系统性红斑狼疮血栓形成的遗传危险因素。
Genetic risk factors for thrombosis in systemic lupus erythematosus.
机构信息
UCSF Division of Rheumatology, San Francisco, CA 94143, USA.
出版信息
J Rheumatol. 2012 Aug;39(8):1603-10. doi: 10.3899/jrheum.111451. Epub 2012 Jun 15.
OBJECTIVE
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.
METHODS
Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications.
RESULTS
In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics.
CONCLUSION
Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.
目的
血栓形成是系统性红斑狼疮（SLE）的严重并发症。我们研究了在两个不同种族的 SLE 队列中，是否与血栓形成途径相关的遗传变异与血栓形成有关。
方法
我们的发现队列包括来自加利福尼亚大学旧金山狼疮遗传学项目的 1698 名 SLE 患者，我们的复制队列包括来自 PROFILE 队列的 1361 名 SLE 患者。患者符合美国风湿病学会 SLE 标准，并且有与血栓形成相关的数据。先前在普通人群中与深静脉血栓形成风险相关或与血栓形成途径相关的 33 个单核苷酸多态性（SNP）进行了基因分型，并在双变量等位基因分析中检测了与血栓形成的相关性。双变量分析中 p<0.1 的 SNP 进一步在多变量逻辑回归模型中进行了测试，这些模型调整了年龄、性别、疾病持续时间、抗磷脂抗体状态、吸烟、肾炎和药物。
结果
在发现队列中，23%的 SLE 患者发生了血栓形成事件。在发现或复制队列中，以下基因中的 SNP 总体上与血栓形成风险相关，并使用荟萃分析方法进行了评估：因子 V Leiden（FVL）rs6025（OR 1.85，p=0.02）和亚甲基四氢叶酸还原酶（MTHFR）rs1801133（OR 0.75，p=0.04）在白人中，和纤维蛋白原γ（FGG）rs2066865（OR 1.91，p=0.01）在西班牙裔美国人中。这些基因中的 SNP 与白人的静脉血栓形成风险相关：MTHFR rs1801131（OR 1.51，p=0.01），MTHFR rs1801133（OR 0.70，p=0.04），FVL rs6025（OR 2.69，p=0.002），和 FGG rs2066865（OR 1.49，p=0.02）。在西班牙裔美国人中，FGG rs2066865 中的 SNP（OR 2.19，p=0.003）与动脉血栓形成风险相关。
结论
我们的结果表明，SLE 患者的血栓形成存在特定的遗传危险因素，并表明血栓形成的遗传风险在不同种族之间存在差异。
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