Rheumatoid Arthritis: Martín J

Balsa A, Pascual-Salcedo D, Martín J. · Servicio de Reumatología, Hospital Universitario La Paz, Madrid, España. · Med Clin (Barc). · Pubmed #17537367 No free full text.

Abstract: Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of the synovial joints leading to progressive joint destruction. The serum of these patients contains a large repertoire of autoantibodies, mainly rheumatoid factor, which is part of the ACR classification criteria in spite of having only moderate specificity. Antibodies directed to citrullinated proteins provide clinicians with a valuable tool for early diagnosis. It has been shown that these antibodies can be detected years before presentation of the first symptom and are very useful for diagnosis and prognosis, due to good sensitivity and specificity and prediction of development of erosive disease. The immune response against citrullinated antigens is characteristic of an immuno-genetic subtype of disease, in which the combined role of genes, environmental factors and autoimmunity has become the prime suspected for disease pathogenesis. A model is proposed of how these antibodies are produced and lead to chronic synovial inflammation.

Delgado-Vega AM, Martín J, Granados J, Anaya JM. · Unidad de Biología Celular e Inmunogenética, Corporación para Investigaciones Biológicas (CIB), Universidad del Rosario, Medellín, Colombia. · Biomedica. · Pubmed #17315483 No free full text.

Abstract: Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammation and destruction of the synovial joints. It affects approximately 0.5% of the Latin-American population and is three times more common in women than in men. Evidence of familial aggregation (lambdas=2-17) was the first indication of a genetic susceptibility to disease. As in other autoimmune diseases, it has a complex genetic basis. Results from whole-genome scans indicate that the HLA region contains a significant and consistent set of linked loci. However, HLA accounts for only one-third of the genetic susceptibility of disease, indicating that non-HLA genes are also involved in the disease susceptibility. In Latin-America, association with HLA-DRB1*0404 and TNF -308A alleles has been uniformly established; however, many other candidate genes remain to be studied. The identification of genetic factors conferring susceptibility to rheumatoid arthritis will contribute to the knowledge of the pathogenic mechanisms, ability to predict its occurrence, the development of diagnostic tools, prognosis, and treatment. The genetic epidemiology of rheumatoid arthritis is herein reviewed; a set of recommendations is provided for the design, analysis and interpretation of genetic association studies in the context of Latin-American populations.

Orozco G, Abelson AK, González-Gay MA, Balsa A, Pascual-Salcedo D, García A, Fernández-Gutierrez B, Petersson I, Pons-Estel B, Eimon A, Paira S, Scherbarth HR, Alarcón-Riquelme M, Martín J. · Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. · Arthritis Rheum. · Pubmed #19180476 No free full text.

Abstract: OBJECTIVE: To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA). METHODS: Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single-nucleotide polymorphisms (SNPs) using a TaqMan 5'-allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi-square test. RESULTS: We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03-1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00-1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04-1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07-1.29]) with RA in the pooled analysis. In a 3-SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04-1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74-0.92]). CONCLUSION: These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.

Orozco G, Alizadeh BZ, Delgado-Vega AM, González-Gay MA, Balsa A, Pascual-Salcedo D, Fernández-Gutierrez B, González-Escribano MF, Petersson IF, van Riel PL, Barrera P, Coenen MJ, Radstake TR, van Leeuwen MA, Wijmenga C, Koeleman BP, Alarcón-Riquelme M, Martín J. · Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. · Arthritis Rheum. · Pubmed #18576336 links to  free full text

Abstract: OBJECTIVE: This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. METHODS: Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). CONCLUSION: Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data.

Palomino-Morales RJ, Rojas-Villarraga A, González CI, Ramírez G, Anaya JM, Martín J. · Instituto de Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain. · Genes Immun. · Pubmed #18432273 No free full text.

Abstract: The aim of this study was to determine the influence of STAT4 (rs7574865) and TRAF1/C5 (rs10818488 and rs2900180) gene polymorphisms on the risk of developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Colombian population. This was a case-control study in which 839 individuals with RA (N=274) and SLE (N=144) and matched healthy controls (N=421) were included. Genotyping was performed by using a polymerase chain reaction system with pre-developed TaqMan allelic discrimination assay. STAT4 rs7574865T allele disclosed a significant influence on the risk of developing SLE (P=0.0005; OR 1.62, 95% CI 1.22-2.16) and RA (P=0.008; OR 1.36; 95% CI 1.08-1.71), whereas no effect on these autoimmune diseases was observed for the TRAF1/C5 polymorphisms examined. Our data strengthen STAT4 rs7574865 polymorphism as a susceptibility factor for RA and SLE and provide further evidence for a common origin of autoimmune diseases.

