Rheumatoid Arthritis: Cornélis F

Dieudé P, Cornélis F. · GenHotel - EA3886, European Research Laboratory for Rheumatoid Arthritis, Evry-Paris 7 University, 2, rue Gaston Crémieux, 91000 Evry, and Rheumatology Federation, Lariboisière Teaching Hospital, 75010 Paris, France. · Joint Bone Spine. · Pubmed #16309943 No free full text.

Abstract: Rheumatoid arthritis (RA) is a multifactorial disease due to a combination of genetic and environmental factors. Identification of the genetic factors involved in the pathogenesis of RA should open up avenues for developing radical treatment strategies directed at the cause of the disease. The Association de Recherche sur la Polyarthrite (ARP) supports research in this field, in which our group has been involved since 1993. Thanks to this support, considerable progress has been made. Several combinations of susceptibility alleles of various genes are probably involved in the development of RA. Although HLA-DRB1 is the main RA gene, it accounts for only part of the familial risk for RA. HLA-DRB1 alleles are neither necessary nor sufficient to cause the development of RA in a given individual. Several genome scans conducted in populations from France, Japan, North America and UK have confirmed the role of the HLA region and suggested several other susceptibility loci. Association studies support a role for several genes, including TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22. However, the imperfect matching of cases and controls requires that confirmation of these results be obtained. To confirm that a gene confers susceptibility to RA, the association must be replicated in several independent studies and, more importantly, evidence of genetic linkage must be obtained in family studies. The identification of genetic factors conferring susceptibility to RA will open up new avenues toward radical treatments for RA and may help to optimize the diagnostic, prognostic, and pharmacogenetic management of today's patients with RA.

Sebbag M, Chapuy-Regaud S, Auger I, Petit-Texeira E, Clavel C, Nogueira L, Vincent C, Cornélis F, Roudier J, Serre G. · Faculté de Médecine, Purpan-IFR30, Unité Différenciation Epidermique et Auto-immunité Rhumatoïde, UMR 5165 CNRS-Toulouse III Université, (CNRS-Inserm-Université Paul Sabatier-CHU de Toulouse), Place du Docteur Baylac, 31059 Toulouse, France. · Joint Bone Spine. · Pubmed #15589429 No free full text.

Abstract: Rheumatoid arthritis (RA) is the most frequent human autoimmune disease, affecting about 1% of the adult population worldwide. A better knowledge of the autoimmune mechanisms involved is essential. We identified the epithelial targets of various autoantibodies specifically associated to RA, as variants of (pro)filaggrin. We also showed that these targets correspond to deiminated ("citrullinated") proteins, of which arginyl residues have been posttranslationally transformed into citrullyl residues by a peptidylarginine deiminase (PAD). Moreover, we and others established that citrullyl residues are indispensable elements of the epitopes recognized by these autoantibodies but only in the context of specific aminoacid sequences. We also demonstrated that these autoantibodies to citrullinated proteins (ACPA) are secreted by plasma cells of the synovial tissue and that their major targets correspond to citrullinated forms of the alpha- and beta-chains of fibrin, abundant in the tissue. These results have allowed the development of new efficient immunochemical methods for the detection of ACPA. Some of them are already commercially available. These new methods have permitted the high diagnostic value of ACPA which are present very early in the course of the disease, and also their prognostic value, to be confirmed. ACPA detection should therefore prove to be also a very valuable tool to guide the choice of therapeutic strategies, from the earliest stages of the disease. The synthesis of ACPA in the rheumatoid synovial tissue and the existence therein of a specific antigenic target constitute a strong argument for the involvement of this specific immunological conflict in the pathophysiology of RA. Indeed, it could lead to activation of effector mechanisms with pro-inflammatory effects, thus to formation in the tissue of new fibrin deposits, secondarily citrullinated. We therefore, propose a new pathophysiological model accounting for the self-maintenance and chronicity of rheumatoid inflammation. Numerous questions about the pathophysiological significance of the autoimmune response to deiminated proteins in RA remain to be answered to confirm this model.

Cornélis F, Anonymous00016. · ECRAF-University Paris 7, GENOPOLE, Evry, France. · Curr Dir Autoimmun. · Pubmed #11791461 No free full text.

This publication has no abstract.

