Polymorphisms of the Genes EncodingCD40and Growth Differentiation Factor 15 and in the 9p21.3 Region in Patients with Rheumatoid Arthritis and Cardiovascular Disease

Abstract

Objective.Genes or gene products associated with coronary artery disease in the general population were analyzed in rheumatoid arthritis (RA) patients with atherothrombotic manifestations (ATM).Methods.A cross-sectional study of 681 individuals (498 women; 183 men) with RA (American College of Rheumatology criteria), a mean age of 60.6 ± 13.2 years, and mean disease duration of 15.5 ± 12.6 years who were consecutively recruited and followed for 6 years. The prevalence of ATM [i.e., myocardial infarction, angina pectoris with intervention, deep vein thrombosis/pulmonary embolism (DVT/PE), and/or stroke/transient ischemic attack (TIA)] was recorded. Polymorphisms were analyzed in the genes coding for growth differentiation factor 15 (GDF15)/monocyte inhibitory cytokine-1 (MIC-1; rs1058587),CD40(rs1535045 and rs3765459), and the 9p21.3 locus (rs1333049). Controls were randomly selected (n = 687; matched for age and sex).Results.The distribution of genotypes ofGDF15/MIC-1differed significantly between patients with RA and controls (chi-squared = 6.40, 2 df, p = 0.041). ATM were associated with polymorphism of theGDF15/MIC-1G allele (OR 2.21, 95% CI 1.17–4.18), and with CC genotype of the 9p21.3 locus (rs1333049; OR 1.92, 95% CI 1.15–3.19). Stroke/TIA in women was associated withGDF15/MIC-1GG genotype (OR 3.75, 95% CI 1.06–13.33), while stroke/TIA in men was associated withCD40homozygous major alleles (OR 6.48, 95% CI 1.31–32.0 and OR 2.78, 95% CI 0.78–9.91, respectively). DVT/PE was associated with polymorphism in theGDF15/MIC-1gene (rs1058587) minor allele (OR 3.53, 95% CI 1.30–9.58).Conclusion.The gene polymorphisms analyzed were associated with different ATM in RA. TheGDF15/MIC-1gene polymorphism was also associated with RAper se, suggesting a common etiology for RA and ATM.

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

“…Since increased carotid IMT is a surrogate marker of atherosclerosis that may allow identifying high risk patients in a subclinical phase of the disease, longer duration of follow-up may be required to see the clinical relevance of the CD40 rs1535045 in the atherosclerosis disease of patients with RA. In keeping with our data showing association of subclinical atherosclerosis with CD40 rs1535045 gene variant, a recent study on 681 Swedish patients with RA disclosed an association between stroke/transient ischemic accident in men with RA that were homozygous for the CD40 rs1535045 polymorphism major allele [48]. Regrettably, although our study encompassed a larger number of patients, we could not confirm association of any of the CD40 gene polymorphisms with clinically evident CV events in Spanish RA patients.…”

CD154: the atherosclerotic risk factor in rheumatoid arthritis?

“…Recently, a polymorphism in the CD40 gene was found to be associated with atherothrombotic manifestations in RA patients, thereby supporting the implication of this axis in the development of accelerated vascular complications in RA [61]. Additional evidence for the contribution of the CD154 axis in the association between RA and atherosclerosis was also described in a study showing that abrogating vasoactive factors such as angiotensin II can affect vascular function and inflammatory markers in RA patients.…”

Relationship between hepcidin and GDF15 in anemic patients with type 2 diabetes without overt renal impairment

“…GDF15 is a member of the transforming growth factor-beta (TGF-b) superfamily [25]. The expression of GDF15 is elevated in many types of malignancies, cardiovascular diseases, inflammatory diseases and type 2 diabetes [26][27][28][29]. Although the exact role and mechanism are as-yet-unknown, the putative role of GDF15 is as an anti-inflammatory cytokine.…”