Rheumatoid Arthritis: Gourraud PA

Barnetche T, Constantin A, Cantagrel A, Cambon-Thomsen A, Gourraud PA. · Department of Epidemiology and Public Health, UMR Inserm U 558, University Paul Sabatier Toulouse III, Faculty of Medicine Purpan, 37 Allées Jules Guesde, Toulouse cedex 7, 31073, France. · Arthritis Res Ther. · Pubmed #18307784 links to  free full text

Abstract: INTRODUCTION: Rheumatoid arthritis (RA) is a complex polygenic disease of unknown etiology. HLA-DRB1 alleles encoding the shared epitope (SE) (RAA amino acid pattern in positions 72 to 74 of the third hypervariable region of the DRbeta1 chain) are associated with RA susceptibility. A new classification of HLA-DRB1 SE alleles has been developed by Tezenas du Montcel and colleagues to refine the association between HLA-DRB1 and RA. In the present study, we used RA samples collected worldwide to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility across various Caucasoid and non-Caucasoid patients. METHODS: Eighteen subsamples were defined from a total number of 759 cases and 789 controls and grouped in 10 samples on the basis of their ethnic origin. HLA-DRB1 alleles were divided into five groups (S1, S2, S3D, S3P, and X) according to the new HLA-DRB1 allele classification. The whole analysis was performed by comparing carrier frequencies for the five HLA-DRB1 allele groups between RA patients and controls across the 10 Caucasoid and non-Caucasoid samples. The Mantel-Haenszel method of meta-analysis provided a global odds ratio (OR) estimate with 95% confidence interval (CI). RESULTS: A positive association with RA susceptibility was found for S2 allele carriers (OR 2.15, 95% CI 1.54 to 3.00; p < 10(-5)) and S3P allele carriers (OR 2.74, 95% CI 2.01 to 3.74; p < 10(-5)). A negative association was found for S1 alleles (OR 0.60, 95% CI 0.48 to 0.76; p < 10(-4)) and X alleles (OR 0.58, 95% CI 0.39 to 0.84; p = 4 x 10(-3)). No significant association was highlighted for the S3D group of alleles (OR 0.89, 95% CI 0.69 to 1.14; p = 0.89). The complementary genotype analysis fit with the genotype risk hierarchy previously reported in Caucasoid RA patients. CONCLUSION: So far, the present study is the first attempt to investigate the relevance of this new HLA-DRB1 classification in terms of RA susceptibility on both Caucasoid and non-Caucasoid samples. Our results support the hypothesis of a differential role played by different HLA-DRB1 allele groups in RA susceptibility across different ethnic backgrounds and confirm the interest of such an HLA-DRB1 classification in differentiating predisposing and protective alleles.

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.

Barnetche T, Constantin A, Gourraud PA, Abbal M, Garnier JG, Cantagrel A, Cambon-Thomsen A. · Institut National de la Santé et de la Recherché Médicale, Unit 558, Department of Public Health and Epidemiology, Faculty of Medicine Purpan, University Paul Sabatier Toulouse III, F-31073 Toulouse, France. · Tissue Antigens. · Pubmed #17092252 No free full text.

Abstract: Within the major histocompatibility complex (MHC), the human leucocyte antigen (HLA)-DRB1 locus is clearly associated with rheumatoid arthritis (RA). Using a microsatellite (MSat) typing approach, we aimed to identify other loci associated with RA susceptibility and/or severity within the MHC. A panel of nine MSat HLA loci [D6S291, D6S2876 (G51152), D6S1666 (DQCAR II), D6S273, D6S2789 (TNFd), D6S2810 (MIB), D6S265, D6S2222, D6S2239], and HLA-A, -B and -DRB1 genes were typed in 170 RA cases and 282 controls. For susceptibility analysis, MSat and HLA allele distribution were compared between cases and controls, before and after stratification on HLA-DRB1*04. Haplotype frequencies were estimated using an expectation-maximization algorithm in a permutation test procedure. For severity analysis, we compared the distribution of structural damage score at onset and after 4 years of follow-up in RA cases carrying susceptibility alleles. Two MSat polymorphisms were positively associated with RA susceptibility: allele*136 of D6S265 [odds ratio, OR (confidence interval, CI) = 1.55 (1.11-2.17), P= 0.007], allele*116 of D6S2239 [OR = 1.34 (1-1.79), P= 0.03] and HLA-A2 [OR = 1.46 (1.08-1.98), P= 0.01]. Two MSat polymorphisms were negatively associated with RA susceptibility: allele*133 of D6S273 [OR = 0.3 (0.1-0.75), P= 0.005] and allele*177 of D6S291 [OR = 0.72 (0.53-0.96), P= 0.02]. The association between allele*136 of D6S265 and RA susceptibility remained unchanged after stratification on HLA-DRB1*04. The haplotypic analysis showed an overrepresentation of D6S265*136/HLA-A*02 haplotype, which suggests an effect independent of HLA-DRB1 locus in RA susceptibility. While HLA-A2 and HLA-DR4 were associated with RA severity, no MSat polymorphism was associated with structural damage score.

Gourraud PA, Boyer JF, Barnetche T, Abbal M, Cambon-Thomsen A, Cantagrel A, Constantin A. · INSERM U558, Toulouse, France. · Arthritis Rheum. · Pubmed #16447236 links to  free full text

Abstract: OBJECTIVE: A new classification of HLA-DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA. METHODS: The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA-DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence-specific oligonucleotide probes. HLA-DRB1 alleles were classified according to the above-mentioned new system. The association between the HLA-DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests. RESULTS: The presence of S2 alleles (HLA-DRB1*0401 and HLA-DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA-DRB1*11001, HLA-DRB1*1104, HLA-DRB1*12, and HLA-DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01). CONCLUSION: The studied classification of HLA-DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70-74 of the third hypervariable region of the HLA-DRbeta chain.