Publications by authors named "Blanca Rueda"

32 Publications

The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis.

PLoS One 2012 24;7(8):e43661. Epub 2012 Aug 24.

Rheumatology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.

Background: The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis.

Methodology And Results: We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype.

Conclusions: Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043661PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427144PMC
February 2013

Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis.

Rheumatology (Oxford) 2012 Jan 15;51(1):52-9. Epub 2011 Nov 15.

Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Via Pace 9, 20122 Milan, Italy.

Objective: To determine the role of Class II HLAs in SSc patients from Italy and Spain and in SSc patients of Caucasian ancestry.

Methods: Nine hundred and forty-four SSc patients (Italy 392 patients; Spain 452 patients) and 1320 ethnically matched healthy controls (Italy 398 patients; Spain 922 patients) were genotyped up to the fourth digit by PCR with sequence-specific oligonucleotides for HLA-DRB1, DQA1 and DQB1 loci. Patients included 390 ACA-positive and 254 anti-topo I-positive subjects. Associations between SSc or SSc-specific antibodies and HLA alleles or HLA haplotypes were sought via the chi-square test after 10 000-fold permutation testing. A meta-analysis including this study cohort and other Caucasoids samples was also conducted.

Results: In both the cohorts, the strongest association was observed between the HLA-DRB1*1104 allele and SSc or anti-topo I antibodies. The HLA-DRB1*1104 -DQA1*0501 -DQB1*0301 haplotype was overrepresented in Italian [odds ratio (OR) = 2.069, 95% asymptotic CIs (CI(95)) 1.486, 2.881; P < 0.001] and in Spanish patients (OR = 6.707, CI(95) 3.974, 11.319; P < 0.001) as well as in anti-topo-positive patients: Italy (OR = 2.642, CI(95) 1.78, 3.924; P < 0.001) and Spain (OR = 20.625, CI(95) 11.536, 36.876; P < 0.001). In both the populations we also identified an additional risk allele (HLA-DQB1*03) and a protective allele (HLA-DQB1*0501) in anti-topo-positive patients. The meta-analysis showed different statistically significant associations, the most interesting being the differential association between HLA-DRB1*01 alleles and ACAs (OR = 1.724, CI(95) 1.482, 2.005; P < 0.001) or topo I antibodies (OR = 0.5, CI(95) 0.384, 0.651; P < 0.001).

Conclusions: We describe multiple robust associations between SSc and HLA Class II antigens in Caucasoids that may help to understand the genetic architecture of SSc.
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http://dx.doi.org/10.1093/rheumatology/ker335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276293PMC
January 2012

Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population.

Rheumatology (Oxford) 2011 Nov 28;50(11):1976-81. Epub 2011 Aug 28.

Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.

Objectives: The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population.

Methods: A total of 3800 SSc patients and 4282 healthy controls of white Caucasian ancestry from eight different European countries were included in the study. The MIF -173 single nucleotide polymorphism (SNP) was selected as genetic marker and genotyped using Taqman 5' allelic discrimination assay.

Results: The MIF -173 SNP showed association with SSc [P = 0.04, odds ratio (OR) = 1.10, 95% CI 1.00, 1.19]. Analysis of the MIF -173 polymorphism according to SSc clinical phenotype revealed that the frequency of the -173*C allele was significantly higher in the dcSSc group compared with controls (P = 5.30E-03, OR = 1.21, 95% CI 1.07, 1.38). Conversely, the frequency of the MIF -173*C allele was significantly underrepresented in the lcSSc group compared with dcSSc patients, supporting previous findings [(P = 0.04, OR = 0.86, 95% CI 0.75, 0.99); meta-analysis including previous results (P = 0.005, OR = 0.83, 95% CI 0.73, 0.94)].

Conclusion: Our results confirm the role of MIF -173 promoter polymorphism in SSc, and provide evidence of a strong association with the dcSSc subgroup of patients. Hence, the MIF -173 variant is confirmed as a promising clinical phenotype genetic marker.
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http://dx.doi.org/10.1093/rheumatology/ker259DOI Listing
November 2011

[Genetics in scleroderma].