Orozco G, Pascual-Salcedo D, López-Nevot MA, Cobo T, Cabezón A, Martín-Mola E, Balsa A, Martín J. · Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain. · Rheumatology (Oxford). · Pubmed #18156150 No free full text.

Abstract: OBJECTIVE: To analyse the relationship between the presence of auto-antibodies [rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)], HLA-DRB1 alleles and PTPN22 1858 C/T polymorphism and test the value of their combination as susceptibility markers for rheumatoid arthritis (RA). METHODS: Patients with early arthritis were included. At entry in the cohort or during follow-up, 191 patients fulfilled the criteria for RA and 184 individuals suffered from other arthropathies. RF was measured by nephelometry and anti-CCP antibody by enzyme-linked immunosorbent assay. HLA class II alleles were determined by polymerase chain reaction. Samples were genotyped for PTPN22 1858C/T variants using a TaqMan 5'-allele discrimination assay. RESULTS: The presence of shared epitope (SE) alleles was strongly associated with anti-CCP and RF-positive RA [P = 7.05 x 10(-10), odds ratio (OR) 4.57, 95% confidence interval (CI) 2.76-7.57 and P = 1.68 x 10(-6), OR 2.99, 95% CI 1.89-4.74, respectively). The combination of the PTPN22 1858T variant and anti-CCP antibodies gave a high specificity for the disease, and was significantly associated with RA (P = 8.86 x 10(-5), OR 10.05, 95% CI 1.88-53.73). CONCLUSION: The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA.

Rueda B, Oliver J, Robledo G, López-Nevot MA, Balsa A, Pascual-Salcedo D, González-Gay MA, González-Escribano MF, Martín J. · CSIC, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n, Armilla, Granada, Spain. · Arthritis Rheum. · Pubmed #18050210 links to  free full text

Abstract: 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.

Martínez A, Orozco G, Varadé J, Sánchez López M, Pascual D, Balsa A, García A, de la Concha EG, Fernández-Gutiérrez B, Martín J, Urcelay E. · Department of Clinical Immunology, Hospital Clinico San Carlos, Madrid, Spain. · Hum Immunol. · Pubmed #17869648 No free full text.

Abstract: The macrophage inhibitory factor (MIF) is a cytokine that has been implicated in several inflammatory and autoimmune diseases, including rheumatoid arthritis, systemic lupus, glomerulonephritis, and multiple sclerosis. In rheumatoid arthritis (RA), results ranging from lack of association of MIF polymorphisms with RA, to involvement in either severity or susceptibility to the disease have been reported in the past. We aimed at investigating the role of this gene in RA in the Spanish population. Two well-known MIF promoter polymorphisms were tested in 606 adult RA patients and 886 healthy controls: a single nucleotide polymorphism at -173G/C and a tetranucleotide repeat (CATT)(5-8) located at -794. We found a significant association of the allele -173C with RA (p = 0.01; odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.06-1.62). The -173C risk allele, previously reported to be transmitted in excess in patients with juvenile idiopathic arthritis, was significantly more frequent in early-onset adult RA patients than in healthy controls (p = 0.003; OR = 1.57; 95% CI = 1.14-2.15), whereas late-onset patients were not significantly different to controls (p = 0.6; OR = 1.09; 95% CI = 0.77-1.55). In conclusion, the -173C allele in the MIF promoter region is associated with increased RA predisposition, mainly in early-onset patients.

Orozco G, Rueda B, Robledo G, García A, Martín J. · Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain. · Hum Immunol. · Pubmed #17678723 No free full text.

Abstract: 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.

Sánchez E, Alizadeh BZ, Valdigem G, Ortego-Centeno N, Jiménez-Alonso J, de Ramón E, García A, López-Nevot MA, Wijmenga C, Martín J, Koeleman BP. · Instituto de Parasitología y Biomedicina López-Neyra (CSIC), Granada, Spain. · Hum Immunol. · Pubmed #17584584 No free full text.