Teixeira VH, Pierlot C, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Vaz C, Fernandes M, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Lopes-Vaz A, Bardin T, Prum B, Cornélis F, Petit-Teixeira E, Anonymous00058. · GenHotel-EA3886, Evry University - Paris 7 University Medical School, AutoCure European Consortium, Evry-Genopole, France. · Arthritis Res Ther. · Pubmed #19302705 links to  free full text

Abstract: INTRODUCTION: A candidate gene approach, in a large case-control association study in the Dutch population, has shown that a 480 kb block on chromosome 4q27 encompassing KIAA1109/Tenr/IL2/IL21 genes is associated with rheumatoid arthritis. Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure. Therefore, our aim was to test this association in populations of European origin by using a family-based approach. METHODS: A total of 1,302 West European white individuals from 434 trio families were genotyped for the rs4505848, rs11732095, rs6822844, rs4492018 and rs1398553 polymorphisms using the TaqMan Allelic discrimination assay (Applied Biosystems). The genetic association analyses for each SNP and haplotype were performed using the Transmission Disequilibrium Test and the genotype relative risk. RESULTS: We observed evidence for association of the heterozygous rs4505848-AG genotype with rheumatoid arthritis (P = 0.04); however, no significance was found after Bonferroni correction. In concordance with previous findings in the Dutch population, we observed a trend of undertransmission for the rs6822844-T allele and rs6822844-GT genotype to rheumatoid arthritis patients. We further investigated the five SNP haplotypes of the KIAA1109/Tenr/IL2/IL21 gene region. We observed, as described in the Dutch population, a nonsignificant undertransmission of the AATGG haplotype to rheumatoid arthritis patients. CONCLUSIONS: Using a family-based study, we have provided a trend for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in populations of European descent. Nevertheless, we failed to replicate a significant association of this region in our rheumatoid arthritis family sample. Further investigation of this region, including detection and testing of all variants, is required to confirm rheumatoid arthritis association.

Michou L, Garnier S, Barbet S, Glikmans E, Ea HK, Uzan B, Asensio C, Ah Kioon MD, Lasbleiz S, Bardin T, Cornélis F, Lioté F. · Fédération de rhumatologie, Hôpital Lariboisière, Pôle Appareil Locomoteur, Assistance Publique-Hôpitaux de Paris, Paris, France. · Clin Exp Rheumatol. · Pubmed #19210874 No free full text.

Abstract: OBJECTIVE:Rheumatoid arthritis (RA) is characterized by hyperplasia of fibro-blast-like synoviocytes (FLSs), in part due to apoptosis resistance. Adrenomedullin, an anti-apoptotic peptide, is secreted more by RA than osteoarthritis FLSs. Adrenomedullin binds to a heterodimeric functional receptor, of calcitonin receptor-like receptor (CRLR) coupled with a receptor activity-modifying protein-2 (RAMP-2), which is also overexpressed by rheumatoid synoviocytes. Since adrenomedullin decreases RA FLS apoptosis, possibly contributing to the development of pannus, study of adrenomedullin and its receptor genes might reveal a linkage and association in French Caucasian RA trio families.METHODS:Within each of 100 families, one RA-affected patient and both parents underwent genotyping for polymorphisms of adrenomedullin, CRLR and RAMP-2, by PCR-restricted fragment-length polymorphism (RFLP) or Taqman 5' allelic discrimination assay. Statistical analysis relied on the transmission disequilibrium test, the affected family-based controls and the genotype relative risk. Haplotypes of CRLR were inferred, and linkage and association studies were performed.RESULTS:No significant transmission disequilibrium or association between the three genes and RA was observed. CRLR haplotypes revealed two major haplotypes, but no significant linkage with RA.CONCLUSION:Our findings provided no significant linkage or association of adrenomedullin and CRLR-RAMP-2 genes with RA in the studied trio families. The two CRLR polymorphisms rs3771076 and rs3771084 should be investigated in larger samples.

Goëb V, Dieudé P, Daveau R, Thomas-L'otellier M, Jouen F, Hau F, Boumier P, Tron F, Gilbert D, Fardellone P, Cornélis F, Le Loët X, Vittecoq O. · Department of Rheumatology, Rouen University Hospital & Inserm, Institute for Biomedical Research, University of Rouen, France. · Rheumatology (Oxford). · Pubmed #18535030 No free full text.

