Rheumatoid Arthritis: Michou L

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.

Kurreeman FA, Rocha D, Houwing-Duistermaat J, Vrijmoet S, Teixeira VH, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Vaz C, Fernandes M, Pascual-Salcedo D, Michou L, Bombardieri S, Radstake T, van Riel P, van de Putte L, Lopes-Vaz A, Prum B, Bardin T, Gut I, Cornelis F, Huizinga TW, Petit-Teixeira E, Toes RE, Anonymous00030. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18759306 No free full text.

Abstract: OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.

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, 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.

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]).

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.

Maalej A, Petit-Teixeira E, Michou L, Rebai A, Cornelis F, Ayadi H. · Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Avenue Majida Boulila, 3029 Sfax, Tunisia. · Genes Immun. · Pubmed #16151416 No free full text.

Abstract: Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease is controversial. The aim of this study was to investigate the role of vitamin D receptor gene (VDR) in rheumatoid arthritis (RA). Three polymorphisms for VDR gene FokI T>C (rs 10735810), BsmI A>G (rs 1544410) and TaqI C>T (rs 731236) were genotyped in 100 RA French nuclear families (set 1) and 100 additional French nuclear families for replication (set 2). The association analysis was performed using comparison of alleles frequencies (AFBAC), transmission disequilibrium test and genotype relative risk. Our results revealed a significant difference of F allele of FokI polymorphism between transmitted and nontransmitted frequencies (P=0.01) in set 1. Furthermore, the F/F genotype was more frequent in RA patients compared to controls (P=0.01) in set 1. The replication in set 2 showed similar patterns of transmission with a nonsignificant association. Association with FokI was found to be significant when the two sets were combined (P=0.006). These data suggest that the F allele and F/F VDR genotype are associated with RA. The mechanisms by which distinct receptor variants might confer disease susceptibility remain to be elucidated.

du Montcel ST, Michou L, Petit-Teixeira E, Osorio J, Lemaire I, Lasbleiz S, Pierlot C, Quillet P, Bardin T, Prum B, Cornelis F, Clerget-Darpoux F. · INSERM U535, Hôpital Paul Brousse, Villejuif, France. · Arthritis Rheum. · Pubmed #15818663 links to  free full text

Abstract: OBJECTIVE: The shared epitope hypothesis was formulated to explain the involvement of HLA-DRB1 in rheumatoid arthritis (RA). However, several studies, which considered only the HLA-DRB1 alleles shown to be associated with RA risk, rejected this hypothesis. In this report, we propose that a different classification of HLA-DRB1 alleles be considered, based on the amino acid sequence at position 70-74. METHODS: The fit of both HLA-DRB1 classifications was tested in 2 groups of RA patients. All subjects were recruited through the European Consortium on Rheumatoid Arthritis Families, and included 100 patients with isolated RA and 132 patients with at least 1 affected sibling. RESULTS: The new classification produced risk estimates that fit all of the observed data, i.e., the distribution of the HLA-DRB1 genotype in the 2 patient groups, and the distribution of parental alleles shared by affected sibpairs. The risk of developing RA under this new classification depends on whether the RAA sequence occupies position 72-74 but is modulated by the amino acid at position 71 (K confers the highest risk, R an intermediate risk, A and E a lower risk) and by the amino acid at position 70 (Q or R confers a higher risk than D). CONCLUSION: A new classification based on amino acid sequence allows us to show that the shared epitope RAA sequence at position 72-74 explains the data, with the risk of developing RA modulated by the amino acids at positions 70 and 71.

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.

Teixeira VH, Dieudé P, Michou L, 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, Cornélis F, Anonymous00026, Petit-Teixeira E. · No affiliation provided · Ann Rheum Dis. · Pubmed #19213753 No free full text.

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