Reumatol Clin 2010 Sep 9;6 Suppl 2:12-5. Epub 2010 Aug 9.

Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, España.

Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1⁎11/⁎06/⁎16 allelles. However, through association studies, different candidate genes that belong to the triad of autoimmunity, endothelial disfunction and fibrosis have been proposed as genes implicated in the predisposition to disease. In spite of these initial advances, up until recently most studies have had little statistical power, due to the small number of patients included and the lack of reproduction in independent populations. Recently, the development of genotyping platforms and data analysis has allowed for the application of a new type of strategy known as «genome wide association studies» the analysis of the genetics to complex diseases, which are potent tools in the study of these multifactorial diseases. This paper pretends to perform a review of the recent advances in the study of the genetics of scleroderma, presenting results obtained in the analysis of the main candidate genes outside the HLA regions and the contribution of GWAS to the understanding of the molecular mechanisms of this disease.
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http://dx.doi.org/10.1016/j.reuma.2010.04.005DOI Listing
September 2010

Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

PLoS Genet 2011 Jul 14;7(7):e1002178. Epub 2011 Jul 14.

Department of Epidemiology, M. D. Anderson Cancer Center, Houston, Texas, USA.

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.
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http://dx.doi.org/10.1371/journal.pgen.1002178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136437PMC
July 2011

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort.

Ann Rheum Dis 2011 Apr 27;70(4):638-41. Epub 2010 Dec 27.

Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan. [corrected]

Objectives: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features.

Methods: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers.

Results: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively).

Conclusions: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.
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http://dx.doi.org/10.1136/ard.2010.141838DOI Listing
April 2011

The functional polymorphism 844 A>G in FcαRI (CD89) does not contribute to systemic sclerosis or rheumatoid arthritis susceptibility.

J Rheumatol 2011 Mar 15;38(3):446-9. Epub 2010 Dec 15.

Department of Rheumatology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

Objective: To investigate the role of the Fc(α)RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility.

Methods: The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc(α)RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing.

Results: We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results.

Conclusion: Our data show that the Fc(α)RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.
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http://dx.doi.org/10.3899/jrheum.100427DOI Listing
March 2011

Functional variants of Fc gamma receptor (FCGR2A) and FCGR3A are not associated with susceptibility to systemic sclerosis in a large European Study (EUSTAR).

J Rheumatol 2010 Aug 15;37(8):1673-9. Epub 2010 Jun 15.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: To investigate the possible role of FCGR2A 519A>G and FCGR3A 559A>C functional polymorphisms in the genetic predisposition to susceptibility to systemic sclerosis (SSc) or clinical phenotype.

Methods: A total of 1566 patients with SSc and 2271 geographically matched controls were included in our study. We analyzed the genotype and allele frequencies of the FCGR2A 519A>G and FCGR3A 559A>C functional variants in 6 independent European cohorts of white patients with SSc, and white controls. The cohorts comprised 165 Dutch patients with SSc and 1326 controls, 236 Spanish patients with SSc and 257 controls, 267 German patients with SSc and 270 controls, 202 Swedish patients with SSc and 261 controls, 416 Italian patients with SSc and 157 controls, and additionally 280 English patients with SSc. Genotyping was performed using Taqman 5' allelic discrimination assay. The study reached a 99% power to detect the effect of a polymorphism at an OR of 1.3.

Results: Neither FCGR2A 519A>G nor FCGR3A 559A>C was significantly associated with susceptibility to SSc. We did not find an association with specific disease phenotypes, limited or diffuse cutaneous involvement, autoantibody profiles, or pulmonary involvement.

Conclusion: Our study strongly suggests the lack of a role for the FCGR2A 519A>G and FCGR3A 559A>C polymorphisms in SSc susceptibility or clinical phenotype in 6 independent European cohorts.
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http://dx.doi.org/10.3899/jrheum.091259DOI Listing
August 2010

Analysis of MIF, FCGR2A and FCGR3A gene polymorphisms with susceptibility to pulmonary tuberculosis in Moroccan population.