Abstract: OBJECTIVES: To evaluate the predictive value of TNFRII 196R, PTPN22 1858T and HLA-shared epitope (SE) alleles, RFs and anti-citrullinated protein antibodies (ACPAs) for RA diagnosis in a cohort of patients with very early arthritis. METHODS: We followed up 284 patients who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for <6 months. At 2 yrs, patients were classified as having RA or non-RA rheumatic diseases according to the ACR criteria. Patients were genotyped with respect to TNFRII 196M/R and PTPN22 1858C/T polymorphisms and HLA-SE. The presence of IgA, IgG and IgM RF isotypes and ACPA was sought in sera collected at disease onset. RESULTS: HLA-SE alleles alone, concomitant presence of TNFRII 196R and PTPN22 1858T alleles, IgA, IgG and IgM RF alone and ACPA were found to be significantly associated with RA diagnosis. Using logistic regression analysis, the concomitant presence of RF and ACPA at disease onset was the best association to predict RA diagnosis. In patients (n = 34) who did not fulfil the ACR criteria for RA at inclusion but who progressed to ACR positivity, the study of the genetic risk markers did not contribute to predict RA diagnosis at 2 yrs. CONCLUSIONS: PTPN22 1858T, TNFRII 196R and HLA-SE alleles do not improve the predictive value of RF and ACPA for RA diagnosis in our cohort, and do not contribute to an earlier diagnosis in undifferentiated patients initially negative for RF and ACPA.

Michou L, Rat AC, Lasbleiz S, Bardin T, Cornélis F. · GenHotel-EA 3886, University Evry-Paris 7 Medical School, Evry-Genopole, France. · J Rheumatol. · Pubmed #18381797 No free full text.

Abstract: OBJECTIVE: To investigate whether frequency of rheumatoid arthritis (RA) and/or other autoimmune (AI) disorders was increased in RA French Caucasian families among the first- (FDR) and second-degree relatives (SDR), and to test whether the presence of AI disease family history identified a specific RA subset. METHODS: We conducted telephone interviews to obtain histories of AI diseases among the FDR and SDR of 368 RA probands, belonging either to trio or affected sib-pair (ASP) families. All the AI diagnoses were confirmed by the physician of the affected relative. RESULTS: Probands of the ASP families were characterized by older age at RA onset, longer disease duration, and larger family size versus trio families. In the trio families, the prevalence of AI diseases was 6.05% (4.76%-7.57%) in FDR and 2.40% (1.85%-3.06%) in SDR. In ASP families, the prevalence of AI diseases was, respectively, 10.24% (8.68%-11.97%) and 1.79% (1.41%-2.25%). The most frequent AI diseases among relatives were RA, thyroid AI diseases, and vitiligo. In trio families, a proband with a mean age of RA onset < 30 years was associated with AI disease prevalence in the relatives, and male gender was associated with prevalence of RA among the FDR. CONCLUSION: The prevalence of AI diseases is increased, particularly among FDR, in French RA families, and some characteristics of the RA proband seem to be associated with prevalence of AI diseases in families.

Jacq L, Teixeira VH, Garnier S, Petit-Teixeira E, Cornélis F. · GenHotel-EA3886, Evry-Paris VII Universities, Evry-Genopole Cedex, France. · Int J Immunogenet. · Pubmed #18205826 No free full text.

Abstract: The MMP2 rs243865-T allele was recently suggested to be associated with rheumatoid arthritis (RA) in a case-control study. MMP2 is a positional RA candidate gene. Our aim was to test rs243865 in a French family based study. No significant result was shown. The MMP2 rs243865-T allele is not a major rheumatoid arthritis genetic factor in this population.

Jacq L, Teixeira VH, Garnier S, Michou L, Dieudé P, Rocha D, Pierlot C, Lemaire I, Quillet P, Hilliquin P, Mbarek H, Petit-Teixeira E, Cornélis F. · GenHotel-EA3886, Evry-Paris VII Universities, 2 rue Gaston Crémieux, 91057 Evry-Genopole cedex, France. · J Hum Genet. · Pubmed #17925998 No free full text.

Abstract: The heat shock 60-kDa protein 1 (HSP60) is involved in immune and inflammatory reactions, which are hallmarks of rheumatoid arthritis (RA). HSP60 is encoded by the HSPD1 gene located on 2q33, one of the suggested RA susceptibility loci in the French Caucasian population. Our aim was to test whether HSPD1 is a major susceptibility gene by studing families from the French Caucasian population. Three single nucleotide polymorphisms (SNPs) were studied in 100 RA trio families, and 100 other families were used for replication. Genetic analyses were performed by comparing allelic frequencies, by applying the transmission disequilibrium test, and by assessing the genotype relative risk. We observed a significant RA association for the C/C genotype of rs2340690 in the first sample. However, this association was not confirmed when the second sample was added. The two other SNPs and the haplotype analysis did not give any significant results. We conclude that HSPD1 is not a major RA susceptibility gene in the French Caucasian population.

Michou L, Teixeira VH, Pierlot C, Lasbleiz S, Bardin T, Dieudé P, Prum B, Cornélis F, Petit-Teixeira E. · GenHotel-EA 3886, Laboratoire de Recherche Européen pour la Polyarthrite Rhumatoïde, ECRAF-Université Paris 7-Université d'Evry, 2 rue Gaston Crémieux, CP 5727, 91057 Evry-Genopole cedex, France. · Ann Rheum Dis. · Pubmed #17660221 No free full text.