Abstract: The aim of the study was to test MYO9B gene polymorphisms for association with three autoimmune diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and celiac disease (CD), in a Spanish population. We analyzed three SNPs (rs2305767, rs1457092, and rs2305764) in a case-control cohort composed of 349 SLE patients, 356 RA patients, 90 CD patients, and 345 healthy controls. All three SNPs showed a consistent increased frequency of the A allele in SLE, RA, and CD patients compared with healthy controls. An association was observed between CD and rs2305764 (p=0.01, OR=2.3), between SLE and rs1457092 (p=0.002, OR=1.4), and between RA and rs1457092 (p=0.02, OR=1.3). The three autoimmune diseases combined showed significant association with rs1457092 and rs2305764 and with the AAA haplotype (p haplotype=0.005, OR=1.3). Our data demonstrate consistent association with the A allele and AAA haplotype of three SNPs in the MYO9B gene, which were previously reported to be associated with CD in the Dutch population. This suggests that genetic variation in MYO9B is associated with CD, SLE, and RA and that MYO9B is a general risk factor for autoimmunity.

Moreno OM, González CI, Saaibi DL, Otero W, Badillo R, Martín J, Ramírez G. · Laboratorio de Inmunología y Biología Molecular, Grupo de Inmunología y Epidemiología Molecular, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia. · Biomedica. · Pubmed #17546224 links to  free full text

Abstract: INTRODUCTION: Rheumatoid arthritis is an inflammatory disease driven by TH1 CD4+ cells. Interleukin-10 is present in higher concentrations in serum and synovial fluid from patients with rheumatoid arthritis and has a marked anti-inflammatory activity. Furthermore, it is capable of stimulating B cells and increasing autoantibody production. Interleukin-10 synthesis is under genetic control. OBJECTIVE: Three polymorphisms of the promoter region were analyzed for interleukin-10 genes -1082, -819 and -592. Subjects were patients with rheumatoid arthritis compared with a control population for these genes. MATERIAL AND METHODS: One hundred two patients with rheumatoid arthritis and 102 matched healthy controls were studied. The following data were taken from the rheumatoid arthritis patients: age of disease onset, presence and titers of rheumatoid factor, and history of replacement joint surgery. Genotypes were obtained by polymerase chain reaction and sequence-specific primer method. The three polymorphisms are in strong linkage-disequilibrium and form three haplotypes -1082A/-819C/-592C, -1082A/-819T/-592A y -1082G/-819C/-592C. RESULTS: No association was detected between Interleukin-10 alleles, haplotypes/genotypes and rheumatoid arthritis. No significant differences occurred between interleukin-10 polymorphisms and age of disease onset, presence and titer of rheumatoid factor and history of major joint replacement. CONCLUSIONS: Interleukin-10 is an important regulator of the immune response and likely plays a role in the pathogenesis of rheumatoid arthritis. The current results suggested that Interleukin-10 promoter polymorphisms were not important for development or severity of rheumatoid arthritis.

García-Lozano JR, Torres B, Fernández O, Orozco G, Alvarez-Márquez A, García A, González-Gay MA, García A, Núñez-Roldán A, Martín J, González-Escribano MF. · Servicio de Inmunología, Hospital Universitario Virgen del Rocío, Avda Manuel Siurot s/n, 41013 Sevilla, Spain. · Rheumatology (Oxford). · Pubmed #17504820 links to  free full text