J Genet Genomics 2010 Apr;37(4):257-64

Human Genomic Unit, Laboratory of Immunology, National Institute of Hygiene, Rabat 10000, Morocco.

In order to investigate the influence of functional polymorphisms of macrophage migration inhibitory factor (MIF), Fcg receptors CD16A (FCGR3A) and CD32A (FCGR2A) genes on susceptibility to pulmonary tuberculosis (PTB) in the Moroccan population, we analyzed 123 patients with PTB and 154 healthy controls. The genotyping for MIF-173 (G/C) (rs755622), FCGR2A-131H/R (rs1801274) and FCGR3A-158V/F (rs396991) was carried out using TaqMan SNP Genotyping Assay method. We found a statistically significant increase of the MIF -173CC homozygote genotype and MIF -173*C allele frequencies in PTB patients compared with healthy controls (17.07%versus 5.84%, P = 0.003; and 35.37%versus 26.30%, P = 0.02; respectively). In contrast, no association was observed between FCGR2A-131H/R and FCGR3A-158V/F polymorphisms and tuberculosis disease. Our finding suggests that MIF -173*C variant may play an important role in the development of active tuberculosis.
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http://dx.doi.org/10.1016/S1673-8527(09)60044-8DOI Listing
April 2010

Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus.

Nat Genet 2010 May 11;42(5):426-9. Epub 2010 Apr 11.

Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.
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http://dx.doi.org/10.1038/ng.565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861917PMC
May 2010

Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.

J Autoimmun 2010 Mar 30;34(2):155-62. Epub 2009 Sep 30.

Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHSC-H), Houston, TX 77030, USA.

Objective: Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.

Methods: Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain.

Results: The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants.

Conclusion: We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.
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http://dx.doi.org/10.1016/j.jaut.2009.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821978PMC
March 2010

The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases.

Ann Rheum Dis 2010 Apr 10;69(4):696-9. Epub 2009 May 10.

Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands.

Objectives: The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE).

Methods: The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete.

Results: A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6 x 10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02 x 10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals.

Conclusion: A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases.
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http://dx.doi.org/10.1136/ard.2008.106567DOI Listing
April 2010

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

Hum Mol Genet 2009 Feb 3;18(3):569-79. Epub 2008 Nov 3.

Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.
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http://dx.doi.org/10.1093/hmg/ddn363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722189PMC
February 2009

Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: altered expression and signal in immune cells.

Arthritis Rheum 2008 Apr;58(4):1010-9

Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.

Objective: Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance. Administration of VIP ameliorates clinical signs in various experimental autoimmune disorders. This study was undertaken to investigate whether the exacerbated inflammatory autoimmune response in rheumatoid arthritis (RA) might result directly from altered expression and/or signaling of VIP receptors in immune cells.

Methods: The effect of specific agonists of different VIP receptors on collagen-induced arthritis in mice was investigated by clinical and histologic assessment and measurement of cytokine and chemokine production. Expression of VIP receptor type 1 (VPAC1) in synovial cells and monocytes from RA patients was determined by flow cytometry. Potential associations of VPAC1 genetic polymorphisms with RA susceptibility were investigated.

Results: A VPAC1 agonist was very efficient in the treatment of experimental arthritis, and deficient expression of VPAC1 in immune cells of RA patients was associated with the predominant proinflammatory Th1 milieu found in this disease. Immune cells derived from RA patients were less responsive to VIP signaling than were cells from healthy individuals and showed reduced VIP-mediated immunosuppressive activity, rendering leukocytes and synovial cells more proinflammatory in RA. A significant association between multiple-marker haplotypes of VPAC1 and susceptibility to RA was found, suggesting that the reduced VPAC1 expression in RA-derived immune cells is associated with the described VPAC1 genetic polymorphism.

Conclusion: These findings are highly relevant to the understanding of RA pathogenesis. They suggest that VIP signaling through VPAC1 is critical to maintaining immune tolerance in RA. In addition, the results indicate that VPAC1 may be a novel therapeutic target in RA.
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http://dx.doi.org/10.1002/art.23482DOI Listing
April 2008

Association of CD24 gene polymorphisms with susceptibility to biopsy-proven giant cell arteritis.

