Study of Association of CD40-CD154 Gene Polymorphisms with Disease Susceptibility and Cardiovascular Risk in Spanish Rheumatoid Arthritis Patients

Abstract

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.

CD40 functional gene polymorphisms and mRNA expression in rheumatoid arthritis patients from western Mexico

“…rs1883832 and rs4810485 distribution of the genotype and allele frequencies (Table 2) did not significantly differ between RA patients and control subjects. Interestingly, the minor allele frequencies of both CD40 genetic variants identified in this study were lower than those reported previously for European and Asian populations (García-Bermúdez et al, 2012;Liu et al, 2012;Lee et al, 2015). In addition, no association with RA was observed under any genetic model.…”

“…Two functional single nucleotide polymorphisms (SNPs) in the CD40 gene, rs1883832 and rs4810485, which are in strong linkage disequilibrium (r 2 = 0.95), have been previously associated with RA in European populations (Raychaudhuri et al, 2008;Orozco et al, 2010;García-Bermúdez et al, 2012;Lee et al, 2015). The former is located at position -1 in the Kozak sequence, and it has been proposed that the major allele of this SNP enhances the efficiency of CD40 mRNA translation, resulting in up to 32% more CD40 protein (Jacobson et al, 2005).…”

“…Moreover, some studies have reported that the minor T allele is associated to decreased CD40 mRNA and increased soluble CD40 levels (Chen et al, 2015;Field et al, 2015;Wagner et al, 2015). Although the T allele of rs1883832 has been associated with increased susceptibility to MS and SLE among Russian and Chinese individuals, respectively (Sokolova et al, 2013;Chen et al, 2015), it has also been reported to have a protective effect for RA in the Spanish population (García-Bermúdez et al, 2012). Meanwhile, rs4810485, located in the second intron of CD40, is thought to affect CD40 mRNA and protein expression in B cells and monocytes (Vazgiourakis et al, 2011).…”

Lack of association between CD40 polymorphisms and acute rejection in German liver transplant recipients

“…Genotype and allele distributions of the selected CD40 SNPs in healthy control individuals were consistent with previously published data, indicating that our PCR-ASRA technique generates appropriate genotyping results [21][22][23]. In addition, 10% of the samples were regenotyped by direct sequencing.…”

Atherosclerosis in Patients with Rheumatoid Arthritis

“…Further, inflammatory disorders, characterized by high levels of CRP, can develop a secondary immune cell activation, which may result in atherogenesis [54]. In addition, studies have demonstrated that inflammatory related markers such as lipoproteins, ox-LDLs [55], NO [55], TNF-a [56], RANKL [57], CD40L [58], IL-18 [59], MMP-9 [60], MCP-1 [61], insulin [45], EPCs [51] in atherosclerosis are altered in patients with RA. These evidences thus support the theory that systemic inflammation plays a crucial role in the pathogenesis of CVD in patients with RA.…”