tnf receptor associated factor 1

Summary

Summary: A signal transducing tumor necrosis factor receptor associated factor that is involved in TNF RECEPTOR feedback regulation. It is similar in structure and appears to work in conjunction with TNF RECEPTOR-ASSOCIATED FACTOR 2 to inhibit APOPTOSIS.

Top Publications

  1. Lee S, Park C, Choi Y. T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors. J Exp Med. 1996;183:669-74 pubmed
    ..These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation. ..
  2. Boldin M, Goncharov T, Goltsev Y, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996;85:803-15 pubmed
    ..These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades. ..
  3. Inada H, Izawa I, Nishizawa M, Fujita E, Kiyono T, Takahashi T, et al. Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J Cell Biol. 2001;155:415-26 pubmed
    ..These results indicate that K18 may sequester TRADD to attenuate interactions between TRADD and activated TNFR1 and moderate TNF-induced apoptosis in simple epithelial cells. ..
  4. Albers H, Kurreeman F, Houwing Duistermaat J, Brinkman D, Kamphuis S, Girschick H, et al. The TRAF1/C5 region is a risk factor for polyarthritis in juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67:1578-80 pubmed publisher
  5. Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol. 2002;3:221-7 pubmed
    ..However, NF-kappaB cannot function alone. A variety of mechanisms exist to modulate its activity and thereby affect the ultimate outcome of a cell's fate. ..
  6. Leo E, Deveraux Q, Buchholtz C, Welsh K, Matsuzawa S, Stennicke H, et al. TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis. J Biol Chem. 2001;276:8087-93 pubmed
    ..These data identify TRAF1 as a specific target of caspases activated during TNF- and Fas-induced apoptosis and illustrate differences in the repertoire of protease substrates cleaved during activation of different apoptotic pathways. ..
  7. Cottin V, Van Linden A, Riches D. Phosphorylation of the tumor necrosis factor receptor CD120a (p55) recruits Bcl-2 and protects against apoptosis. J Biol Chem. 2001;276:17252-60 pubmed
  8. Denecker G, Vercammen D, Declercq W, Vandenabeele P. Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci. 2001;58:356-70 pubmed
    ..Principal elements of necrosis include mitochondrial oxidative phosphorylation, reactive oxygen production, and non-caspase proteolytic cascades depending on serine proteases, calpains, or cathepsins. ..
  9. Wajant H, Henkler F, Scheurich P. The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators. Cell Signal. 2001;13:389-400 pubmed
    ..In this review, we address the structural and molecular basis of TRAF protein functions and highlight their role in cytokine signalling. ..

More Information

Publications61

  1. Heyninck K, Beyaert R. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. FEBS Lett. 1999;442:147-50 pubmed
    ..More importantly, we present evidence that A20 interferes with IL-1-induced NF-kappaB activation at the level of TRAF6, upstream of NIK. Moreover, A20 was shown to directly interact with TRAF6. ..
  2. Jones S, Ledgerwood E, Prins J, Galbraith J, Johnson D, Pober J, et al. TNF recruits TRADD to the plasma membrane but not the trans-Golgi network, the principal subcellular location of TNF-R1. J Immunol. 1999;162:1042-8 pubmed
    ..These results suggest that although TNF-R1 is predominantly a Golgi-associated protein and TRADD also localizes to the Golgi region, exogenous TNF causes TRADD to bind to TNF-R1 only at the plasma membrane. ..
  3. Shu H, Takeuchi M, Goeddel D. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci U S A. 1996;93:13973-8 pubmed
    ..These data establish the physiological involvement of TRAF2 and c-IAP1 in TNF-R1 signaling and help provide a molecular explanation for both the overlapping and distinct signals generated by the two TNF receptors. ..
  4. Uren A, Pakusch M, Hawkins C, Puls K, Vaux D. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci U S A. 1996;93:4974-8 pubmed
  5. Savage K, Monti S, Kutok J, Cattoretti G, Neuberg D, de Leval L, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003;102:3871-9 pubmed
    ..In almost all cases, c-REL was localized to the nucleus, consistent with activation of the NF-kappa B pathway. These studies identify a molecular link between MLBCL and cHL and a shared survival pathway. ..