J Rheumatol 2008 May;35(5):850-4

Division of Rheumatology, Hospital Xeral-Calde, Lugo, Spain.

Objective: To investigate the possible implication of CD24 gene in the genetic predisposition to giant cell arteritis (GCA).

Methods: A total of 120 patients diagnosed with biopsy-proven GCA and 195 ethnically matched controls from the same region were studied. Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646) were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay.

Results: The 2 genetic variants showed statistically significant differences between patients with GCA and controls. The strongest association was observed for the rs3838646 TG/del polymorphism, conferring on the "del" allele an increased risk of GCA genetic susceptibility (odds ratio 1.94, 95% confidence interval 1.15-3.27, p = 0.01). In addition, genotypes carrying the rs3838646 "del" allele showed an increased frequency among GCA patients compared to controls (OR 2.31, 95% CI 1.30-4.1, p = 0.003). For the rs8743, an increased frequency of Val/Val homozygous individuals in patients with GCA compared to controls (OR 6.08, 95% CI 1.50-24.63, p = 0.001) was observed. A high degree of linkage disequilibrium was estimated between the 2 polymorphisms (D' = 0.7) and the C/del haplotype was associated with an increased risk of GCA susceptibility (OR 2.10, 95% CI 1.23-3.60, p = 0.005), whereas the C/TG haplotype showed a protective effect (OR 0.63, 95% CI 0.45-0.87, p = 0.005).

Conclusion: Our results suggest a potential role for the CD24 gene in the susceptibility to GCA in our population.
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May 2008

[Common genetic factors in autoimmunity].

Reumatol Clin 2008 Mar 3;4 Suppl 1:1-4. Epub 2009 Feb 3.

Instituto de Parasitología y Biomedicina López-Neyra. CSIC. Granada. España.

Autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) among others, are characterized by a complex etiology in which the combination of several genetic and environmental factors leads to an altered immune response. Several lines of evidence, such as the presence of chromosomal regions associated with several AIDs and the existence of similar gene expression patterns in autoimmune disorders, suggest that different AIDs share common genetic factors. The identification of common genetic factors associated with autoimmunity is of great relevance, since it will allow a better understanding of disease pathogenesis and could help for the development of molecular diagnosis tools and new therapeutic targets. In the past few years, a great progress has been made in the knowledge of the common genetic factors associated with autoimmunity. The PTPN22 gene, an important regulator of T cell response, has been identified as a relevant genetic marker for AIDs. This gene is implicated in the susceptibility to autoimmune disorders such as, RA, SLE, and type 1 diabetes (T1D). In the case of RA the association with the PTPN22 gene is the most replicated after association with HLA genes. In addition, genes implicated in the altered balance between cytokines, such as MIF and IRF5, have been identified as genetic factors predisposing to AIDs.
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http://dx.doi.org/10.1016/S1699-258X(08)76131-XDOI Listing
March 2008

HO-1 promoter polymorphism associated with rheumatoid arthritis.

Arthritis Rheum 2007 Dec;56(12):3953-8

CSIC, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n, Armilla, Granada, Spain.

Objective: To investigate the role of the HO-1 gene as a novel functional candidate gene for rheumatoid arthritis (RA).

Methods: We performed a case-control study including 736 RA patients and 846 healthy controls of Spanish Caucasian origin. Two putative functional HO-1 promoter polymorphisms, a (GT)(n) microsatellite and a -413 A/T single-nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction-based methods. In addition, the intracellular expression of heme oxygenase 1 (HO-1) was determined in healthy individuals with different (GT)(n) genotypes.

Results: The distribution of HO-1 (GT)(n) short (S) alleles (< or =25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT)(n) alleles (P = 0.019) (odds ratio [OR] 0.8, 95% confidence interval [95% CI] 0.7-0.9) and the SS (GT)(n) genotype (P = 0.002) (OR 0.6, 95% CI 0.4-0.9). In contrast, the -413 HO-1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P = 7 x 10(-7), corrected P [P(corr)] = 3 x 10(-6)) (OR 0.4, 95% CI 0.3-0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, P(corr) = 0.03) (OR 1.2, 95% CI 1.0-1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT)(n) genotype showed a significantly higher percentage of HO-1 expression than did cells from LL homozygous individuals (P = 0.0003).