Abstract: OBJECTIVES: The objective of this study was to investigate the association between genes (HLA-DRB1 and PTPN22) and tobacco smoking, separately as well as combined, and serological markers of rheumatoid arthritis (RA) in a French population with RA. METHODS: 274 patients with RA with half of them belonging to RA multicase families, were genotyped for HLA-DRB1 allele and for PTPN22-1858 polymorphism. IgM rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies were determined by ELISA method. The search for association relied on chi(2) test and odds ratio with 95% confidence interval calculation. The interaction study relied on the departure-from-additivity-based method. RESULTS: The presence of at least one shared epitope (SE) allele was associated with anti-CCP antibodies presence (82.5% vs. 68.4%, p = 0.02), particularly with HLA-DRB1*0401 allele (28.0% vs. 16.4%, p = 0.01). Tobacco exposure was associated with anti-CCP antibodies, but only in presence of SE. A tendency toward an interaction was found between tobacco, the presence of at least one HLA-DRB1*0401 allele and anti-CCP antibodies (attributable proportion due to interaction = +0.24 (-0.21+0.76)). The cumulative dose of cigarette smoking was correlated with anti-CCP antibody titres (r = 0.19, p = 0.04). The presence of both SE and 1858T alleles was associated with a higher, but not significantly different, risk for anti-CCP antibodies presence than for each separately. No association was found between PTPN22-1858T allele and tobacco smoking for autoantibody positivity. CONCLUSIONS: Our findings suggest an association between SE alleles and tobacco smoking for anti-CCP positivity and a tendency toward an interaction between the HLA-DRB1*0401 allele and smoking for anti-CCP positivity in this sample of RA.

Jacq L, Garnier S, Dieudé P, Michou L, Pierlot C, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Vaz C, Fernandes M, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Lopes-Vaz A, Glikmans E, Barbet S, Lasbleiz S, Lemaire I, Quillet P, Hilliquin P, Teixeira VH, Petit-Teixeira E, Mbarek H, Prum B, Bardin T, Cornélis F, Anonymous00262. · GenHotel-EA3886, Evry-Paris VII Universities, 91057 Evry-Genopole cedex, France. · Arthritis Res Ther. · Pubmed #17615072 links to  free full text

Abstract: The integrin alpha(v)beta3, whose alpha(v) subunit is encoded by the ITGAV gene, plays a key role in angiogenesis. Hyperangiogenesis is involved in rheumatoid arthritis (RA) and the ITGAV gene is located in 2q31, one of the suggested RA susceptibility loci. Our aim was to test the ITGAV gene for association and linkage to RA in a family-based study from the European Caucasian population. Two single nucleotide polymorphisms were genotyped by PCR-restriction fragment length polymorphism in 100 French Caucasian RA trio families (one RA patient and both parents), 100 other French families and 265 European families available for replication. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies (affected family-based controls), the transmission disequilibrium test, and the genotype relative risk.We observed a significant RA association for the C allele of rs3738919 in the first sample (affected family-based controls, RA index cases 66.5% versus controls 56.7%; P = 0.04). The second sample showed the same trend, and the third sample again showed a significant RA association. When all sets were combined, the association was confirmed (affected family-based controls, RA index cases 64.6% versus controls 58.1%; P = 0.005). The rs3738919-C allele was also linked to RA (transmission disequilibrium test, 56.5% versus 50% of transmission; P = 0.009) and the C-allele-containing genotype was more frequent in RA index cases than in controls (RA index cases 372 versus controls 339; P = 0.002, odds ratio = 1.94, 95% confidence interval = 1.3-2.9). The rs3738919-C allele of the ITGAV gene is associated with RA in the European Caucasian population, suggesting ITGAV as a new minor RA susceptibility gene.

Gourraud PA, Dieudé P, Boyer JF, Nogueira L, Cambon-Thomsen A, Mazières B, Cornélis F, Serre G, Cantagrel A, Constantin A. · Service d'Epidémiologie CHU Toulouse, INSERM, U558, Université Paul Sabatier Toulouse III, Faculté de Médecine, 37 allées Jules Guesde, Toulouse Cedex 7, 31073, France. · Arthritis Res Ther. · Pubmed #17328818 links to  free full text

Abstract: The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity. We investigated the relevance of this new classification of HLA-DRB1 SE+ alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients. We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification. The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity. The new classification of HLA-DRB1 SE+ alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.