  6. Rothe M, Pan M, Henzel W, Ayres T, Goeddel D. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell. 1995;83:1243-52 pubmed
    ..The recruitment of c-IAP1 or c-IAP2 to the TNFR2 signaling complex requires a TRAF2-TRAF1 heterocomplex. ..
  7. Panoulas V, Smith J, Nightingale P, Kitas G. Association of the TRAF1/C5 locus with increased mortality, particularly from malignancy or sepsis, in patients with rheumatoid arthritis. Arthritis Rheum. 2009;60:39-46 pubmed publisher
    ..If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis. ..
  8. Hsu H, Xiong J, Goeddel D. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81:495-504 pubmed
    ..However, NF-kappa B activation by TRADD is not inhibited by crmA expression, demonstrating that the signaling pathways for TNF-induced cell death and NF-kappa B activation are distinct. ..
  9. Sabbagh L, Srokowski C, Pulle G, Snell L, Sedgmen B, Liu Y, et al. A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival. Proc Natl Acad Sci U S A. 2006;103:18703-8 pubmed
    ..These studies identify the TRAF1 signaling axis and Bim down-regulation as critical for CD8 memory T cell survival in vivo. ..
  10. Morgan M, Thorburn J, Thomas L, Maxwell T, Brothman A, Thorburn A. An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells. Cell Death Differ. 2001;8:696-705 pubmed
    ..Therefore, the death domain of FADD has a previously unrecognized role in cell survival that is epithelial-specific and defective in cancer cells. This FADD-dependent signaling pathway may be important in prostate carcinogenesis. ..
  11. Lee H, Choi J, Li M, Kaye K, Kieff E, Jung J. Role of cellular tumor necrosis factor receptor-associated factors in NF-kappaB activation and lymphocyte transformation by herpesvirus Saimiri STP. J Virol. 1999;73:3913-9 pubmed
    ..Other factors are implicated in immortalization of common marmoset T lymphocytes and may also be critical in the transformation of human lymphocytes and rodent fibroblasts. ..
  12. Speiser D, Lee S, Wong B, Arron J, Santana A, Kong Y, et al. A regulatory role for TRAF1 in antigen-induced apoptosis of T cells. J Exp Med. 1997;185:1777-83 pubmed
  13. Song H, Rothe M, Goeddel D. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci U S A. 1996;93:6721-5 pubmed
    ..Our findings suggest a possible molecular mechanism that could explain A20's ability to negatively regulate its own TNF-inducible expression. ..
  14. Tsitsikov E, Laouini D, Dunn I, Sannikova T, Davidson L, Alt F, et al. TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice. Immunity. 2001;15:647-57 pubmed
    ..This TNF effect was mediated by TNFR2 (p75) but not by TNFR1 (p55). Furthermore, skin from TRAF1(-/-) mice was hypersensitive to TNF-induced necrosis. These findings suggest that TRAF1 is a negative regulator of TNF signaling. ..
  15. Takeuchi M, Rothe M, Goeddel D. Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins. J Biol Chem. 1996;271:19935-42 pubmed
    ..Thus, distinct domains of TRAF2 are involved in recruitment and signaling functions. ..
  16. Lin Y, Devin A, Rodriguez Y, Liu Z. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 1999;13:2514-26 pubmed
    ..Further more, RIP cleavage was also detected in other death receptor-mediated apoptosis. Therefore, our study provides a potential mechanism to convert cells from life to death in death receptor-mediated apoptosis. ..
  17. Ameyar Zazoua M, Larochette N, Dorothee G, Daugas E, Haddada H, Gouloumet V, et al. Wild-type p53 induced sensitization of mutant p53 TNF-resistant cells: role of caspase-8 and mitochondria. Cancer Gene Ther. 2002;9:219-27 pubmed
  18. Hsu H, Shu H, Pan M, Goeddel D. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84:299-308 pubmed
    ..Thus, these two TNFR1-TRADD signaling cascades appear to bifurcate at TRADD. ..
