骨保护素和 MTHFR 基因变异与类风湿关节炎：与疾病易感性和亚临床动脉粥样硬化标志物的关联。
Osteoprotegerin and MTHFR gene variations in rheumatoid arthritis: association with disease susceptibility and markers of subclinical atherosclerosis.
机构信息
First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.
Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece.
出版信息
Sci Rep. 2022 Jun 9;12(1):9534. doi: 10.1038/s41598-022-13265-3.
We aimed to explore whether the rs2073618 variant (G1181C) of the osteoprotegerin (OPG) gene and the methylenetetrahydrofolate reductase (MTHFR) rs1801131 (A1298AC) and rs1801133 (C677T) gene polymorphisms contribute to rheumatoid arthritis (RA) susceptibility and RA related subclinical atherosclerosis. Overall 283 RA patients and 595 healthy controls (HC) were genotyped for common variants of the OPG and MTHFR genes using PCR based assays. Clinical and laboratory parameters were recorded following thorough chart review. Surrogate markers of subclinical atherosclerosis (Carotid/Femoral intima media thickness/plaque formation) along with traditional risk factors for atherosclerosis were assessed in all RA patients and 280HC. Increased prevalence of the CC genotype of the rs2073618 variant was detected in RA patients vs HC (42.4% vs. 33%, p-value: 0.04). RA patients with high serum titers of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies displayed increased prevalence of the CC genotype of the rs2073618 variant of the OPG gene compared to HC (48.6% and 47.5 vs 33.3%, p-values: 0.0029and 0.0077 respectively). Of interest, this genotype turned to be associated with higher carotid IMT scores (0.872 ± 0.264 vs 0.816 ± 0.284, p-value: 0.01) and marginally with higher rates of carotid plaque formation (66% vs 54.1%, p = 0.06). The MTHFR 1298CC genotype was more prevalent only in the anti-CCP positive group compared to HC, with no associations detected with markers of subclinical atherosclerosis, following adjustment for traditional cardiovascular (CVD) risk factors. Reduced rates of carotid/femoral plaque formation were detected among RA patients harboring the MTHFR TT genotype (52.4 vs 72.7, p-value: 0.009, respectively). This association remained significant following adjustment for classical CVD risk factors (OR [95% CI 0.364 [0.173-0.765], p-value: 0.008). Genetic variations of the osteoprotegerin and MTHFR genes seem to increase susceptibility for seropositive RA and potentially contribute to subclinical atherosclerosis linked to RA. Larger studies are needed to confirm these findings.
我们旨在探讨骨保护素（OPG）基因 rs2073618 变异（G1181C）和亚甲基四氢叶酸还原酶（MTHFR）rs1801131（A1298AC）和 rs1801133（C677T）基因多态性是否与类风湿关节炎（RA）易感性和 RA 相关的亚临床动脉粥样硬化有关。使用基于 PCR 的检测方法，对 283 例 RA 患者和 595 名健康对照者（HC）的 OPG 和 MTHFR 基因常见变体进行了常见变体的基因分型。在所有 RA 患者和 280HC 中评估了亚临床动脉粥样硬化（颈动脉/股动脉内膜中层厚度/斑块形成）的替代标志物以及动脉粥样硬化的传统危险因素。与 HC 相比，RA 患者 rs2073618 变异的 CC 基因型的患病率增加（42.4% vs. 33%，p 值：0.04）。与 HC 相比，血清类风湿因子（RF）或抗环瓜氨酸肽（CCP）抗体滴度高的 RA 患者中 OPG 基因 rs2073618 变异的 CC 基因型的患病率更高（48.6%和 47.5%比 33.3%，p 值：0.0029 和 0.0077）。有趣的是，这种基因型与更高的颈动脉 IMT 评分相关（0.872 ± 0.264 vs 0.816 ± 0.284，p 值：0.01），并且与颈动脉斑块形成的发生率略高相关（66%比 54.1%，p=0.06）。与 HC 相比，仅在抗 CCP 阳性组中更常发现 MTHFR 1298CC 基因型，并且在调整传统心血管（CVD）危险因素后，未发现与亚临床动脉粥样硬化标志物有关。与 MTHFR TT 基因型相比，RA 患者中颈动脉/股动脉斑块形成的发生率降低（52.4%比 72.7%，p 值：0.009）。在调整经典 CVD 危险因素后，这种相关性仍然显著（OR[95%CI]0.364[0.173-0.765]，p 值：0.008）。骨保护素和 MTHFR 基因的遗传变异似乎增加了血清阳性 RA 的易感性，并可能导致与 RA 相关的亚临床动脉粥样硬化。需要更大的研究来证实这些发现。
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