Zivotić Ivan, Djurić Tamara, Stanković Aleksandra, Ivančević Ilija, Končar Igor, Milasinovic Dejan, Stankovic Goran, Alavantić Dragan, Zivković Maja
Laboratory for Radiobiology and Molecular Genetics, VINCA Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Clinic for the Vascular and Endovascular Surgery, Clinical Center of Serbia, 11000 Belgrade, Serbia.
Gene. 2018 Jan 30;641:35-40. doi: 10.1016/j.gene.2017.10.030. Epub 2017 Oct 12.
The 9p21.3 region is rich in regulatory elements and the variants in this region had been robustly associated with carotid plaque (CP) and coronary artery disease (CAD). Recently, the HACD4 was detected as one of the six 9p21.3 differentially expressed genes associated with accelerated atherosclerosis and greater mean lesion area in the Athsq1 congenic mice. We aimed to investigate association of two potentially regulatory HACD4 variants (rs36212560 I/D, rs2275888 T/C) and their haplotypes with CP occurrence and the level of HACD4 and FOCAD mRNA in human CP tissue. Association study was replicated in CAD patients who suffered the first myocardial infarction. Study included 477 CP patients, 303 healthy controls and replication sample of 224 CAD males from the population of Serbia. Genotypes were determined by polymerase chain reaction (PCR) and real-time PCR using TaqMan® technology. The gene expression was detected with TaqMan® technology. We have found significant and independent association of DT haplotype with CP presence in men (adjusted OR=1.64 CI=1.12-2.42, p=0.011). The result was replicated in CAD males (adjusted OR=1.84 CI=1.21-2.80, p=0.004). We have found significant effect of the HACD4 rs2275888 on FOCAD mRNA level in human CP tissue. Correction for multiple testing was performed. Independent association of HACD4 haplotypes with atherosclerotic phenotypes connotes a further validation and replication in larger cohorts as well as functional studies to enlighten the potential mechanism of its action in pathophysiology of atherosclerosis.
9p21.3区域富含调控元件，该区域的变异与颈动脉斑块（CP）和冠状动脉疾病（CAD）密切相关。最近，在Athsq1同源基因小鼠中，HACD4被检测为与动脉粥样硬化加速和更大平均病变面积相关的6个9p21.3差异表达基因之一。我们旨在研究两个潜在调控性HACD4变异（rs36212560 I/D、rs2275888 T/C）及其单倍型与CP发生情况以及人CP组织中HACD4和FOCAD mRNA水平的关联。在首次发生心肌梗死的CAD患者中重复进行关联研究。研究纳入了477例CP患者、303例健康对照以及来自塞尔维亚人群的224例CAD男性的重复样本。通过聚合酶链反应（PCR）和使用TaqMan®技术的实时PCR确定基因型。使用TaqMan®技术检测基因表达。我们发现DT单倍型与男性CP存在显著且独立的关联（校正OR = 1.64，CI = 1.12 - 2.42，p = 0.011）。该结果在CAD男性中得到重复（校正OR = 1.84，CI = 1.21 - 2.80，p = 0.004）。我们发现HACD4 rs2275888对人CP组织中FOCAD mRNA水平有显著影响。进行了多重检验校正。HACD4单倍型与动脉粥样硬化表型的独立关联意味着需要在更大队列中进一步验证和重复，以及进行功能研究以阐明其在动脉粥样硬化病理生理学中作用的潜在机制。
