Background Patients with Rheumatoid Arthritis (RA) show a higher risk for cardiovascular events than general population. We have reported previously the impact of persistent disease activity in the lipid profile of patients with early arthritis (EA) where a drop in HDL levels is accompanied by a rise in LDL oxidation. In this sense, IL-6 serum (sIL-6) levels can play a key role, as its reduction in cardioprotective HDL is more pronounced than reduction induced in LDL and total cholesterol levels. Regarding the regulation of this cytokine and its receptor (R), the functional effect of rs2228145 in IL-6 gene and rs1800795 in IL-6R has been described. Interestingly, the latter SNP drives to an alternative splicing mRNA leading to higher levels of soluble R (IL-6Rs) that may amplify the inflammatory response.
Objectives To assess the effect of IL-6/IL-6R system on the levels of oxidised LDL (oxLDL) in patients with EA.
Methods We analysed data from 172 patients recruited to our prospective EA registry: 74% women, median age [IQR p25-p75] at disease onset 52 years [42-65] and time of follow-up 2-5 years (342 visits). Rheumatoid factor was positive in 41% of the patients and ACPA in 45%. According to a scheduled protocol, sociodemographic variables were collected at baseline (gender, age, smoking habit, education, etc.) and clinical and laboratory variables (DAS28, HAQ, PCR, among others) along with medications prescribed were recorded at each visit. Serum IL6 levels were measured using an ELISA kit from R&D Systems. Genotyping of rs2228145 and rs1800795 was performed using specific TaqMan probes (Applied Biosystems). Serum oxLDL levels (range of serum frozen storage from 1 week to 20 months) were measured by ELISA (Mercodia AB, Uppsala, Suecia). To determine the effect of the independent variables on oxLDL levels, a generalised linear model, nested by patient and visit, was fitted using the xtgee command of Stata 10.1 for Windows (StataCorp LP, College Station, TX, USA)
Results The rs2228145 genotype frequencies in our population were: AA 13%, AC 49% and CC 38%; and concerning rs1800795: GG 9%, GC 39% and CC 52%. After adjustment for the variables that we have previously describe to be associated with changes in oxLDL levels (female gender, LDL concentration, disease activity assessed through DAS28, serum freezing time), the C allele in the rs2228145 on IL-6R gene correlated with increased oxLDL levels either in homozygous (p=0.04) and heterozygous patients (p=0.06), compared to patients carrying the homozygous ancestral A allele. By contrast, sIL6 levels, the genotype of rs1800795 in IL-6 gene, smoking, race, age or prescribed medications did not show significant statistical correlation with oxLDL levels.
Conclusions The presence of the C allele on SNP rs2228145 on the IL-6R gene, which is carried by a majority of our EA population, contributes to the raise in their oxLDL levels that could explain, at least in part, the increased cardiovascular risk in these patients.
Disclosure of Interest R. Garcia-Vicuña Grant/Research support from: RETICS program, RD08/0075 (RIER) and FIS 080754 from ISCIII and a Roche Farma unrestricted grant, Consultant for: Roche, Pfizer, MSD, Actelion, S. Pérez-Esteban: None Declared, A. Lamana Grant/Research support from: RETICS program, RD08/0075 (RIER) and FIS 080754 ISCIII, A. Ortiz-Garcia Grant/Research support from: RETICS program, RD08/0075 (RIER) and FIS 080754 ISCIII and Roche Farma unrestricted grant, A. Fernández-Ortiz: None Declared, R. Lόpez-Mejías: None Declared, M. García-Bermúdez: None Declared, M. González-Gay: None Declared, J. Martín: None Declared, I. González-Alvaro Grant/Research support from: RETICS program, RD08/0075 (RIER) and FIS 080754 from ISCIII and a Roche Farma unrestricted grant. Consultant for: Roche