title: SMAD3 rs17228212 gene polymorphism is associated with reduced risk to cerebrovascular accidents and subclinical atherosclerosis in anti-CCP negative Spanish rheumatoid arthritis patients.
abstract: Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. Previous genome-wide association studies have described SMAD3 rs17228212 polymorphism as an important signal associated with CV events. The aim of the present study was to evaluate for the first time the relationship between this gene polymorphism and the susceptibility to CV manifestations and its potential association with the presence of subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in patients with RA.
  
  
  METHODS
  One thousand eight hundred and ninety-seven patients fulfilling classification criteria for RA were genotyped for SMAD3 rs17228212 gene polymorphism through TaqMan genotyping assay. Also, subclinical atherosclerosis determined by the assessment of cIMT was analyzed in a subgroup of these patients by carotid ultrasonography.
  
  
  RESULTS
  No statistically significant differences were observed when allele frequencies of RA patients with or without CV events were compared. Nevertheless, when RA patients were stratified according to anti-cyclic citrullinated peptide (anti-CCP) status, we found that in RA patients who were negative for anti-CCP antibodies, the presence of C allele of SMAD3 rs17228212 polymorphism conferred a protective effect against the risk of cerebrovascular accident (CVA) after adjustment for demographic and classic CV risk factors (HR [95%CI]=0.36 [0.14-0.94], p=0.038) in a Cox regression model. Additionally, correlation between the presence of C allele of SMAD3 rs17228212 polymorphism and lower values of cIMT was found after adjustment for demographic and classic CV risk factors (p-value=0.0094) in the anti-CCP negative RA patients.
  
  
  CONCLUSIONS
  Our results revealed that SMAD3 rs17228212 gene variant is associated with lower risk of CVA and less severe subclinical atherosclerosis in RA patients negative for anti-CCP antibodies. These findings may have importance to establish predictive models of CV disease in RA patients according to anti-CCP status.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: García-Bermúdez
authors.forename: Raquel
authors.initials: R
authors.lastname: López-Mejías
authors.forename: Fernanda
authors.initials: F
authors.lastname: Genre
authors.forename: Santos
authors.initials: S
authors.lastname: Castañeda
authors.forename: Carlos
authors.initials: C
authors.lastname: González-Juanatey
authors.forename: Javier
authors.initials: J
authors.lastname: Llorca
authors.forename: Alfonso
authors.initials: A
authors.lastname: Corrales
authors.forename: José A
authors.initials: JA
authors.lastname: Miranda-Filloy
authors.forename: Javier
authors.initials: J
authors.lastname: Rueda-Gotor
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Vaquero
authors.forename: Luis
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Longo
authors.forename: Patricia
authors.initials: P
authors.lastname: Carreira
authors.forename: Ricardo
authors.initials: R
authors.lastname: Blanco
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000235:genetics*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics; D059168:Carotid Intima-Media Thickness; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012306:Risk; D051900:Smad3 Protein / Q000235:genetics*; D013030:Spain; D020521:Stroke / Q000209:etiology* / Q000235:genetics*
chemical_list: C497790:SMAD3 protein, human; D051900:Smad3 Protein