Conclusion: In this study, we identified the HO-1 (GT)(n) microsatellite as a new genetic marker involved in RA genetics in our population.
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http://dx.doi.org/10.1002/art.23048DOI Listing
December 2007

Replication of an association between IL23R gene polymorphism with inflammatory bowel disease.

Clin Gastroenterol Hepatol 2007 Aug;5(8):977-81, 981.e1-2

Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain.

Background & Aims: Recently, the interleukin 23 receptor (IL23R) gene encoding a subunit of the receptor of the inflammatory cytokine IL-23 has been identified as a novel genetic factor strongly associated with inflammatory bowel disease (IBD). We aimed to replicate the IBD association of IL23R genetic markers in an IBD independent Spanish cohort.

Methods: Four hundred sixty IBD patients of Spanish white origin (238 CD and 222 UC) and 342 ethnically matched healthy controls comprised the study population. Eight single nucleotide polymorphisms (SNPs) spanning the IL23R gene and its downstream intergenic region were selected as genetic markers and genotyped by using Taqman 5' allelic discrimination assay.

Results: All genetic variants located within the IL23R gene were observed to confer a strong protective effect against IBD susceptibility in our population. The Arg381Gln (rs11209026) non-synonymous SNP was most significantly associated with IBD protection (odds ratio, 0.4; 95% confidence interval, 0.3-0.7). In addition to the single SNP analysis, we performed a haplotype analysis identifying 2 haplotypes significantly associated with IBD protection.

Conclusions: In this study we replicate the association of IL23R genetic variants with IBD in a Spanish population. These findings, together with the previous results, suggest that the IL23R gene is one of the genetic factors implicated in the genetics of IBD in the general population.
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http://dx.doi.org/10.1016/j.cgh.2007.05.002DOI Listing
August 2007

Investigation of the IL23R gene in a Spanish rheumatoid arthritis cohort.

Hum Immunol 2007 Aug 19;68(8):681-4. Epub 2007 Jun 19.

Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain.

Recently, a genome-wide association study identified the interleukin-23 receptor gene (IL23R) as an inflammatory bowel disease (IBD) associated gene. Given the involvement of IL23R in T-cell regulation, we decided to test whether this gene is associated with rheumatoid arthritis (RA). Eight IL23R gene polymorphisms (rs1,004,819, rs7,517,847, rs10,489,629, rs11,209,026, rs1,343,151, rs10,889,677, rs11,209,032, and rs1,495,965) were selected among the 10 most associated SNPs from the IBD study. A total of 322 RA patients and 342 healthy controls were genotyped for the selected SNPs using a Taqman 5' allelic discrimination assay. We did not find statistically significant differences when we compared allele and genotype frequencies between RA patients and controls for none of the IL23R gene polymorphisms under study. We did not observe significant differences when RA patients were stratified according to their clinical and demographic features. We conclude that the IL23R gene does not seem to be associated with RA predisposition in a Spanish population.
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http://dx.doi.org/10.1016/j.humimm.2007.05.008DOI Listing
August 2007

Molecular screening and association study of IL15 gene polymorphisms in rheumatoid arthritis.

Cytokine 2007 May 5;38(2):84-9. Epub 2007 Jul 5.

Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.

Interleukin 15 (IL-15) is a pleiotropic pro-inflammatory cytokine known to play a relevant role in rheumatoid arthritis (RA) pathogenesis. In this study we aimed to investigate for the first time the contribution of IL15 gene to RA susceptibility. We screened 13 single nucleotide polymorphisms (SNPs) localised within IL15 regulatory regions (promoter, 5' UTR region and 3' UTR region) in a total of 420 individuals, who were genotyped by direct sequencing of PCR products. In addition, an association study of these IL15 SNPs was conducted in three independent case-control cohorts of Spanish Caucasian origin, including a total of 645 RA patients and 656 healthy controls. The presence of the 13 selected IL15 SNPs in our population was confirmed and no new genetic variants were found. The distribution of the IL15 selected SNPs in RA patients and controls showed no statistically significant deviation in any of the populations studied. Additionally, we performed a haplotype analysis that revealed three IL15 haplotype blocks. None of the haplotype blocks was associated with RA susceptibility or severity in the three cohorts analysed. Our results suggest that the IL15 gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.
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http://dx.doi.org/10.1016/j.cyto.2007.05.005DOI Listing
May 2007

Influence of interleukin 10 promoter polymorphisms in susceptibility to giant cell arteritis in Northwestern Spain.

