Identification of a 3′-Untranslated Genetic Variant of RARB Associated With Carotid Intima-Media Thickness in Rheumatoid Arthritis: A Genome-Wide Association Study

Objective To investigate the genetic background influencing the development of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). Methods 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. Results A genetic variant of the RARB gene (rs116199914) was associated with CIMT values at the genome-wide level of significance (minor allele [G] beta coefficient 0.142, P = 1.86 x 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 x 10(-3)). Furthermore, our data suggest potential influences of the previously described candidate CV risk loci NFKB1, MSRA, and ZC3HC1 (P = 8.12 x 10(-4), P = 5.94 x 10(-4), and P = 2.46 x 10(-4), respectively). Conclusion The present findings strongly suggest that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA.
Supported in part by the European Union FEDER fund and the Instituto de Salud Carlos III (ISCIII) (Fondo de Investigacion Sanitaria grants PI06/0024, PS09/00748, PI12/00060, PI15/00525, and CP16/00033), the ISCIII RETICS programs (RD12/0009 and RD16/0012), the European IMI BTCure Program. Dr. Lopez-Mejias is recipient of the Miguel Servet type I Program Fellowship from the ISCIII and the European Social Fund (ESF) (grant CP16/00033). Dr. Carmona's work was supported by the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal Program grant RYC-2014-16458). Dr. Genre is recipient of a Sara Borrell postdoctoral fellowship from the ISCIII and ESF (grant CD15/00095). Dr. Remuzgo-Martinez' work was supported by the ISCIII and European Regional Development Fund (ERDF) (RETICS Program RD16/0012/0009). Ms Pulito-Cueto's work was supported by a predoctoral grant from the Instituto de Investigacion Sanitaria Valdecilla (PREVAL 18/01). Ms Mijares' work was supported by the Miguel Servet type I Program from the ISCIII and ESF (grant CP16/00033). Dr. Gualillo is staff personnel of Xunta de Galicia (Servizo Galego de Saude [SERGAS]) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and FEDER (grants RD16/0012/0014 [RIER] and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899-Olive-Net.