Michou L, Lasbleiz S, Rat AC, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Pierlot C, Glikmans E, Garnier S, Dausset J, Vaz C, Fernandes M, Petit-Teixeira E, Lemaire I, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Lopes-Vaz A, Prum B, Bardin T, Dieudé P, Cornélis F, Anonymous00173. · GenHotel-EA 3886, University Evry-Paris 7 Medical School, Member of the AutoCure European Consortium, CP5727, 91057 Evry-Genopole Cedex, France. · Proc Natl Acad Sci U S A. · Pubmed #17237219 links to  free full text

Abstract: The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF+). No interaction was shown with HLA-DRB1, the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of approximately 5% on average and large variations of population allele frequencies (2.1-15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22-1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 "trio" families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF+ families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF+ RA for the French Caucasian population and the susceptibility genotype (1858T/T or T/C) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2-2.8)]. In conclusion, we provided the linkage proof for the PTPN22-1858T allele and RF+ RA. With diabetes and RA, PTPN22 is therefore a "linkage-proven" autoimmunity gene. PTPN22 accounting for approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.

Dieudé P, Goossens M, Cornélis F, Michou L, Bardin T, Tchernitchko DO, Anonymous00134. · Service de Rhumatologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France. · Ann Rheum Dis. · Pubmed #17234651 No free full text.

Abstract: OBJECTIVE: TNFRSF1A mutations cause TNFRSF1A-associated periodic syndrome (MIM#142680). A recent study suggested that the R92Q mutation was associated with polyarthritis. We aimed to search for this and other TNFRSF1A mutations in rheumatoid arthritis (RA), and to test for linkage. METHODS: The DNA of 100 trio families and 86 index cases of RA-affected sib-pair (ASP) families from the French Caucasian population were investigated by denatured high-performance liquid chromatography for TNFRSF1A mutations in exons 2 to 4. The test for association compared cases and controls (derived from un-transmitted parental chromosomes). The test for linkage relied on the transmission disequilibrium test (TDT) in trio families and cosegregation in ASP families. RESULTS: Only the R92Q mutation was detected--in 2 of the 100 index cases of trio families and in 5 (5.8%) of the index cases of ASP families, but also in 5% of the controls, showing no association with the disease. No RA linkage evidence was found in TDT and ASP RA families. CONCLUSION: This TNFRSF1A investigation in RA from the French Caucasian population showed only the R92Q mutation, with a frequency of 4.5%, but no evidence for RA association or linkage to the disease. The R92Q mutation could be considered to be a low-penetrance variant.

Garnier S, Dieudé P, Michou L, Barbet S, Tan A, Lasbleiz S, Bardin T, Prum B, Cornélis F. · GenHotel-EA3886, Laboratoire Européen de Recherche pour la Polyarthrite Rhumatoïde, 2 rue Gaston Crémieux, 91057 Evry-Genopole Cedex, France. · Ann Rheum Dis. · Pubmed #17158136 No free full text.

Abstract: BACKGROUND: Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene. AIM: To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA. PATIENTS AND METHODS: 100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE. RESULTS: The analysis showed the absence of linkage and association globally and in "autoimmune" RA subsets, with a weak non-significant trend against the IRF5 rs20046470-T allele. Given the robustness of familial-based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE. CONCLUSION: Our results exclude the IRF5 rs2004640-T allele as a major genetic factor for RA in this French Caucasian population.

Michou L, Croiseau P, Petit-Teixeira E, du Montcel ST, Lemaire I, Pierlot C, Osorio J, Frigui W, Lasbleiz S, Quillet P, Bardin T, Prum B, Clerget-Darpoux F, Cornélis F, Anonymous00304. · GenHotel-EA 3886, University Evry-ParisVII Medical School, Member of the Autocure European Consortium, Evry-Genopole, France. · Arthritis Res Ther. · Pubmed #16646982 links to  free full text

Abstract: Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72-74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S1 alleles for the sequences A-RAA or E-RAA; S2 for Q or D-K-RAA; S3D for D-R-RAA; S3P for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S2 and S3P alleles were significantly over-transmitted and the S1, S3D and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S2/S3P, S2/S2, S3P/S3P, S2/L and S3P/L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S2/S3P [OR 22.2, 95% confidence interval 9.9-49.7]) to the lowest (S3P/L [OR 4.4, 95% confidence interval 2.3-8.4]).

Wipff J, Allanore Y, Kahan A, Meyer O, Mouthon L, Guillevin L, Pierlot C, Glikmans E, Bardin T, Boileau C, Cornélis F, Dieudé P. · Rheumatology A Department, Cochin Hospital, Paris, France. · Ann Rheum Dis. · Pubmed #16464986 No free full text.