J Rheumatol 2007 Jul 1;34(7):1535-9. Epub 2007 Jun 1.

Consejo Superior de Investigaciones Cientificas, Granada.

Objective: Proinflammatory cytokines such as interferon-g (IFN-g) play an important role in the pathogenesis of giant cell arteritis (GCA). Interleukin 10 (IL-10) is a Th2 cytokine with a suppressor effect on IFN-g production. We assessed the influence of functional IL-10 gene promoter polymorphisms in susceptibility to GCA in individuals from Northwestern Spain.

Methods: One hundred three patients with biopsy-proven GCA and 226 matched controls from the Lugo region of Northwest Spain were genotyped for IL-10 -1082 G/A (rs1800896) and -592 C/A (rs1800872) promoter single nucleotide polymorphisms (SNP) by Taqman 5' allelic discrimination assay using Taqman predesigned SNP genotyping assays (numbers C_1747360_10 and C_1747363_10, respectively).

Results: A significant difference in the distribution of -1082 G/A genotypes between GCA patients and controls was observed (p = 0.034). It was mainly due to a decreased number of GCA patients carrying the -1082 A/A genotype (23.3%) compared with controls (36.7%) [p = 0.01, corrected p (pc) = 0.03; OR 0.53, 95% CI 0.31- 0.90]. In addition, haplotype analysis showed that the ATA haplotype frequency was slightly decreased (p = 0.05, pc = 0.2; OR 0.6, 95% CI 0.4-1.0), whereas the uncommon GTA haplotype was significantly increased in GCA patients compared with controls (p = 0.00005, pc = 0.0002; OR 8.7, 95% CI 2.2-34.8). CONCLUSION Our results suggest a potential implication of IL-10 -1082 promoter polymorphism in susceptibility to GCA in Northwestern Spain.
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July 2007

Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis.

Arthritis Rheum 2006 Dec;54(12):3815-9

Instituto de Biomedicina López-Neyra, Granada, Spain.

Objective: Recent findings suggest that interferon regulatory factor 5 (IRF-5) may play a crucial role in several cellular processes, including the transcription of genes for inflammatory cytokines. Two genetic variants of the IRF5 gene (rs2004640 in exon 1 and rs2280714 in the 3'-untranslated region) have been shown to exert functional modifications affecting IRF5 messenger RNA splicing and expression, and have been associated with genetic predisposition to systemic lupus erythematosus (SLE). The aim of this study was to analyze the possible contribution of the IRF5 gene to the predisposition to rheumatoid arthritis (RA).

Methods: Three case-control cohorts from Spain (724 RA patients and 542 healthy controls), Sweden (281 RA patients 474 healthy controls), and Argentina (284 RA patients and 286 healthy controls) were independently analyzed. Genotyping for IRF5 rs2004640 and rs2280714 was performed using a TaqMan 5' allele-discrimination assay.

Results: In the 3 cohorts studied, no statistically significant differences in allele or genotype frequencies of the rs2004640 and rs2280714 IRF5 polymorphisms were observed between RA patients and controls. Accordingly, haplotype analysis revealed that none of the IRF5 haplotypes was associated with genetic predisposition to RA.

Conclusion: Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to RA.
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http://dx.doi.org/10.1002/art.22271DOI Listing
December 2006

Functional polymorphism of the NFKB1 gene promoter is not relevant in predisposition to celiac disease.

Scand J Gastroenterol 2006 Apr;41(4):420-3

Instituto de Parasitología y Biomedicina López Neyra, Granada, Spain.

