Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

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与系统性红斑狼疮和类风湿性关节炎心血管疾病相关的新基因变异

目的 系统性红斑狼疮 (SLE) 和类风湿性关节炎 (RA) 患者患心血管疾病 (CVD) 的风险增加。我们研究了自身免疫风险位点的单核苷酸多态性 (SNP) 是否与 SLE 和 RA 的 CVD 相关。方法 使用 200K 免疫芯片 SNP 阵列 (Illumina) 对 SLE 患者 (n=1045) 进行基因分型。比较了有和没有不同 CVD 表现的患者的等位基因频率。结果在第二个 SLE 队列 (n=1043) 和 RA 队列 (n=824) 中重复。我们分析了来自一般人群的公开遗传数据，进行了电泳迁移率变化分析，并测量了细胞因子水平和抗磷脂抗体 (aPL) 的出现。结果 我们在两个 SLE 人群中确定了两个与 CVD 风险增加相关的新推定风险位点，这些位点在调整传统 CVD 风险因素后仍然存在。IL19 风险等位基因 rs17581834(T) 与 SLE（OR 2.3（1.5 至 3.4），P=8.5×10-5）和 RA（OR 2.8（1.4 至 5.6），P =3.8×10−3)，荟萃分析（OR 2.5（2.0 到 2.9），P=3.5×10−7），但在人群对照中没有。IL19 风险等位基因影响蛋白质结合，具有风险等位基因的 SLE 患者的血浆 IL10 (P=0.004) 和 aPL (P=0.01) 水平升高。SRP54-AS1 风险等位基因 rs799454(G) 与 SLE 中的中风/短暂性脑缺血发作相关（OR 1.7（1.3 至 2.2），P=2.5×10-5），但与 RA 无关。SRP54-AS1 风险等位基因是四个基因的表达数量性状基因座。