Abstract: The minor allele of the R620W missense single-nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo. Systemic sclerosis (SSc) is a connective tissue disease with some autoimmune abnormalities. The aim of our study was to test for association of the PTPN22*620W allele with SSc in a French Caucasian cohort with a case-control study of 121 patients with SSc and 103 controls. All patients and controls were genotyped for the PTPN22*R620W SNP. No association was found between the PTPN22*620W allele and SSc (7% v 9.2%, p = 0.39). The frequency of genotypes carrying at least one 620W allele was similar in both groups (13% v 17%, p = 0.38). The PTPN22*620W allele was also not associated with autoantibody patterns. Thus, the PTPN22*R620W polymorphism cannot be regarded as a genetic susceptibility factor for SSc in the French Caucasian population.

Dieudé P, Garnier S, Michou L, Petit-Teixeira E, Glikmans E, Pierlot C, Lasbleiz S, Bardin T, Prum B, Cornélis F, Anonymous00229. · GenHotel-EA3886, Evry-Genopole, Evry, France. · Arthritis Res Ther. · Pubmed #16277672 links to  free full text

Abstract: The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes for lymphoid tyrosine phosphatase LYP, involved in the negative regulation of early T-cell activation. An association has recently been reported between the PTPN22-620W functional allele and rheumatoid factor-positive (RF+) rheumatoid arthritis (RA), among other autoimmune diseases. Expected linkage proof for consistency cannot be definitely produced by an affected sib-pair (ASP) analysis. Our aim was therefore to search for linkage evidence with the transmission disequilibrium test. DNA from the French Caucasian population was available for two samples of 100 families with one RA patient and both parents, and for 88 RA index cases from RA ASP families. Genotyping was carried out by PCR-restriction fragment length polymorphism. The analysis was performed using the transmission disequilibrium test, genotype relative risk and ASP-based analysis. The transmission disequilibrium test of the PTPN22-620W allele revealed linkage and association for RF+ RA (61% of transmission, P = 0.037). The genotype relative risk showed the risk allele in 34% of RF+ RA patients and in 24% of controls derived from nontransmitted parental chromosomes (P = 0.047, odds ratio = 1.69, 95% confidence interval = 1.03-2.78). The ASP investigation showed no enriched risk allele in RA multiplex families, resulting in a lack of power of ASP analysis, explaining the published negative results.This study is the first to show linkage of PTPN22 to RF+ RA, consistent with PTPN22 as a new RA gene.

Goëb V, Dieudé P, Vittecoq O, Mejjad O, Ménard JF, Thomas M, Gilbert D, Boumier P, Pouplin S, Daragon A, Fardellone P, Tron F, Cornélis F, Le Loët X. · Rheumatology Department, University Hospital of Rouen, Rouen, France. · Arthritis Res Ther. · Pubmed #16207322 links to  free full text

Abstract: Tumour necrosis factor (TNF)-alpha plays a key role in the pathogenesis of rheumatoid arthritis (RA). It binds to two receptors, namely TNF receptor (TNFR)I and TNFRII. Several studies have suggested an association between TNFRII 196R/R genotype and RA. The objective of the present study was to evaluate the predictive value of the TNFRII 196R allele for RA diagnosis and prognosis in a cohort of patients with very early arthritis. We followed up a total of 278 patients recruited from the community, who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for less than 6 months, and who had not received disease-modifying antirheumatic drugs or steroid therapy. At 2 years, patients were classified according to the American College of Rheumatology criteria. All patients were genotyped with respect to TNFRII 196M/R polymorphism. Radiographs of hands and feet (read according to the modified Sharp method) and the Health Assessment Questionnaire were used to quantify structural and functional severity. The cohort of 278 patients was found to include 156 and 122 RA and non-RA patients, respectively. The TNFRII 196R allele was found to be associated with RA (P = 0.002). However, progression of radiographic severity and Health Assessment Questionnaire scores over 1 year did not differ between carriers of the 196R allele and noncarriers. Our findings suggest that the TNFRII 196R allele may be associated with RA diagnosis but that it does not predict early radiographic progression or functional severity in patients with very early, unclassified arthritis.