  19. Siemienski K, Peters N, Scheurich P, Wajant H. Organization of the human tumour necrosis factor receptor-associated factor 1 (TRAF1) gene and mapping to chromosome 9q33-34. Gene. 1997;195:35-9 pubmed
    ..The putative promotor region of the TRAFI gene was isolated by use of a PCR-based genomic walking approach. Fluorescence in situ hybridization was used to map this gene to chromosome 9q33-34. ..
  20. Jang I, Lee Z, Kim Y, Kim S, Kwon B. Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochem Biophys Res Commun. 1998;242:613-20 pubmed
    ..4-1BB-mediated NF-kappa B activation was inhibited by a dominant negative-TRAF2 or -NF-kappa B-inducing kinase (NIK). These data suggest that 4-1BB functions may be mediated by NF-kappa B activation, which requires a TRAF2/NIK pathway. ..
  21. Jang H, Chung Y, Baik J, Choi Y, Park I, Jung Y, et al. Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death. Biochem Biophys Res Commun. 2001;281:499-505 pubmed
    ..These results indicate that caspase-dependent cleavage of TRAF1 generates TRAF1-c fragments that are able to bind TRAF2, and then sequester TRAF2 from the TNF-R1 complex, rendering cells, at least in part, sensitive to TNF. ..
  22. Fotin Mleczek M, Henkler F, Samel D, Reichwein M, Hausser A, Parmryd I, et al. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. J Cell Sci. 2002;115:2757-70 pubmed
    ..Hence, TNF-R2 triggering can interfere with TNF-R1-induced apoptosis by inhibition of NF-kappaB-dependent production of anti-apoptotic factors and by blocking the action of anti-apoptotic factors at the post-transcriptional level. ..
  23. Munzert G, Kirchner D, Stobbe H, Bergmann L, Schmid R, Dohner H, et al. Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosis. Blood. 2002;100:3749-56 pubmed
    ..Thus, although our study revealed a common expression pattern of NF-kappaB/Rel-regulated inhibitors of apoptosis, our findings indicate an IKK-independent regulation of TRAF1 in B-CLL. ..
  24. Boucher L, Marengere L, Lu Y, Thukral S, Mak T. Binding sites of cytoplasmic effectors TRAF1, 2, and 3 on CD30 and other members of the TNF receptor superfamily. Biochem Biophys Res Commun. 1997;233:592-600 pubmed
    ..We show that these amino acid motifs are conserved in TNFRp75 and CD40 and that sequences in these receptors homologous to TRAF-binding sequences found in CD30 can selectively bind the TRAFs in a predictable manner. ..
  25. Dürkop H, Hirsch B, Hahn C, Foss H, Stein H. Differential expression and function of A20 and TRAF1 in Hodgkin lymphoma and anaplastic large cell lymphoma and their induction by CD30 stimulation. J Pathol. 2003;200:229-39 pubmed
    ..TRAF1 transfection decreased CD30-induced apoptosis. Our data suggest that A20 and TRAF1 contribute to apoptosis resistance and, therefore, play an important role in the pathogenesis of classical HL. ..
  26. Li X, Wang Y, Debatin K, Hug H. The serine/threonine kinase HIPK2 interacts with TRADD, but not with CD95 or TNF-R1 in 293T cells. Biochem Biophys Res Commun. 2000;277:513-7 pubmed
    ..Under the conditions where HIPK2/TRADD association was found, no direct interaction of HIPK2 with CD95, TNF-R1, FADD or caspase-8 could be detected. Therefore, HIPK2 may play a role in TNF-R1 mediated signaling. ..
  27. Feng X, Gaeta M, Madge L, Yang J, Bradley J, Pober J. Caveolin-1 associates with TRAF2 to form a complex that is recruited to tumor necrosis factor receptors. J Biol Chem. 2001;276:8341-9 pubmed
    ..These findings suggest that intracellular distribution of activated TNF receptors may be regulated by caveolin-1 via its interaction with TRAF2. ..
