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Lack of association between JAK3 gene polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. JAK/STAT signalling pathway is involved in autoimmune diseases and in the atherosclerotic process. JAK3 is a highly promising target for immunomodulatory drugs and polymorphisms in JAK3 gene have been associated with CV events in incident dialysis patients. Therefore, the aim of this study was to assess the potential role of JAK3 polymorphisms in the development of CV disease in patients with RA. 2136 Spanish RA patients were genotyped for the rs3212780 and rs3212752 JAK3 gene polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 539 of these patients by carotid ultrasonography (US). No statistically significant differences were found when each polymorphism was assessed according to carotid intima-media thickness values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV events after adjusting for potential confounders. In conclusion, our results do not confirm association between JAK3 polymorphisms and CV disease in RA.

SUBMITTER: Garcia-Bermudez M

PROVIDER: S-EPMC4359874 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Lack of association between JAK3 gene polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis.

García-Bermúdez Mercedes M López-Mejías Raquel R Genre Fernanda F Castañeda Santos S Corrales Alfonso A Llorca Javier J Llorca Javier J González-Juanatey Carlos C Ubilla Begoña B Miranda-Filloy José A JA Pina Trinitario T Gómez-Vaquero Carmen C Rodríguez-Rodríguez Luis L Fernández-Gutiérrez Benjamín B Balsa Alejandro A Pascual-Salcedo Dora D López-Longo Francisco J FJ Carreira Patricia P Blanco Ricardo R Martín Javier J González-Gay Miguel A MA

BioMed research international 20150301

Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. JAK/STAT signalling pathway is involved in autoimmune diseases and in the atherosclerotic process. JAK3 is a highly promising target for immunomodulatory drugs and polymorphisms in JAK3 gene have been associated with CV events in incident dialysis patients. Therefore, the aim of this study was to assess the potential role of JAK3 polymorphisms in the developme ...[more]

PMID: 25815310

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Project description:ObjectiveRheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Since CD40-CD154 binding has direct consequences on inflammation process initiation, we aimed to replicate previous findings related to disease susceptibility in Spanish RA population. Furthermore, as the major complication in RA disease patients is the development of CV events due to accelerated atherosclerosis, and elevated levels of CD40L/CD154 are present in patients with acute myocardial infarction, we assessed the potential association of CD40 and CD154/CD40L gene variants with CV risk in Spanish RA patients.MethodsOne thousand five hundred and seventy-five patients fulfilling the 1987 ACR classification criteria for RA and 1600 matched controls were genotyped for the CD40 rs1883832, rs4810485 and rs1535045 and CD154 rs3092952 and rs3092920 gene polymorphisms, using predesigned TaqMan single nucleotide polymorphism genotyping assays. Afterwards, we investigated the influence of CD40-CD154 gene variants in the development of CV events. Also, in a subgroup of 273 patients without history of CV events, we assessed the influence of these polymorphisms in the risk of subclinical atherosclerosis determined by carotid ultrasonography.ResultsNominally significant differences in the allele frequencies for the rs1883832 CD40 gene polymorphism between RA patients and controls were found (p=0.038). Although we did not observe a significant association of CD40-CD154 gene variants with the development of CV events, an ANCOVA model adjusted for sex, age at the time of the ultrasonography assessment, follow-up time, traditional CV risk factors and anti-cyclic citrullinated peptide antibodies disclosed a significant association (p=0.0047) between CD40 rs1535045 polymorphism and carotid intima media thickness, a surrogate marker of atherosclerosis.ConclusionData from our pilot study indicate a potential association of rs1883832 CD40 gene polymorphism with susceptibility to RA. Also, the CD40 rs1535045 gene variant may influence development of subclinical atherosclerosis in RA patients.

