Hospital Universitario Clinico San Cecilio

Granada, Spain

Hospital Universitario Clinico San Cecilio

Granada, Spain

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Martin J.-E.,Institute Parasitologia Y Biomedicina Lopez Neyra | Alizadeh B.Z.,University of Groningen | Gonzalez-Gay M.A.,Hospital Universitario Marques Of Valdecilla | Balsa A.,Hospital Universitario La Paz | And 13 more authors.
Journal of Rheumatology | Year: 2011

Objective. The PTPN22 rs2476601 genetic variant has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. Some reports suggest that this single-nucleotide polymorphism (SNP) may not be the only causal variant in the region of PTPN22. Our aim was to identify new independent RA-associated common gene variants in the PTPN22 region. Methods. We analyzed Wellcome Trust Case-Control Consortium genome-wide association study data for associations in the 397.2 kb PTPN22 region and selected 9 associated SNP (with p < 5 × 10 -3) for replication and dependence analysis. The replication cohorts comprised 2857 patients with RA and 2994 controls from Spain, Netherlands, and Norway. Results. We found that 6 of the 9 selected SNP were associated in the Spanish cohort. Of these, 4 were also associated in the Dutch and Norwegian cohorts, and all 6 were associated with RA in the combined analysis. Conditional analyses showed that none of these associations was independent of rs2476601. Conclusion. The SNP rs2476601 located in the PTPN22 gene is the sole common genetic variant associated with RA in the 1p13.2 region, suggesting that neighbor genes of PTPN22 do not have a major influence in RA. The Journal of Rheumatology Copyright © 2011. All rights reserved.


Rodriguez-Rodriguez L.,Armilla and Hospital Clinico San Carlos | Taib W.R.W.,University of Otago | Topless R.,University of Otago | Steer S.,King's College | And 19 more authors.
Arthritis and Rheumatism | Year: 2011

Objective Recently, a functional PTPN22 variant (R263Q; rs33996649) was found to be associated with systemic lupus erythematosus (SLE). This study was undertaken to analyze the influence of this polymorphism on the risk of rheumatoid arthritis (RA). Methods RA patients (n = 5,579) were recruited from outpatient clinics from 6 different countries (Spain, New Zealand, the UK, Norway, The Netherlands, and Germany). Healthy controls (n = 5,392) were recruited from the same areas. There was 100% power to detect an effect equivalent to that observed in SLE. Samples were genotyped for the PTPN22 R263Q (rs33996649) and PTPN22 R620W (rs2476601) polymorphisms using a TaqMan 5′-allele discrimination assay. The effect of the R263Q variant was analyzed in isolation and in combination with the effect of R620W, using Unphased and Stata 10 software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined. Results The minor allele A of PTPN22 R263Q was significantly associated with a lower risk of RA in the pooled analysis of the 6 populations (P = 0.016, Mantel-Haenszel pooled OR 0.80 [95% CI 0.67-0.96]), independent of the effect of the R620W polymorphism. Both polymorphisms had an additive effect. The more RA risk alleles carried (R263Q G allele, R620W T allele), the higher the RA risk (for 2 versus 1 risk allele P = 0.014, OR 1.28 [95% CI 1.05-1.55], for 3 versus 1 risk allele P = 6.67 × 10 -11, OR 2.01 [1.63-2.48], and for 4 versus 1 risk allele P = 6.50 × 10-11, OR 3.55 [2.42-5.20]). Conclusion Our findings indicate that the minor allele of the PTPN22 R263Q polymorphism is associated with a lower risk of RA. This association is independent of the well-established association between PTPN22 R620W and RA. Both polymorphisms have an additive effect on the risk of RA. © 2011 by the American College of Rheumatology.


Gutierrez B.,University of Granada | Gutierrez B.,King College | Bellon J.A.,University of Malaga | Rivera M.,University of Granada | And 14 more authors.
Journal of Psychiatry and Neuroscience | Year: 2015

Background: There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. Methods: We explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. Results: Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. Limitations: Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. Conclusion: Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes. © 2015 8872147 Canada Inc.