Osorio Y Fortéa J, Bukulmez H, Petit-Teixeira E, Michou L, Pierlot C, Cailleau-Moindrault S, Lemaire I, Lasbleiz S, Alibert O, Quillet P, Bardin T, Prum B, Olson JM, Cornélis F. · GenHotel, Evry, France. · Arthritis Rheum. · Pubmed #15457443 links to  free full text

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan. METHODS: In a study of 88 French Caucasian families (105 RA sibpairs), 1,088 microsatellite markers were genotyped (3.3-cM genome scan), and a multipoint model-free linkage analysis was performed. The statistical assessment of the results relied on 10,000 computer simulations. A covariate-based multipoint model-free linkage analysis was performed on the locations of regions with suggestive evidence for linkage. RESULTS: Involvement of the HLA region was strongly confirmed (P = 6 x 10(-5)), and 19 non-HLA regions showed suggestive evidence for linkage (P < 0.05); 9 of these overlapped with regions suggested in other published RA genome scans. A routine 12-cM genome scan with the same families would have detected only 7 of the 19 regions, including only 4 of the 9 overlapping regions. From the 10,000 computer simulations, we estimated that 8 +/- 4 regions (mean +/- SD) were true-positives. RA covariate-based analysis provided additional linkage evidence for 3 regions, with age at disease onset, erosions, and HLA-DRB1 shared epitope as covariates. CONCLUSION: The results of this study provide evidence of 19 non-HLA RA gene regions, with an estimate of 8 +/- 4 as true-positives, and provide additional evidence for 3 regions from covariate-based analysis.

van der Helm-van Mil AH, Dieudé P, Schonkeren JJ, Cornélis F, Huizinga TW. · Department of Rheumatology, C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. · Rheumatology (Oxford). · Pubmed #15252214 links to  free full text

Abstract: OBJECTIVES: To assess the association between the tumour necrosis factor receptor 2 (TNFR2) 196 M/R single-nucleotide polymorphism and rheumatoid arthritis (RA) severity by taking advantage of the extremes of phenotype that exist in arthritis. METHODS: From the Leiden Early Arthritis Cohort (1700 patients), we selected patients who initially had the diagnosis of definite or probable RA according to the ACR criteria and developed complete remission (71 patients) or had the worst progression, to destructive disease (72 patients). A group of 135 healthy controls was included. The TNFR2 genotype was determined in these groups. RESULTS: The extremes of phenotypes did not differ significantly in genotype distribution. No difference in genotype distribution between rheumatoid arthritis patients and healthy controls was observed. CONCLUSION: Our study demonstrates that even by comparing the extremes of phenotypes no association between the TNFR2 genotype and disease severity can be detected in Caucasian patients with sporadic RA.

Constantin A, Dieudé P, Lauwers-Cancès V, Jamard B, Mazières B, Cambon-Thomsen A, Cornélis F, Cantagrel A. · Centre Hospitalier Universitaire Rangueil, INSERM U558, and INSERM U563, Toulouse, France. · Arthritis Rheum. · Pubmed #15022314 links to  free full text

Abstract: OBJECTIVE: The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA. METHODS: One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F-HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F-HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not. CONCLUSION: The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.

Dieudé P, Osorio J, Petit-Teixeira E, Moreno S, Garnier S, Cailleau-Moindrault S, Stalens C, Lasbleiz S, Bardin T, Prum B, Cornélis F, Anonymous00060. · GenHotel, Evry-Genopole, France. · Arthritis Rheum. · Pubmed #14872483 links to  free full text

Abstract: OBJECTIVE: Results of genome scans in rheumatoid arthritis (RA) have suggested that the tumor necrosis factor receptor I (TNFRI) and TNFRII loci (TNFR1 and TNFR2) are susceptibility loci. A TNFR2 polymorphism was found to be associated with familial RA. TNFR1 is mutated in TNFR-associated periodic syndrome (TRAPS). We undertook this study to test the TNFR1 exonic polymorphism closest to the TRAPS mutations site (+36 A/G) for association with RA. METHODS: DNA samples were available from two groups of the French Caucasian population: 1) 100 families with 1 RA patient and both parents and 2) 86 RA index patients from families with at least 2 siblings with RA (affected sibpairs [ASPs]). The +36 A/G polymorphism of TNFR1 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The analysis was performed using the transmission disequilibrium test, the genotype relative risk, and a linkage-based test previously described. RESULTS: A negative association between RA and the +36 A/A genotype, suggested in the first sample (P = 0.084), was demonstrated in the second (ASP RA) sample (odds ratio [OR] 0.465; P = 0.012) and confirmed by the linkage-based test (OR 0.17; P = 0.008). The protective genotype, present in 41% of controls, was less frequent in RA patients: 33% in the first sample, 24% in the ASP RA sample, and 11% in the linkage-derived subgroup. Distribution of both TNFR2 196 R/R and TNFR1 +36 A/A genotypes in the ASP RA sample showed that both suspected genotypes were exclusive. CONCLUSION: We found evidence for an association between RA and a TNFR1 protective genotype, restricted to familial RA. Distribution of the TNFR2 196 R/R and TNFR1 +36 A/A genotypes in familial RA could suggest an interaction between TNFR1 and TNFR2 in the genetic susceptibility for RA.

