TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study

Robert M. Plenge, Mark Seielstad, Leonid Padyukov, Annette T. Lee, Elaine F. Remmers, Bo Ding, Anthony Liew, Houman Khalili, Alamelu Chandrasekaran, Leela R L Davies, Wentian Li, Adrian K S Tan, Carine Bonnard, Rick T H Ong, Anbupalam Thalamuthu, Sven Pettersson, Chunyu Liu, Chao Tian, Wei V. Chen, John P. CarulliEvan M. Beckman, David Altshuler, Lars Alfredsson, Lindsey A. Criswell, Christopher I. Amos, Michael F Seldin, Daniel L. Kastner, Lars Klareskog, Peter K. Gregersen

Research output: Contribution to journalArticle

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Abstract

Background: Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. Methods: We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10-8) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). Results: We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4×10-14). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Conclusions: A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.

Original languageEnglish (US)
Pages (from-to)1199-1209
Number of pages11
JournalNew England Journal of Medicine
Volume357
Issue number12
DOIs
StatePublished - Sep 20 2007

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Complement C5
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Rheumatoid Arthritis
Single Nucleotide Polymorphism
Chromosomes, Human, Pair 9
HLA-DRB1 Chains
Genetic Loci
Linkage Disequilibrium
Major Histocompatibility Complex

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Plenge, R. M., Seielstad, M., Padyukov, L., Lee, A. T., Remmers, E. F., Ding, B., ... Gregersen, P. K. (2007). TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study. New England Journal of Medicine, 357(12), 1199-1209. https://doi.org/10.1056/NEJMoa073491

TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study. / Plenge, Robert M.; Seielstad, Mark; Padyukov, Leonid; Lee, Annette T.; Remmers, Elaine F.; Ding, Bo; Liew, Anthony; Khalili, Houman; Chandrasekaran, Alamelu; Davies, Leela R L; Li, Wentian; Tan, Adrian K S; Bonnard, Carine; Ong, Rick T H; Thalamuthu, Anbupalam; Pettersson, Sven; Liu, Chunyu; Tian, Chao; Chen, Wei V.; Carulli, John P.; Beckman, Evan M.; Altshuler, David; Alfredsson, Lars; Criswell, Lindsey A.; Amos, Christopher I.; Seldin, Michael F; Kastner, Daniel L.; Klareskog, Lars; Gregersen, Peter K.

In: New England Journal of Medicine, Vol. 357, No. 12, 20.09.2007, p. 1199-1209.

Research output: Contribution to journalArticle

Plenge, RM, Seielstad, M, Padyukov, L, Lee, AT, Remmers, EF, Ding, B, Liew, A, Khalili, H, Chandrasekaran, A, Davies, LRL, Li, W, Tan, AKS, Bonnard, C, Ong, RTH, Thalamuthu, A, Pettersson, S, Liu, C, Tian, C, Chen, WV, Carulli, JP, Beckman, EM, Altshuler, D, Alfredsson, L, Criswell, LA, Amos, CI, Seldin, MF, Kastner, DL, Klareskog, L & Gregersen, PK 2007, 'TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study', New England Journal of Medicine, vol. 357, no. 12, pp. 1199-1209. https://doi.org/10.1056/NEJMoa073491
Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study. New England Journal of Medicine. 2007 Sep 20;357(12):1199-1209. https://doi.org/10.1056/NEJMoa073491
Plenge, Robert M. ; Seielstad, Mark ; Padyukov, Leonid ; Lee, Annette T. ; Remmers, Elaine F. ; Ding, Bo ; Liew, Anthony ; Khalili, Houman ; Chandrasekaran, Alamelu ; Davies, Leela R L ; Li, Wentian ; Tan, Adrian K S ; Bonnard, Carine ; Ong, Rick T H ; Thalamuthu, Anbupalam ; Pettersson, Sven ; Liu, Chunyu ; Tian, Chao ; Chen, Wei V. ; Carulli, John P. ; Beckman, Evan M. ; Altshuler, David ; Alfredsson, Lars ; Criswell, Lindsey A. ; Amos, Christopher I. ; Seldin, Michael F ; Kastner, Daniel L. ; Klareskog, Lars ; Gregersen, Peter K. / TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study. In: New England Journal of Medicine. 2007 ; Vol. 357, No. 12. pp. 1199-1209.
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abstract = "Background: Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. Methods: We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10-8) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). Results: We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95{\%} confidence interval, 1.23 to 1.42; P = 4×10-14). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Conclusions: A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.",
author = "Plenge, {Robert M.} and Mark Seielstad and Leonid Padyukov and Lee, {Annette T.} and Remmers, {Elaine F.} and Bo Ding and Anthony Liew and Houman Khalili and Alamelu Chandrasekaran and Davies, {Leela R L} and Wentian Li and Tan, {Adrian K S} and Carine Bonnard and Ong, {Rick T H} and Anbupalam Thalamuthu and Sven Pettersson and Chunyu Liu and Chao Tian and Chen, {Wei V.} and Carulli, {John P.} and Beckman, {Evan M.} and David Altshuler and Lars Alfredsson and Criswell, {Lindsey A.} and Amos, {Christopher I.} and Seldin, {Michael F} and Kastner, {Daniel L.} and Lars Klareskog and Gregersen, {Peter K.}",
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TY - JOUR

T1 - TRAF1-C5 as a risk locus for rheumatoid arthritis - A genomewide study

AU - Plenge, Robert M.

AU - Seielstad, Mark

AU - Padyukov, Leonid

AU - Lee, Annette T.

AU - Remmers, Elaine F.

AU - Ding, Bo

AU - Liew, Anthony

AU - Khalili, Houman

AU - Chandrasekaran, Alamelu

AU - Davies, Leela R L

AU - Li, Wentian

AU - Tan, Adrian K S

AU - Bonnard, Carine

AU - Ong, Rick T H

AU - Thalamuthu, Anbupalam

AU - Pettersson, Sven

AU - Liu, Chunyu

AU - Tian, Chao

AU - Chen, Wei V.

AU - Carulli, John P.

AU - Beckman, Evan M.

AU - Altshuler, David

AU - Alfredsson, Lars

AU - Criswell, Lindsey A.

AU - Amos, Christopher I.

AU - Seldin, Michael F

AU - Kastner, Daniel L.

AU - Klareskog, Lars

AU - Gregersen, Peter K.

PY - 2007/9/20

Y1 - 2007/9/20

N2 - Background: Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. Methods: We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10-8) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). Results: We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4×10-14). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Conclusions: A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.

AB - Background: Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. Methods: We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10-8) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). Results: We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4×10-14). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). Conclusions: A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.

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