A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis

Background Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting ∼1% of the population. The disease results from the interplay between an individual's genetic background and unknown environmental triggers. Although human leukocyte antigens (HLAs) account for ∼30% of the heritable risk, the identities of non-HLA genes explaining the remainder of the genetic component are largely unknown. Based on functional data in mice, we hypothesized that the immune-related genes complement component 5 (C5) and/or TNF receptor-associated factor 1 (TRAF1), located on Chromosome 9q33–34, would represent relevant candidate genes for RA. We therefore aimed to investigate whether this locus would play a role in RA. Methods and Findings We performed a multitiered case-control study using 40 single-nucleotide polymorphisms (SNPs) from the TRAF1 and C5 (TRAF1/C5) region in a set of 290 RA patients and 254 unaffected participants (controls) of Dutch origin. Stepwise replication of significant SNPs was performed in three independent sample sets from the Netherlands (n cases/controls = 454/270), Sweden (n cases/controls = 1,500/1,000) and US (n cases/controls = 475/475). We observed a significant association (p < 0.05) of SNPs located in a haplotype block that encompasses a 65 kb region including the 3′ end of C5 as well as TRAF1. A sliding window analysis revealed an association peak at an intergenic region located ∼10 kb from both C5 and TRAF1. This peak, defined by SNP14/rs10818488, was confirmed in a total of 2,719 RA patients and 1,999 controls (odds ratiocommon = 1.28, 95% confidence interval 1.17–1.39, p combined = 1.40 × 10−8) with a population-attributable risk of 6.1%. The A (minor susceptibility) allele of this SNP also significantly correlates with increased disease progression as determined by radiographic damage over time in RA patients (p = 0.008). Conclusions Using a candidate-gene approach we have identified a novel genetic risk factor for RA. Our findings indicate that a polymorphism in the TRAF1/C5 region increases the susceptibility to and severity of RA, possibly by influencing the structure, function, and/or expression levels of TRAF1 and/or C5.

[1]  C. Allaart,et al.  The Leiden Early Arthritis Clinic. , 2003, Clinical and experimental rheumatology.

[2]  E. Grant,et al.  Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis , 2002, The Journal of experimental medicine.

[3]  Steven J. Schrodi,et al.  A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. , 2004, American journal of human genetics.

[4]  Désirée van der Heijde,et al.  Plain X-rays in rheumatoid arthritis: overview of scoring methods, their reliability and applicability. , 1996 .

[5]  B. Dijkmans,et al.  Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. , 2005, Arthritis and rheumatism.

[6]  P. Gregersen,et al.  Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. , 2007, American journal of human genetics.

[7]  C. Deighton,et al.  The contribution of H LA to rheumatoid arthritis , 1989 .

[8]  Alberto Riva,et al.  MAPPER: a search engine for the computational identification of putative transcription factor binding sites in multiple genomes , 2005, BMC Bioinformatics.

[9]  P. Scheurich,et al.  The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators. , 2001, Cellular signalling.

[10]  G. Firestein Evolving concepts of rheumatoid arthritis , 2003, Nature.

[11]  F. Arnett Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[12]  T. Watts,et al.  A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival , 2006, Proceedings of the National Academy of Sciences.

[13]  L. Matis,et al.  A role for complement in antibody-mediated inflammation: C5 deficient DBA/1 mice are resistant to collagen-induced arthritis , 2000 .

[14]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[15]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[16]  R. Gascoyne,et al.  TNFR-Associated Factor Family Protein Expression in Normal Tissues and Lymphoid Malignancies , 2000, The Journal of Immunology.

[17]  M. Oppermann,et al.  Terminal complement pathway activation and low lysis inhibitors in rheumatoid arthritis synovial fluid. , 1995, The Journal of rheumatology.

[18]  K. Mossman The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[19]  A. Silman,et al.  Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole-genome scan in a further series of 217 UK affected sibling pairs. , 2004, Arthritis and rheumatism.

[20]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[21]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[22]  T. Huizinga,et al.  The Devil in the Details: The Emerging Role of Anticitrulline Autoimmunity in Rheumatoid Arthritis , 2005, The Journal of Immunology.

[23]  L. Alfredsson,et al.  A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. , 2004, Arthritis and rheumatism.

[24]  N. Breslow,et al.  Statistical methods in cancer research: volume 1- The analysis of case-control studies , 1980 .

[25]  L. Matis,et al.  Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[26]  F. Breedveld,et al.  Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? , 1997, British journal of rheumatology.

[27]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[28]  A S Rigby,et al.  Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. , 2000, Arthritis and rheumatism.

[29]  J P Boissel,et al.  EasyMA: a program for the meta-analysis of clinical trials. , 1997, Computer methods and programs in biomedicine.

[30]  P. Gregersen,et al.  The genetics revolution and the assault on rheumatoid arthritis. , 1999, Arthritis and rheumatism.

[31]  D. Gauguier,et al.  Genetic Influences on the End-Stage Effector Phase of Arthritis , 2001, The Journal of experimental medicine.

[32]  Christopher A. Haiman,et al.  Choosing Haplotype-Tagging SNPS Based on Unphased Genotype Data Using a Preliminary Sample of Unrelated Subjects with an Example from the Multiethnic Cohort Study , 2003, Human Heredity.

[33]  R. Maini Current and new antitumor necrosis factor agents in perspective , 2004, Arthritis research & therapy.

[34]  E. Lander,et al.  Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease , 2003, Nature Genetics.

[35]  L. Cardon,et al.  Population stratification and spurious allelic association , 2003, The Lancet.