Dieudé P, Petit E, Cailleau-Moindrault S, Osorio J, Pierlot C, Martinez M, Fauré S, Alibert O, Lasbleiz S, De Toma C, Bardin T, Prum B, Cornélis F, Anonymous00321. · GenHotel, Evry-Genopole, France. · Arthritis Rheum. · Pubmed #12209506 links to  free full text

Abstract: OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) binds the receptors TNFRI and TNFRII. Results of genome scans have suggested that TNFR2 is a candidate rheumatoid arthritis (RA) locus. A case-control study in a UK Caucasian population has shown an association between a TNFR2 genotype (196R/R in exon 6) and familial, but not sporadic, RA. The present study was undertaken to test this association in the French Caucasian population. METHODS: To test for an association in sporadic RA, 100 families were genotyped for the 196M/R polymorphism and analyzed using the transmission disequilibrium test and haplotype relative risk. To test for an association in familial RA, RA index cases from 100 affected sibpair (ASP) families were genotyped for 196M/R. Linkage analysis was performed with 3 TNFR2 microsatellite markers. RESULTS: The TNFR2 196R/R genotype was not associated with sporadic RA (odds ratio [OR] 0.59, P = 0.72), but was associated with familial RA (OR 4.0, P = 0.026). The association was most marked in the context of TNFR2 "twin-like" RA sibs (affected sibs sharing both TNFR2 haplotypes) (OR 9.2, P = 0.0017). Linkage analysis results were consistent with the association; most of the TNFR2 linkage evidence was found in the subgroup of families with 196R/R ASP index cases. CONCLUSION: This study is the first to replicate evidence of the involvement of TNFR2 in RA genetic heterogeneity. Our data refine the initial hypothesis, to suggest that a TNFR2 recessive factor, in linkage disequilibrium with the 196R allele, plays a major role in a subset of families with multiple cases of RA.

Barrera P, Fauré S, Prud'homme JF, Balsa A, Migliorini P, Chimenti D, Radstake TR, van de Putte LB, Pascual-Salcedo D, Westhovens R, Maenaut K, Alves H, Lopes-Vaz A, Stravopoulos C, Spyropoulou M, Fritz P, Bardin T, Charron D, Lepage V, Alibert, Martinez M, Cornélis F, Anonymous00013. · Department of Rheumatology, University Hospital, Nijmegen, The Netherlands. · Clin Exp Rheumatol. · Pubmed #11791644 No free full text.

Abstract: The genetic predisposition for rheumatoid arthritis (RA) is only partly explained by the HLA locus and most genetic factors involved in the susceptibility (and/or severity) of the disease await further identification. The first European genome scan in RA families provided suggestive evidence for linkage with a region (3.1/3q13) on chromosome 3, but many other potential RA susceptibility genes have yet to be analysed. AIMS: To perform a linkage analysis with microsatellite markers located in the vicinity of the interleukin-1 (IL-1) gene superfamily, the IL-10 gene and the IL-4 gene cluster which might be considered putative candidate loci for RA. METHODS: 107 Caucasoid European RA sibpairs from 90 nuclear families were genotyped for markers flanking the genes for the IL-1 superfamily, IL-10 and the IL-4 gene cluster. Linkage analysis based on the identity by descent (IBD) in affected siblings was analysed with the program SIBPALNA. Affected sibpairs were stratified according to the identity by state (IBS) for three markers in the HLA region (DRB1 oligotyping, D6S276 and TNFa microsatellites) and to the presence/absence of erosive disease on X-ray examination. RESULTS: Analysis of the whole family set showed an excess of allele sharing for markers of the IL-1 gene cluster (IBD 60%; P = 0.012) but not for IL-10 or IL-4. After stratification, the evidence of linkage to IL-1 was restricted to HLA concordant sibpairs (n = 32; IBD 70%; P = 0.006). Some evidence of linkage to IL-10 was also observed in HLA concordant sibpairs (IBD 66%; P = 0.03) and in sibpairs with erosive disease (n = 61; IBD 62%; P = 0.02). CONCLUSIONS: We found suggestive evidence of linkage of RA to the IL-1 locus. The increased linkage to IL-1 and IL-10 in HLA-identical sibs suggests a possible interaction between these cytokines and the HLA loci. Moreover IL-10 could interact with HLA factors in predisposing to erosive disease. These results need to be tested in additional families for consistency and replication.