Objective: The nuclear factor (NF)-kappaB is one of the pivotal regulators of autoimmunity and inflammation, which has been shown to be activated in the inflamed mucosa of patients with celiac disease (CD). Recently, in the NFKB1 gene promoter region, a common insertion/deletion (-94ins/delATTG) polymorphism located between two putative key promoter regulatory elements was described. The aim of this study was to investigate the contribution of the -94ins/delATTG NFKB1 gene promoter functional variant to CD genetic predisposition.

Material And Methods: A case-control cohort comprising 478 patients with CD and 711 healthy controls as well as a panel of 196 celiac families was genotyped for the 94ins/delATTG NFKB1 polymorphism, using a polymerase chain reaction (PCR) method combined with fluorescence technology.

Results: We found no statistically significant differences between CD patients and controls when the -94ins/delATTG genotype and allele distributions were compared. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of -94ins/delATTG alleles to the affected offspring.

Conclusions: From these results, it could be suggested that the -94ins/delATTG NFKB1 polymorphism does not play a major role in CD susceptibility.
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http://dx.doi.org/10.1080/00365520500325929DOI Listing
April 2006

Association between functional haplotypes of vascular endothelial growth factor and renal complications in Henoch-Schönlein purpura.

J Rheumatol 2006 Jan;33(1):69-73

Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.

Objective: High expression of circulating vascular endothelial growth factor (VEGF) has been reported in patients with Henoch-Schönlein purpura (HSP). We investigated the role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants in the susceptibility to HSP, to identify associations with severe systemic complications of HSP, in particular with renal complications.

Methods: Fifty-seven patients from the Lugo region of Northwest Spain with primary cutaneous vasculitis classified as HSP according to proposed criteria were studied. All patients were required to have had at least 2 years' followup. Patients and ethnically matched controls (n = 226) were genotyped for the VEGF -1154 G-->A and -634 G-->C polymorphisms using real-time PCR technology based on TaqMan 5' allelic discrimination assay.

Results: No significant differences in the allele or genotype frequencies for the 2 VEGF polymorphisms were observed between HSP patients and controls. However, the high VEGF producer VEGF -1154 G allele was increased in HSP patients with nephritis compared with healthy controls (p = 0.02, OR 2.13, 95% CI 1.11-4.08; pc = 0.04). Similarly, the high VEGF producer VEGF -634 C allele was increased in patients with nephritis compared to controls (p = 0.04, OR 1.66, 95% CI 1.01-2.73; pc = 0.08). The -1154G/-634C haplotype was associated with susceptibility to nephritis (p = 0.03, OR 1.71, 95% CI 1.01-2.89). A protective effect against nephritis was observed for the -1154A/-634G VEGF promoter haplotype (p = 0.02, OR 0.49, 95% CI 0.30-0.95).

Conclusion: Our results suggest a potential implication of the VEGF -1154 G-->A and -634 G-->C polymorphisms in the development of nephritis in patients with HSP.
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January 2006

Analysis of a GT microsatellite in the promoter of the foxp3/scurfin gene in autoimmune diseases.

Hum Immunol 2005 Aug 20;66(8):869-73. Epub 2005 Jul 20.

Instituto de Parasitología y Biomedicina López Neyra, Granada, Spain.

The aim of this study was to assess the possible association of the functional (GT)(n) microsatellite polymorphism in the FOXP3 gene with predisposition to several autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn's disease, and celiac disease. We analyzed a case-control cohort composed of 231 SLE patients, 293 RA patients, 528 inflammatory bowel disease (354 Crohn's disease patients and 260 UC patients) patients, 103 celiac disease patients, and 274 healthy controls ethnically matched. Genotyping of (GT)(n) microsatellite was performed by polymerase chain reaction (PCR)-based method combined with fluorescent technology. We found no evidence for association of this polymorphism between controls and these autoimmune disease patients. Additionally, no differences in the genotype and allele distribution were found when patients were stratified according to clinical manifestation. The (GT)(n) microsatellite of the FOXP3 gene may not play a relevant role in the susceptibility to SLE, RA, inflammatory bowel disease, and celiac disease in our population.
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http://dx.doi.org/10.1016/j.humimm.2005.06.001DOI Listing
August 2005

Analysis of vascular endothelial growth factor (VEGF) functional variants in rheumatoid arthritis.

Hum Immunol 2005 Aug 19;66(8):864-8. Epub 2005 Jul 19.

Instituto de Parasitología y Biomedicina, Granada, Spain.

The vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic mediators related to inflammation-associated synovial angiogenesis. The aim of this study was to asses the role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants with rheumatoid arthritis (RA). The population under study was composed of a total of 753 unrelated RA patients and 801 healthy controls. The VEGF -1154 G-->A and -634 G-->C polymorphism genotyping was performed by real-time polymerase chain reaction technology, using TaqMan 5' allelic discrimination assay. No evidence of association was observed between the -1154 G-->A and the -634 G-->C VEGF polymorphisms, or inferred VEGF haplotypes with RA susceptibility or clinical manifestations. Our results suggest that the analyzed VEGF promoter polymorphisms may not play a relevant role in RA pathogenesis in our population.
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http://dx.doi.org/10.1016/j.humimm.2005.05.004DOI Listing
August 2005

A functional variant of vascular endothelial growth factor is associated with severe ischemic complications in giant cell arteritis.

J Rheumatol 2005 Sep;32(9):1737-41

Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC.

Objective: Angiogenesis, the formation of new blood vessels, may play a role in giant cell arteritis (GCA), the most common type of systemic vasculitis in the elderly in Western countries. Vascular endothelial growth factor (VEGF) is one of the most important proangiogenic mediators. We wanted to assess the potential role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants in GCA susceptibility and clinical ischemic complications.

Methods: One hundred and three patients with biopsy-proven GCA and 226 ethnically matched controls from the Lugo region (Northwest Spain) were genotyped for the VEGF -1154 G-->A and -634 G-->C polymorphisms using a real time polymerase chain reaction technology based on TaqMan 5' allelic discrimination assay.

Results: No significant differences in allele or genotype frequencies for the 2 VEGF polymorphisms were observed between patients and controls. However, the VEGF -634 G allele was significantly more frequent among GCA patients with severe ischemic complications compared with GCA patients not affected by ischemic events (p = 0.017, odds ratio, OR: 2.05; 95% confidence interval, CI: 1.13-3.71; pc = 0.034) or with controls (p = 0.021, OR: 1.75; 95% CI: 1.08-2.88; pc = 0.042). In this regard, the carriage rate of the risk allele G showed statistically significant skewing comparing GCA patients with severe ischemic events with the remaining GCA patients (GG + GC vs CC: p = 0.009, OR: 5.26; 95% CI: 1.39-19.98; pc= 0.018).

Conclusion: Our results suggest a potential implication of the VEGF gene -634 G-->C polymorphism in the development of severe ischemic manifestations of GCA.
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September 2005

C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition.

Hum Immunol 2005 Jul;66(7):848-52

Instituto de Parasitología y Biomedicina López Neyra, Armilla, Granada, Spain.

Recent findings have demonstrated that the single nucleotide polymorphism 1858C-->T located at the P1 motif of the PTPN22 (protein tyrosine phosphatase nonreceptor 22) gene has functional relevance and is associated with a variety of autoimmune diseases. The aim of this study was to assess the role of the PTPN22 1858C-->T polymorphism in the genetic predisposition to celiac disease (CD). We analyzed a case-control cohort composed by 534 patients with CD and 653 healthy controls and additionally a panel of 271 celiac families. The PTPN22 1858C-->T genotyping was performed by TaqMan 5' allelic discrimination assay. We did not observed any statistically significant deviation after comparing allele and genotypic frequencies of PTPN22 1858C-->T between patients with CD and controls. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of PTPN22 1858C-->T alleles to the affected offspring. Therefore, our data suggest that the PTPN22 1858 single nucleotide polymorphism has no, or only a negligible, effect on CD susceptibility in this Spanish population.
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http://dx.doi.org/10.1016/j.humimm.2005.04.008DOI Listing
July 2005