Project description:Rheumatoid arthritis (RA) is the most common systemic inflammatory disease and is of unknown etiology. The altered balance between immunosuppressive and inflammatory T cell subpopulations exerts a huge impact on RA pathogenesis. The STAT3 protein regulates genes involved in the immune responses. It regulates maturation of T and B cells. Its abnormal activity is significantly associated with autoimmune diseases and cancer development. We aimed to evaluate the contribution of three potentially functional single nucleotide polymorphisms (SNPs) within the STAT3 gene to susceptibility and severity of RA in the Polish population.A total of 595 patients with RA and 330 healthy individuals were included in the study. DNA from patients and healthy subjects was obtained from peripheral blood using standard DNA isolating methods. The STAT3 rs1053005, rs1026916 and rs2293152 polymorphisms were genotyped using the TaqMan SNP genotyping assay. The accuracy of SNP genotyping was confirmed using direct DNA sequence analysis.The distribution of STAT3 polymorphisms did not differ significantly between cases and controls. Our results revealed a tendency only, where rs1026916 AA genotype occurred more frequently in RA patients compared to healthy controls, in codominant (p = 0.09), dominant (p = 0.06) and recessive (p = 0.09) models. STAT3 rs2293152 polymorphism was associated with higher DAS28 (p = 0.014 codominant model; p = 0.003 dominant model), increased number of swollen joints (p = 0.02), higher VAS (p = 0.01) and higher HAQ score (p = 0.05).We did not observe a significant association between the three studied STAT3 genetic variants and increased susceptibility to or severity of RA. Only the STAT3 rs2293152 polymorphism was associated with parameters that indicate a more severe course of the disease. However, its distribution did not differ between RA and control groups. According to our observations these 3 studied STAT3 SNPs may not be used as risk factors for developing RA.

Project description:INTRODUCTION: Approximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they explain only a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) × protein tyrosine phosphatase nonreceptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including their replication in a second sample collection. In one of them, researchers identified interactions between PTPN22 and seven single-nucleotide polymorphisms (SNPs). The other showed interactions between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide-positive (anti-CCP+) patients. In the present study, we aimed to replicate association with RA susceptibility of interactions described in these two high-quality studies. METHODS: A total of 1,744 patients with RA and 1,650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single-base extension. SE genotypes of 736 patients were available from previous studies. Interaction analysis was done using multiple methods, including those originally reported and the most powerful methods described. RESULTS: Genotypes of one of the SNPs (rs4695888) failed quality control tests. The call rate for the other eight polymorphisms was 99.9%. The frequencies of the polymorphisms were similar in RA patients and controls, except for PTPN22 SNP. None of the interactions between PTPN22 SNPs and the six SNPs that met quality control tests was replicated as a significant interaction term--the originally reported finding--or with any of the other methods. Nor was the interaction between GSTM1 and the SE replicated as a departure from additivity in anti-CCP+ patients or with any of the other methods. CONCLUSIONS: None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that whether interactions are significant contributors to RA susceptibility remains unknown and that strict standards need to be applied to claim that an interaction exists.

Project description:Lower levels of low-density lipoprotein (LDL) cholesterol may be associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). This study was undertaken to determine whether the complex relationship between levels of LDL and high-density lipoprotein (HDL) cholesterol and CV risk is different in RA patients as compared to non-RA controls.Using data from a US health insurance plan (2003-2012), we conducted a cohort study that included patients with RA and non-RA control subjects matched with regard to age, sex, and index date. The nonlinearity of associations between lipid levels and incidence of major adverse CV events (MACE) was tested. We used multivariable Cox proportional hazards regression models to examine for an interaction between lipid levels and RA status in relation to the risk of MACE, after adjustment for CV risk factors.In total, 16,085 RA patients and 48,499 non-RA controls were studied. The mean age was 52.6 years and 78.6% were women. The relationship between LDL cholesterol levels and incidence of MACE was nonlinear and similar between RA patients and non-RA controls (P for interaction?=?0.72). No significant increase in CV risk was observed between the lowest quintile of LDL cholesterol levels (?91.0 mg/dl) and the second, third, or fourth quintiles, whereas the highest quintile (>190.0 mg/dl) conveyed a 40% increase in risk of MACE (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.17-1.68). The relationship between HDL cholesterol levels and incidence of MACE was also nonlinear and similar between RA patients and non-RA controls (P for interaction?=?0.39). Compared to the lowest quintile of HDL cholesterol levels, each successive quintile was associated with a reduced risk of MACE (HR 0.45, 95% CI 0.48-0.72 for lowest quintile [?43.0 mg/dl] versus highest quintile [>71.0 mg/dl]).The complex relationship between LDL cholesterol levels, HDL cholesterol levels, and risk of MACE was nonlinear in RA patients and also not statistically significantly different from that in an age- and sex-matched non-RA cohort.

Dataset Information

Lack of association between JAK3 gene polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis.

Publications

Lack of association between JAK3 gene polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis.

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