Abstract: OBJECTIVE: The aim of this study was to investigate the possible role of the caspase 7 (CASP7) in susceptibility to rheumatoid arthritis (RA). METHODS: Genotyping of three single nucleotide polymorphisms (SNPs) of the CASP7 gene: rs11593766 (G/ T), rs2227310 (C/G) and rs2227309 (G/A) was performed in a total of 906 RA patients and 528 matched healthy controls using TaqMan assays. All the subjects were of Spanish Caucasian origin. A relative quantification of mRNA encoding the non-functional variant of procaspase 7 (isoform beta) vs functional isoforms was performed in total RNA from 32 healthy individuals using real-time PCR. RESULTS: Only the rs2227309 SNP was found to be associated with susceptibility to RA. Frequency of the G allele was significantly higher among RA patients [overall frequency of the G allele 74.0% in cases vs 68.4% in controls, P = 0.001, Odds ratio (OR) = 1.32, 95% Confidence intervals (95% CI) 1.11-1.56] and a higher frequency of GG homozygous individuals was found in the RA patient group (overall frequency of GG genotype 56.0% in cases and 46.4% in controls, P = 0.0005, OR = 1.47, 95%CI 1.18-1.83). A statistically significant deviation was observed to compare the relative expression of the procaspase 7 isoform beta in samples from individuals stratified according their rs2227309 genotypes (AA + AG: 1.36 +/- 0.55, n = 19, vs GG: 2.35 +/- 0.74, n = 13; P = 0.0002). CONCLUSION: Our results support involvement of the CASP7 gene in the susceptibility to RA. The higher production of the no functional variant of CASP7 by individuals with a particular genotype could be the basis of this association.

Núñez C, Rueda B, Martínez A, López-Nevot MA, Fernández-Arquero M, de la Concha EG, Martín J, Urcelay E. · Servicio de Inmunología Clínica, Hospital Clínico San Carlos, Madrid, Spain. · Genes Immun. · Pubmed #17215861 No free full text.

Abstract: The MIF gene has been associated with several diseases with inflammatory and autoimmune background, such as ulcerative colitis, rheumatoid arthritis and systemic lupus erythematosus. We aimed at testing the influence of two functional MIF promoter variants in celiac disease (CD) susceptibility. A (CAAT)(5-8) tetranucleotide repeat at position -794 and a single-nucleotide polymorphism at -173G/C were analyzed in the Spanish population (531 patients and 887 healthy controls). chi(2) statistics or Fisher exact test were used for comparisons. The -173C allele significantly increased risk ((CC+GC) vs GG: odds ratio (OR) (95% confidence interval (CI))=1.41 (1.10-1.81); P=0.005), as did carriage of the (CAAT)(7) allele (OR (95% CI)=1.36 (1.02-1.82); P=0.03) and of the haplotype (CAAT)(7)//-173C (OR (95% CI)=1.33 (1.00-1.76); P=0.04). Our data evidence for first time the role of the MIF gene increasing predisposition to CD. A common effect of MIF variants seems to underlie the etiology of these complex conditions.

Moreno O, González CI, Saaibi DL, Otero W, Badillo R, Martín J, Ramírez G. · Laboratorio de Inmunología y Biología Molecular, Grupo de Inmunología y Epidemiología Molecular, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Spain. · J Rheumatol. · Pubmed #17143971 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is considered a Th1-driven disease. Interleukin 4 (IL-4) binds to its receptor, promoting Th2 differentiation and limiting Th1 responses, but its role in the pathogenesis of RA is conflicting. We analyzed 2 polymorphisms of the IL4 gene and 4 polymorphisms of the IL4RA gene in patients with RA and in a control population, as well as rheumatoid factor (RF) seropositivity, titers of RF, and history of replacement joint surgery among patients with RA. METHODS: The study population consisted of 102 patients with RA and 102 matched healthy controls. Genotyping of IL4 -590, IL4RA +148, +1124, +1218, and +1902 was determined by restriction fragment length polymorphism-polymerase chain reaction (PCR) and sequence-specific primer-PCR. IL4 variable number tandem repeat polymorphism was determined by direct amplification. RESULTS: The IL4 -590TT genotype was significantly more frequent in patients with RA than in controls (p = 0.018, OR 3.34, 95% CI 1.08-11.04). The IL4RA +148A allele was significantly associated with the presence of RF (p = 0.0019, OR 2.55, 95% CI 1.55-4.86) and a history of articular joint replacement (p = 0.024, OR 2.08, 95% CI 1.04-4.18). The IL4RA +1902G allele was more frequently seen in patients with RA and high RF titers (p = 0.00067, OR 4, 95% CI 1.64-9.93). CONCLUSION: Highly complex pathways lead to the development of RA and may not be similar in all patients. Our findings of higher frequency of IL4 and IL4RA genotypes and alleles with RA, presence of RF, RF titers, and history of articular joint replacement support the polygenic expression of RA and the likely role of IL-4 in influencing its initiation and development.

