Identification of a 3'-Untranslated Genetic Variant of RARB Associated With Carotid Intima-Media Thickness in Rheumatoid Arthritis: A Genome-Wide Association Study
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AuthorLópez Mejías, Raquel; Carmona, F. David; Genre, Fernanda; Remuzgo-Martínez, Sara; González-Juanatey, Carlos; Corrales Martínez, Alfonso; Vicente, Esther F.; Pulito Cueto, Verónica; Miranda-Filloy, José A.; Ramírez Huaranga, Marco A.; Blanco Alonso, Ricardo; Robustillo-Villarino, Montserrat; Rodríguez-Carrio, Javier; Alperi-López, Mercedes; Alegre-Sancho, Juan J.; Mijares Díaz, Verónica; Lera-Gómez, Leticia; Llorca Díaz, Francisco Javier; González-Gay Mantecón, Miguel Ángel; [et al.]
To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA).
We performed a genome-wide association study (GWAS) in which, after quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analyzed in 2,989 RA patients of European origin. Data on subclinical atherosclerosis, obtained through assessment of carotid intima-media thickness (CIMT) and presence/absence of carotid plaques by carotid ultrasonography, were available for 1,355 individuals.
A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome-wide level of significance (minor allele [G] ? coefficient 0.142, P = 1.86 × 10-8 ). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biologic pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (Gene Ontology no. 0032964; false discovery rate-adjusted P = 4.01 × 10-3 ). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 × 10-4 , P = 5.94 × 10-4 , and P = 2.46 × 10-4 , respectively).
The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA.