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.
Highlights
Rheumatoid arthritis (RA), the prototype of inflammatory chronic disease, is characterized by a consistent increase of cardiovascular (CV) mortality and morbidity, mainly due to a process of accelerated atherosclerosis [1,2,3]
CD40/CD154 interactions may induce the expression of matrix metalloproteinases that degrade components of the atherosclerotic plaques and promote neovascularization, instability and plaque rupture leading to acute CV events or sudden death [8] and can play a prominent role in thrombotic events after plaque rupture [5]
Smoking habit was more frequent in men than in women RA patients (44.76% vs. 22.82%)
Summary
Rheumatoid arthritis (RA), the prototype of inflammatory chronic disease, is characterized by a consistent increase of cardiovascular (CV) mortality and morbidity, mainly due to a process of accelerated atherosclerosis [1,2,3]. CD40/CD154 interactions may induce the expression of matrix metalloproteinases that degrade components of the atherosclerotic plaques and promote neovascularization, instability and plaque rupture leading to acute CV events or sudden death [8] and can play a prominent role in thrombotic events after plaque rupture [5]. This is relevant as the main cause of mortality and morbidity of RA is atherosclerosis, driving to CV events that are preceded by subclinical atherosclerosis
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