Rueda B, Reddy MV, González-Gay MA, Balsa A, Pascual-Salcedo D, Petersson IF, Eimon A, Paira S, Scherbarth HR, Pons-Estel BA, González-Escribano MF, Alarcón-Riquelme ME, Martín J. · Instituto de Biomedicina López-Neyra, Granada, Spain. · Arthritis Rheum. · Pubmed #17133578 links to  free full text

Abstract: 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.

Orozco G, Robledo G, Linga Reddy MV, García A, Pascual-Salcedo D, Balsa A, González-Gay MA, Eimon A, Paira S, Scherbarth HR, Pons-Estel BA, Petersson IF, Alarcón-Riquelme M, Martín J. · No affiliation provided · Rheumatology (Oxford). · Pubmed #16935917 links to  free full text

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Orozco G, Sánchez E, González-Gay MA, López-Nevot MA, Torres B, Pascual-Salcedo D, Balsa A, Pablos JL, García A, González-Escribano MF, Martín J. · Instituto de Parasitología y Biomedicina, Granada, Spain. · J Rheumatol. · Pubmed #16821265 No free full text.

Abstract: OBJECTIVE: To replicate the association reported in Japanese individuals of functional SLC22A4 and RUNX1 polymorphisms with rheumatoid arthritis (RA), and to test the possible role in this trait of a functional variant of the SUMO4 gene that was shown to be associated with another related autoimmune disease, type 1 diabetes (T1D). METHODS: Our study population consisted of 886 patients with RA and 987 healthy controls. All subjects were of Spanish Caucasian origin. We conducted a case-control association study with 6 single-nucleotide polymorphisms (SNP) spanning the SLC22A4 gene. SNP mapping in the RUNX1 gene associated with RA in a Japanese population and a SUMO4 polymorphism associated with T1D were also studied. RESULTS: No statistically significant differences between patients with RA and healthy controls were observed when comparing the distribution of the genotypes or alleles of any of the SLC22A4 polymorphisms tested. Similarly, no evidence of association between RA and the SLC22A4 haplotype previously reported to be associated in a Japanese population was found. With regard to the RUNX1 and SUMO4 SNP, we did not observe statistically significant differences in the distribution of genotypes or alleles between patients with RA and healthy controls. CONCLUSION: These results suggest that the SLC22A4, RUNX1, and SUMO4 polymorphisms analyzed do not confer a relevant role in susceptibility to RA in the Spanish population.

Torres B, Orozco G, García-Lozano JR, Oliver J, Fernández O, González-Gay MA, Balsa A, García A, Pascual-Salcedo D, López-Nevot MA, Núñez-Roldán A, Martín J, González-Escribano MF. · Servicio de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain. · Ann Rheum Dis. · Pubmed #16707531 No free full text.

Abstract: BACKGROUND: Asporin belongs to a family of proteins associated with the cartilage matrix. OBJECTIVE: To investigate the role of the functional polymorphism consisting of an aspartic acid (D) repeat polymorphism located in the ASPN gene in the susceptibility to and clinical outcome of rheumatoid arthritis. METHODS: A total of 803 Spanish Caucasian patients with rheumatoid arthritis and 904 controls of the same ethnic origin and matched for age and sex were included in the study. The asporin D repeat polymorphism was genotyped using polymerase chain reaction with a fluorescent primer. RESULTS: No significant differences were detected in the distribution of the 10 alleles found in our population on comparing patients with rheumatoid arthritis with control groups. Nevertheless, individuals bearing D14 produced rheumatoid factor more often than the rest (85.7% v 72.1%, p = 0.006, odds ratio (OR) = 2.35, 95% confidence interval 1.21 to 4.50), and the mean (SD) onset age was higher in the group of individuals bearing D13 (50.09 (13.94)) compared with the rest (47.21 (14.31)), although the difference did not reach significance (p = 0.06). CONCLUSION: The results do not support a major role for asporin D repeat polymorphism in the susceptibility to rheumatoid arthritis. Nevertheless, they support the influence of this gene on the outcome of the disease.

