FRI0706 HLA-DRB1 alleles are associated with markers of endothelial injury in first-degree relatives of rheumatoid arthritis patients

Abstract

BackgroundRheumatoid arthritis (RA) patients experience higher cardiovascular disease (CVD) risk and CVD-related mortality. MHC class II HLA-DRB1 alleles, or the shared epitope (SE), has also been linked to endothelial dysfunction in RA patients. It is not known whether this association exists in individuals who are RA-free, but who are at higher risk due to being a first-degree relative (FDR) of an RA patient.ObjectivesTo determine the association between HLA-DRB1 alleles (*0401, *0404, *0405, *0408) and markers of endothelial injury in FDRs of RA patients, a population free of RA and RA-related medications.MethodsFrom the Studies of the Etiology of RA, SERA, (a multicenter prospective study of preclinical RA, started in 2002), 113 FDRs who had been positive for any of 5 RA-related autoantibodies (Abs): rheumatoid factor (RF), RF isotypes – IgM, IgG, IgA, or anti-cyclic citrullinated peptide (anti-CCP2) on at least one of their visits, and 100 FDRs who had never been Ab positive were selected, frequency matched on age, sex, and field center site. No FDR met the 1987 ACR Criteria or 2010 EULAR/ACR Criteria for RA. In cross-sectional testing of single samples from baseline, the following were measured: endothelial injury markers: soluble intracellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin; and high resolution HLA-DRB1 typing for the*0401, *0404, *0405, and *0408 alleles using real-time polymerase chain reaction. ANCOVA was used to evaluate associations between HLA-DRB1 alleles, sVCAM, sICAM, and E-selectin, adjusting for age, sex, race, body mass index (BMI), Ab status, ever smoking, and current statin use.ResultsAmong 213 FDRs, age was 50±18 yr, BMI was 27±6, 75% were women, 83% were Caucasian, 35% ever smoked, 11% were currently taking statins, and 38% were SE positive. sVCAM was significantly higher by 135ng/mL in FDRs with the HLA-DRB1*0404 allele (p=0.009) compared to FDRs without the *0404 allele (Table 1). E-selectin was higher by 23ng/mL in FDRs with the HLA-DRB1*0405 allele (p=0.03) compared to FDRs without the *0405 allele. Being positive for the SE was not significantly associated with sICAM, sVCAM, or E-selectin levels.Table 1.Differences in levels of endothelial injury markers by HLA-DRB1 alleles in FDRs of RA patientsn (%)ICAMp-valueVCAMp-valueE-selectinp-value (ng/mL)(ng/mL)(ng/mL) SE Positive81 (38)11.6 (8.8)0.1955.7 (32.5)0.093.7 (2.2)0.0940155 (26)2.6 (10.0)0.80-14.1 (37.0)0.700.4 (2.5)0.8640423 (11)21.1 (13.9)0.13135.4 (50.9)0.0096.4 (3.4)0.064052 (1)55.1 (44.0)0.21186.0 (163.1)0.2622.9 (10.8)0.034086 (3)-6.6 (25.4)0.797.1 (94.1)0.948.1 (6.2)0.19*n=213 (92 Ab+, 121 Ab−).ConclusionsIn RA-free FDRs, having an HLA-DRB1*0404 or HLA-DRB1*0405 allele was associated with markers of endothelial injury. Therefore, the genetic predisposition to RA could contribute to parallel development of atherosclerosis during the preclinical period of RA.References Gonzalez-Juanatey C et al., Am J Med 2003; 114:647–52.Gonzalez-Gay MA et al., Arth Rheum 2007; 57(...