Isaac T W

AU - Alarcõn-Riquelme, Marta E.

AU - Kelly, Jennifer A.

AU - Glenn, Stuart B.

AU - Ojwang, Joshua O.

AU - Adler, Adam

AU - Kim, Kwangwoo

AU - Gallant, Caroline J.

AU - Boackle, Susan A.

AU - Criswell, Lindsey A.

AU - Kimberly, Robert P.

AU - Brown, Elizabeth E.

AU - Edberg, Jeffrey

AU - Alarcõn, Graciela S.

AU - Stevens, Anne M.

AU - Jacob, Chaim O.

AU - Gilkeson, Gary S.

AU - Kamen, Diane L.

AU - Tsao, Betty P.

AU - Anaya, Juan Manuel

AU - Kim, Eun Mi

AU - Park, So Yeon

AU - Sung, Yoon Kyoung

AU - Guthridge, Joel M.

AU - Merrill, Joan T.

AU - Petri, Michelle

AU - Ramsey-Goldman, Rosalind

AU - Vilá, Luis M.

AU - Niewold, Timothy B.

AU - Martin, Javier

AU - Pons-Estel, Bernardo A.

AU - Vyse, Timothy J.

AU - Freedman, Barry I.

AU - Moser, Kathy L.

AU - Gaffney, Patrick M.

AU - Williams, Adrienne H.

AU - Comeau, Mary E.

AU - Reveille, John D.

AU - Kang, Changwon

AU - James, Judith A.

AU - Scofield, R. Hal

AU - Langefeld, Carl D.

AU - Kaufman, Kenneth M.

AU - Harley, John B.

AU - Bae, Sang Cheol

PY - 2012/6

Y1 - 2012/6

N2 - Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10 -5 and P = 4.73 × 10 -5, respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r 2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10 -4, OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10 -6, OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

AB - Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10 -5 and P = 4.73 × 10 -5, respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r 2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10 -4, OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10 -6, OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.

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