  28. Malinin N, Boldin M, Kovalenko A, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997;385:540-4 pubmed
    ..It also blocked NF-kappaB induction by interleukin-1. Our findings indicate that NIK participates in an NF-kappaB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor. ..
  29. Wang C, Mayo M, Korneluk R, Goeddel D, Baldwin A. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680-3 pubmed
    ..Thus, NF-kappaB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and that function more distally to suppress genotoxic agent-mediated apoptosis. ..
  30. Natoli G, Costanzo A, Ianni A, Templeton D, Woodgett J, Balsano C, et al. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science. 1997;275:200-3 pubmed
    ..Therefore, SAPK activation occurs through a pathway that is not required for TNF-R1-induced apoptosis. ..
  31. Gedrich R, Gilfillan M, Duckett C, van Dongen J, Thompson C. CD30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor-associated factor family of signal transducing proteins. J Biol Chem. 1996;271:12852-8 pubmed
  32. Hsu H, Huang J, Shu H, Baichwal V, Goeddel D. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity. 1996;4:387-96 pubmed
    ..These results suggest that distinct domains of RIP participate in the TNF signaling cascades leading to apoptosis and NF-kappa B activation. ..
  33. Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell. 1995;80:389-99 pubmed
    ..The interaction of LMP1 with these TNFR family-associated proteins is further evidence for their role in signaling and links LMP1-mediated transformation to signal transduction from the TNFR family. ..
  34. Hu H, O Rourke K, Boguski M, Dixit V. A novel RING finger protein interacts with the cytoplasmic domain of CD40. J Biol Chem. 1994;269:30069-72 pubmed
    ..This is the first identification of a molecule that interacts with CD40 and whose sequence suggests a potential role in signaling. ..
  35. Tsao D, McDonagh T, Telliez J, Hsu S, Malakian K, Xu G, et al. Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway. Mol Cell. 2000;5:1051-7 pubmed
    ..A combination of NMR, BIAcore, and mutagenesis experiments was used to help identify the site of interaction of N-TRADD with C-TRAF2, providing a framework for future attempts to selectively inhibit the TNF signaling pathways. ..
  36. Park A, Baichwal V. Systematic mutational analysis of the death domain of the tumor necrosis factor receptor 1-associated protein TRADD. J Biol Chem. 1996;271:9858-62 pubmed
    ..Such observations provide evidence that TRADD performs an obligate role in TNF-induced NF-kappaB activation. ..
  37. Rothe M, Wong S, Henzel W, Goeddel D. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell. 1994;78:681-92 pubmed
    ..TRAF1 interacts with TNF-R2 indirectly through heterodimer formation with TRAF2. ..
  38. Potter C, Eyre S, Cope A, Worthington J, Barton A. Investigation of association between the TRAF family genes and RA susceptibility. Ann Rheum Dis. 2007;66:1322-6 pubmed
    ..Further association and functional studies are required to investigate the role of this variant, or one in linkage disequilibrium with it, in RA disease causation. ..
  39. Kurreeman F, Padyukov L, Marques R, Schrodi S, Seddighzadeh M, Stoeken Rijsbergen G, et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med. 2007;4:e278 pubmed
    ..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. ..
  40. Plenge R, Seielstad M, Padyukov L, Lee A, Remmers E, Ding B, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. N Engl J Med. 2007;357:1199-209 pubmed
    ..A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis. ..
  41. Cheng G, Cleary A, Ye Z, Hong D, Lederman S, Baltimore D. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science. 1995;267:1494-8 pubmed
    ..It is likely that other members of the TNF receptor superfamily use CRAF-related proteins in their signal transduction processes. ..