Orozco G, Eerligh P, Sánchez E, Zhernakova S, Roep BO, González-Gay MA, López-Nevot MA, Callejas JL, Hidalgo C, Pascual-Salcedo D, Balsa A, González-Escribano MF, Koeleman BP, Martín J. · Instituto de Biomedicina, CSIC, Granada, Spain. · Hum Immunol. · Pubmed #16690410 No free full text.

Abstract: The aim of this study was to test whether the functional variant rs2076530 of the BTNL2 gene confers susceptibility to the autoimmune diseases type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Our study populations consisted of 326 patients with T1D and 351 healthy subjects, 808 patients with RA and 1137 healthy controls, and 372 patients with SLE and 280 healthy controls. Genotyping of the BTNL2 gene rs2076530 polymorphism was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed statistically significant differences in the distribution of BTNL2rs2076530 alleles between patients with T1D, RA, and SLE and healthy controls (p=0.0035, 0.000003, and 0.00002, respectively), but in two divergent ways: the G allele was associated with T1D and RA, and the A allele was associated with SLE. However, the polymorphism exhibited strong linkage disequilibrium with HLA DQB1-DRB1 haplotypes previously identified as predisposing to the diseases. When the BTNL2 polymorphism was tested conditional on HLA DQB1-DRB1haplotypes, the BTNL2 effect was no longer significant in all three study populations. The BTNL2 rs2076530 polymorphism is associated with T1D, RA, and SLE because of its strong linkage disequalibrium with predisposing HLA DQB1-DRB1 haplotypes in Caucasian populations.

Martínez A, Sánchez E, Valdivia A, Orozco G, López-Nevot MA, Pascual-Salcedo D, Balsa A, Fernández-Gutiérrez B, de la Concha EG, García-Sánchez A, Koeleman BP, Urcelay E, Martín J. · Immunology Department, Hospital Clinico San Carlos, C/Martín Lagos, s/n, 28040 Madrid, Spain. · Ann Rheum Dis. · Pubmed #16476711 No free full text.

Abstract: BACKGROUND: A Japanese study has described a strong association between rheumatoid arthritis and several polymorphisms located in the Fc receptor-like 3 (FCRL3) gene, a member of a family of genes related to Fc receptors located on chromosome 1q21-23. OBJECTIVES: To evaluate the association between rheumatoid arthritis and FCLR3 polymorphisms in a large cohort of Caucasian patients with rheumatoid arthritis and healthy controls of Spanish origin. Owing to the described functional link between the FCRL3 polymorphisms and the transcription factor nuclear factor kappaB (NFkappaB), a functional polymorphism located in the NFkappaB1 gene was included. METHODS: 734 patients with rheumatoid arthritis from Madrid and Granada, Spain, were included in the study, along with 736 healthy controls. Polymorphisms in the FCRL3 gene were studied by TaqMan technology. The -94ins/delATTG NFkappaB1 promoter polymorphism was analysed by fragment analysis after polymerase chain reaction with labelled primers. Genotypes were compared using 3x2 contingency tables and chi2 values. RESULTS: No overall differences were found in any of the FCRL3 polymorphisms and in the NFkappaB1 promoter polymorphism when patients were compared with controls. However, when stratified according to NFkappaB1 genotypes, a susceptibility effect of FCRL3 polymorphisms was observed in patients who were heterozygotes for NFkappaB1 (pc = 0.003). CONCLUSIONS: The FCRL3 polymorphisms associated with rheumatoid arthritis in a Japanese population are not associated per se with rheumatoid arthritis in a Spanish population. A genetic interaction was found between NFkappaB1 and FCRL3 in Spanish patients with rheumatoid arthritis. These findings may provide a general rationale for divergent genetic association results in different populations.

Sánchez E, Rueda B, Orozco G, Oliver J, Vilchez JR, Paco L, López-Nevot MA, Callejas JL, Sabio JM, Gómez-Garcia M, Nieto A, Delgado M, Martín J. · Instituto de Parasitología y Biomedicina López Neyra, Granada, Spain. · Hum Immunol. · Pubmed #16216670 No free full text.

Abstract: 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.

Rueda B, González-Gay MA, López-Nevot MA, García A, Fernández-Arquero M, Balsa A, Pablos JL, Pascual-Salcedo D, de la Concha EG, González-Escribano MF, Martín J. · Instituto de Parasitología y Biomedicina, Granada, Spain. · Hum Immunol. · Pubmed #16216669 No free full text.

