Institute of Biomedical Sciences, MacKay Medical College, New Taipei City 252005, Taiwan.
Department of Medicine, MacKay Medical College, New Taipei City 252005, Taiwan.
Int J Mol Sci. 2022 Sep 29;23(19):11511. doi: 10.3390/ijms231911511.
Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in genes on preclinical atherosclerosis. A total of 564 and 746 subjects who had thicker and normal carotid intima-media thickness (cIMT), respectively, were enrolled. Among 55 screened SNPs, rs35145102, rs201641962, rs12466587, rs4131583, and rs16862482 in showed significant associations with cIMT. SNP rs35145102 is a 3'-utr variant and correlates with the differential expression of OLA1 in immune cells. These five genetic markers form a single closely linked block and H1-ATTGT and H2-GCCTC were the top two most prevalent 5-locus haplotypes. The H1 + H1 genotype negatively and H1 + H2 genotype positively correlated with thicker cIMT. The five identified SNPs in the gene showed significant correlations with cIMT. Furthermore, we found that OLA1 was required for migration and proliferation of human aortic endothelial and smooth muscle cells and regulated vascular tube formation by human aortic endothelial cells. Therefore, these genetic variants in the gene may serve as markers for risk prediction of atherosclerotic diseases.
活性氧物种损害血管，导致动脉粥样硬化的发生，血管外膜的血管平滑肌细胞和内皮细胞的迁移和增殖对于动脉粥样硬化的发展是必不可少的。Obg-like ATPase 1（OLA1）是细胞对氧化应激反应的负调控因子，它与乳腺癌易感基因 1（BRCA1）结合，保护血管内皮和平滑肌细胞免受活性氧的侵害。然而，OLA1 是否与动脉粥样硬化存在遗传相关性尚不清楚。在这里，我们进行了两项独立的基于人群的病例对照研究，以探讨基因中的变体对临床前动脉粥样硬化的影响。共有 564 名和 746 名分别具有较厚和正常颈动脉内膜中层厚度（cIMT）的受试者被纳入研究。在筛选出的 55 个 SNP 中，位于 上的 rs35145102、rs201641962、rs12466587、rs4131583 和 rs16862482 与 cIMT 显著相关。SNP rs35145102 是一个 3'-utr 变体，与免疫细胞中 OLA1 的差异表达相关。这 5 个遗传标记形成了一个紧密连锁的块，H1-ATTGT 和 H2-GCCTC 是最常见的两个 5 个位点单倍型。H1+H1 基因型与较厚的 cIMT 呈负相关，H1+H2 基因型与较厚的 cIMT 呈正相关。基因中的 5 个鉴定 SNP 与 cIMT 显著相关。此外，我们发现 OLA1 对于人主动脉内皮和平滑肌细胞的迁移和增殖是必需的，并调节人主动脉内皮细胞的血管管腔形成。因此，基因中的这些遗传变异可能作为动脉粥样硬化疾病风险预测的标志物。