  42. Murray P, Flavell J, Baumforth K, Toomey S, Lowe D, Crocker J, et al. Expression of the tumour necrosis factor receptor-associated factors 1 and 2 in Hodgkin's disease. J Pathol. 2001;194:158-64 pubmed
    ..In contrast, TRAF2 expression by HRS cells appeared to be independent of EBV status. Using a sequential labelling approach, co-localization of LMP1 with either TRAF1 or TRAF2 was also demonstrated in HRS cells from EBV-positive tumours. ..
  43. Park Y, Ye H, Hsia C, Segal D, Rich R, Liou H, et al. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Cell. 2000;101:777-87 pubmed
    ..The stronger affinity and unique specificity of the TRADD-TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbation of TRAF recruitment in sensitizing cell death induction. ..
  44. Zapata J, Krajewska M, Krajewski S, Kitada S, Welsh K, Monks A, et al. TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies. J Immunol. 2000;165:5084-96 pubmed
    ..01), as determined by immunoblotting. These findings contribute to an improved understanding of the cell-specific roles of TRAFs in normal tissues and provide evidence of altered TRAF1 expression in lymphoid malignancies. ..
  45. Ikezawa I, Tai H, Shimada Y, Komatsu Y, Galicia J, Yoshie H. Imbalance between soluble tumour necrosis factor receptors type 1 and 2 in chronic periodontitis. J Clin Periodontol. 2005;32:1047-54 pubmed
    ..0001). The imbalance between soluble TNF receptor type 1 and 2 levels in GCF could be related to CP severity. ..
  46. Su X, Li S, Meng M, Qian W, Xie W, Chen D, et al. TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling. Eur J Immunol. 2006;36:199-206 pubmed
    ..Our findings provide a novel mechanism for negative regulation of TRIF-mediated signaling. ..
  47. Liu Z, Bohatschek M, Pfeffer K, Bluethmann H, Raivich G. Major histocompatibility complex (MHC2+) perivascular macrophages in the axotomized facial motor nucleus are regulated by receptors for interferon-gamma (IFNgamma) and tumor necrosis factor (TNF). Neuroscience. 2005;131:283-92 pubmed
  48. Siwkowski A, Madge L, Koo S, McMillan E, Monia B, Pober J, et al. Effects of antisense oligonucleotide-mediated depletion of tumor necrosis factor (TNF) receptor 1-associated death domain protein on TNF-induced gene expression. Mol Pharmacol. 2004;66:572-9 pubmed
    ..These results indicate usage of antisense inhibitors of TRADD expression for modulating diseases associated with TRADD-dependent signal transduction pathways. ..
  49. Greis A, Murgott J, Rafalzik S, Gerstberger R, Hübschle T, Roth J. Characterization of the febrile response induced by fibroblast-stimulating lipopeptide-1 in guinea pigs. Am J Physiol Regul Integr Comp Physiol. 2007;293:R152-61 pubmed
    ..In conclusion, FSL-1-induced fever in guinea pigs depends, in shape and duration, on the route of administration and is, to a high degree, mediated by pyrogenic cytokines and COX products. ..
  50. Sanz L, Sanchez P, Lallena M, Diaz Meco M, Moscat J. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J. 1999;18:3044-53 pubmed
    ..Together, these results demonstrate that the interaction of p62 with RIP serves to link the atypical PKCs to the activation of NF-kappaB by the TNFalpha signaling pathway. ..
  51. Wang C, Wen T, Routy J, Bernard N, Sekaly R, Watts T. 4-1BBL induces TNF receptor-associated factor 1-dependent Bim modulation in human T cells and is a critical component in the costimulation-dependent rescue of functionally impaired HIV-specific CD8 T cells. J Immunol. 2007;179:8252-63 pubmed
    ..These studies identify 4-1BBL as a critical component in therapeutic strategies aimed at improving CD8 T cell function. ..
  52. Kurreeman F, Rocha D, Houwing Duistermaat J, Vrijmoet S, Teixeira V, Migliorini P, et al. Replication of the tumor necrosis factor receptor-associated factor 1/complement component 5 region as a susceptibility locus for rheumatoid arthritis in a European family-based study. Arthritis Rheum. 2008;58:2670-4 pubmed publisher
    ..Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA. ..