Abstract: 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.

Gomez LM, Anaya JM, Gonzalez CI, Pineda-Tamayo R, Otero W, Arango A, Martín J. · Cellular Biology and Immunogenetics Unit (CBIU), Corporación para Investigaciones Biológicas (CIB) and Universidad de Antioquia, Medellin, Colombia, CSIC, Granada, Spain. · Genes Immun. · Pubmed #16163373 No free full text.

Abstract: A functional single nucleotide polymorphism (SNP) C1858T in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene encoding an intracellular phosphatase with negative regulatory effects on T-cell activation is associated with some autoimmune diseases in Caucasians. Taking into account firstly, that SNP frequencies may vary across populations and, secondly, that replication studies are important to confirm previous associations, we examined the influence of PTPN22 polymorphism in 621 Colombian patients with four autoimmune diseases. Accordingly, 298 patients with rheumatoid arthritis (RA), 143 with systemic lupus erythematosus (SLE), 70 with primary Sjogren's syndrome (pSS) and 110 with Type 1 diabetes (T1D) were studied. The control group consisted of 308 matched healthy individuals. Genotyping of PTPN22 was performed by the real-time polymerase chain reaction technology, using the Taq Man 5'-allele discrimination assay. The 1858 T allele was found to be a risk factor for pSS (odds ratio (OR)=2.42), SLE (OR=2.56), and T1D (OR=1.83). A lower but nonsignificant trend was observed for RA (OR=1.26). These results confirm the influence of PTPN22 in autoimmunity and indicate that autoimmune phenotypes could represent pleiotropic outcomes of nonspecific disease genes that underlie similar immunogenetic mechanisms.

Orozco G, González-Gay MA, Paco L, López-Nevot MA, Guzmán M, Pascual-Salcedo D, Balsa A, Martín J. · Instituto de Parasitología y Biomedicina, Granada. · Hum Immunol. · Pubmed #15993716 No free full text.

Abstract: The aim of this study was to assess the possible association between the IL12B and the IL12RB1 gene polymorphisms and the systemic autoimmune disease rheumatoid arthritis (RA). Our study population consisted of 545 patients with RA and 393 healthy subjects. All the individuals were of white Spanish origin. Genotyping of the IL12B (IL12Bpro and IL12B 3' untranslated region) and IL12RB1 (641A-->G, 1094T-->C, and 1132G-->C) polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction-fluorescent methods. No statistically significant differences in the distribution of the IL12B and the IL12RB1 genotypes and alleles between patients with RA and control subjects were observed. In addition, no association was found between the above-mentioned polymorphisms with any of the demographic and clinical parameters tested in patients with RA. These results suggest that IL12B and IL12RB1 genes may not play a relevant role in the susceptibility or severity of RA in the Spanish population.

Rueda B, González-Gay MA, Mataran L, López-Nevot MA, Martín J. · Instituto de Parasitología y Biomedicina, 18100 Armilla, Granada, Spain. · Tissue Antigens. · Pubmed #15896202 No free full text.

Abstract: Interleukin-18 (IL-18), a member of the IL-1 family, is known to play a relevant role in rheumatoid arthritis (RA) physiopathology mainly by promoting the inflammatory response. The aim of this work was to investigate the possible implication of two single-nucleotide polymorphisms (SNPs) [-607 A/C (rs1946518) and -137 G/C (rs187238)] within the IL-18-promoter region in RA predisposition and clinical course. A total of 362 unrelated RA patients and 339 healthy controls were genotyped using a real-time polymerase chain reaction (PCR) method for the -607 A/C SNP and a sequence-specific PCR method (PCR-SSP) for the -137 G/C polymorphism. No statistically significant differences were observed for both -607 and -137 IL-18-promoter polymorphisms between RA patients and controls, considering either allelic or genotypic frequencies. In addition, no association was found with the haplotypes inferred by the two polymorphisms and RA susceptibility. This was also the case when RA patients were stratified according to sex, age at the onset of the disease, rheumatoid factor status, and extraarticular manifestations. Our data suggest that -607 A/C (rs1946518) and -137 G/C (rs187238) polymorphisms within the IL-18-promoter region do not play a major role in RA predisposition.