title: Study of association of CD40-CD154 gene polymorphisms with disease susceptibility and cardiovascular risk in Spanish rheumatoid arthritis patients.
abstract: OBJECTIVE
  Rheumatoid 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.
  
  
  METHODS
  One 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.
  
  
  RESULTS
  Nominally 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.
  
  
  CONCLUSIONS
  Data 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.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-C.S.I.C., Granada, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: García-Bermúdez
authors.forename: Carlos
authors.initials: C
authors.lastname: González-Juanatey
authors.forename: Raquel
authors.initials: R
authors.lastname: López-Mejías
authors.forename: María
authors.initials: M
authors.lastname: Teruel
authors.forename: Alfonso
authors.initials: A
authors.lastname: Corrales
authors.forename: José A
authors.initials: JA
authors.lastname: Miranda-Filloy
authors.forename: Santos
authors.initials: S
authors.lastname: Castañeda
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutierrez
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Vaquero
authors.forename: Ricardo
authors.initials: R
authors.lastname: Blanco
authors.forename: Javier
authors.initials: J
authors.lastname: Llorca
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
mesh_terms: D000704:Analysis of Variance; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000235:genetics*; D019013:CD40 Antigens / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013030:Spain
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand