Objective

Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase (MTHFR) to atherosclerotic disease characterizing SLE patients.

Methods

Peripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the MTHFR gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0).

Results

Hyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR 677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0–35.8) and 5.2 (1.1–24.0), respectively]. MTHFR 677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2–20.6)].

Conclusions

Hyperhomocysteinemia and MTHFR 677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.

中文翻译：

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MTHFR基因变异在狼疮相关的亚临床动脉粥样硬化中的作用

客观的

先前已确定高半胱氨酸浓度是系统性红斑狼疮（SLE）患者亚临床动脉粥样硬化的独立危险因素。鉴于已知高半胱氨酸水平受到遗传因素的强烈影响，在当前研究中，我们研究了高同型半胱氨酸水平以及5、10-亚甲基四氢叶酸还原酶（MTHFR）编码基因的功能多态性SLE患者的动脉粥样硬化性疾病。

方法

通过基于PCR的检测方法对150例SLE患者，214例类风湿性关节炎（RA）患者和561名年龄/性别相匹配的健康志愿者（HC）的外周DNA样本进行了基因分型，以检测MTHFR基因多态性（c。677C> T和c 1298A> C）。所有SLE患者和30位年龄相匹配的RA患者均接受亚临床动脉粥样硬化评估[超声测量内膜中层厚度评分（IMT）并检测颈动脉和/或股骨（C / F）斑块]，并进行完整的临床和实验室评估，包括血清同型半胱氨酸水平。使用单变量和多变量模型（SPSS 21.0）分析数据。

结果

在26.0％的SLE患者中检测到高同型半胱氨酸血症，而与年龄/性别匹配的RA对照者则为6.7％（p = 0.02）。RA患者中较高的血清B12水平和MTHFR 677TT变体的频率降低可能是造成两组之间观察到的差异的潜在原因。在调整传统的心血管危险因素和疾病相关特征（包括年龄，性别，BMI，胆固醇和甘油三酸酯水平，存在动脉高压，吸烟后，SLE患者中，高同型半胱氨酸血症和MTHFR 677TT基因型均被确定为斑块形成的独立因素）。包/年），疾病持续时间和类固醇总剂量[OR 95％（CI）：分别为5.8（1.0–35.8）和5.2（1.1–24.0）]。还发现MTHFR 677TT基因型（而非高同型半胱氨酸血症）导致动脉壁增厚的风险增加，

结论

高同型半胱氨酸血症和MTHFR 677TT基因变异已成为SLE患者亚临床动脉粥样硬化的独立危险因素，这暗示遗传因素可能是导致SLE的动脉粥样硬化疾病负担增加的潜在因素。