Martin J.-E.,Institute Parasitologia y Biomedicina Lopez Neyra | Alizadeh B.Z.,University Utrecht | Gonzalez-Gay M.A.,Hospital Marques Of Valdecilla | Balsa A.,Hospital Universitario La Paz | And 10 more authors.
Arthritis and Rheumatism | Year: 2010

Objective Genome-wide association studies carried out in rheumatoid arthritis (RA) have led to the discovery of several genetic associations with this disease. Still, the current associated genetic variations can explain only part of the genetic risk involved in RA, and it is well recognized that these genome-wide association studies are likely underpowered to detect all common disease variants. This study was undertaken to explore the genomic regions showing low-significance associations in previous genome-wide association studies of RA. Methods To reduce the false-positive signal fraction, we exploited pathway analysis to prioritize regions containing genes most likely to be implicated in RA. We hypothesized that true disease genes would be in a similar pathway. Therefore, genes from similar pathways but located in different regions were prioritized for replication using Prioritizer software. A total of 384 genetic variants selected from previous RA genome-wide association studies were tested in a Spanish case-control discovery cohort comprising 376 RA patients and 478 healthy controls for replication. Statistically significant associations were further validated in replication cohorts from Spain and The Netherlands. The study consisted of a total of 1,818 RA patients and 2,498 controls. Results We detected a novel genetic association between RA and the MSRA gene (rs10903323) in the Spanish combined population (P = 2.91 - 10 -5, odds ratio [OR] 1.51). This association was further tested in our independent Dutch replication cohort. Combined analysis showed an overall association of MSRA with RA (P = 3.19 - 10-4, OR 1.28). Conclusion Our findings indicate that a novel association in the MSRA gene is related to oxidative stress and support the notion of a major role for this process in RA. © 2010 by the American College of Rheumatology.


Robledo G.,Institute Parasitologia y Biomedicina Lopez Neyra | Rueda B.,Institute Parasitologia y Biomedicina Lopez Neyra | Gonzalez-Gay M.A.,Hospital Xeral Calde | Fernandez B.,Hospital Clinico San Carlos | And 6 more authors.
Clinical and Experimental Rheumatology | Year: 2010

Objective: Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that may play an important role in the regulation of metabolic balance in inflammatory diseases such as rheumatoid arthritis (RA) by decreasing the pro-inflammatory Th1 responses. In this study we investigated the possible contribution of several polymorphisms in the functional Ghrelin receptor to RA susceptibility. Methods: A screening of 3 single nucleotide polymorphisms (SNPs) was performed in a total of 950 RA patients and 990 healthy controls of Spanish Caucasian origin. Genotyping of all 3 SNPs was performed by real-time polymerase chain reaction technology, using the TaqMan 5′-allele discrimination assay. Results: We observed no statistically significant deviation between RA patients and controls for the GHSR SNPs analysed. In addition, we performed a haplotype analysis that did not reveal an association with RA susceptibility. The stratification analysis for the presence of shared epitope (SE), rheumatoid factor (RF) or antibodies anti cyclic citrullinated peptide (anti-CCP) did not detect significant association of the GHSR polymorphisms with RA. Conclusion: These findings suggest that the GHSR gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population. © Copyright Clinical and Experimental Rheumatology 2010.


Robledo G.,Institute Parasitologia Y Biomedicina Lopez Neyra | Gonzalez-Gay M.A.,Hospital Universitario Marques Of Valdecilla | Fernandez-Gutierrez B.,Hospital Clinico San Carlos | Lamas J.R.,Hospital Clinico San Carlos | And 10 more authors.
Journal of Rheumatology | Year: 2012

Objective. Neuropeptide S receptor 1 (NPSR1) is a G protein-coupled receptor involved in immune response and is associated with several inflammatory diseases. We investigated the possible contribution of several polymorphisms in the intronic region of NPSR1 to rheumatoid arthritis (RA). Methods. Genotyping of 7 single-nucleotide polymorphisms (SNP) was performed in a total of 1232 patients with RA and 983 healthy controls of Spanish white origin by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. Results. One out of the 7 SNP analyzed (rs740347) was associated with RA [p after Bonferroni correction (pBNF) = 1.2 × 10 -3, OR 0.73]. An association was also observed with rheumatoid factor-positive and shared epitope-positive RA (p BNF = 0.011, OR 0.73; p BNF = 0.037, OR 0.75, respectively). Conclusion. Our results show that variations in the NPSR1 intronic region are associated with low risk in patients with RA, supporting other evidence that this locus represents a common genetic factor in inflammatory diseases. The Journal of Rheumatology Copyright © 2012. All rights reserved.

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