Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University Utrecht, The Netherlands (S.W.v.d.L., M.A.S., S.H., H.M.d.R., G.P.).
Department of Clinical Genetics, University Medical Center Utrecht, University Utrecht, The Netherlands (M.A.S.).
Circ Genom Precis Med. 2018 Sep;11(9):e002115. doi: 10.1161/CIRCGEN.118.002115.
Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms.
We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression.
A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood.
Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics.
动脉粥样硬化是一种慢性炎症性疾病，部分是由于血管壁内脂质的摄取所致，但导致急性心肌梗死和中风的确切潜在机制仍知之甚少。大型研究联盟确定了与大动脉缺血性中风和冠心病相关的遗传易感性位点。然而，解析它们的潜在机制具有挑战性。组织学研究确定了与临床结果相关的人类动脉粥样硬化斑块的不稳定特征。因此，到目前为止，尚不清楚已确立的大动脉缺血性中风和冠心病的易感基因座与斑块特征有多大关系，但可能指向新的机制。
我们研究了 61 个已确立的心血管风险基因座与 1443 个颈动脉斑块标本中 7 个组织学斑块特征的关联，这些标本来自 Athero-Express 生物样本库研究。我们还评估了在 2 个独立的生物样本库（Karolinska 内膜切除术生物样本库和斯德哥尔摩动脉粥样硬化基因表达生物样本库）中，基因分型的心血管风险基因座是否会影响组织特异性基因表达。
共有 21 个已确立的风险变异（61 个中的）与斑块特征有显著关联。位于 7q22 的一个变异（风险等位基因 A，rs12539895）与斑块内脂肪减少相关，经多重检验校正后 P=5.09×10。我们进一步对该 7q22 基因座进行了特征分析，并显示 rs12539895 在斑块中对 HBP1 表达和全血中对 COG5 表达的组织特异性效应，并提供来自公共资源的数据表明与血液中 LDL（低密度脂蛋白）降低和 HDL（高密度脂蛋白）增加相关。
我们的研究支持这样一种观点，即心血管易感性基因座可能通过影响动脉粥样硬化斑块特征来发挥其作用。
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