Haitjema Saskia, Kofink Daniel, van Setten Jessica, van der Laan Sander W, Schoneveld Arjan H, Eales James, Tomaszewski Maciej, de Jager Saskia C A, Pasterkamp Gerard, Asselbergs Folkert W, den Ruijter Hester M
From the Laboratory of Experimental Cardiology, Division Heart and Lungs (S.H., J.v.S., S.W.v.d.L., A.H.S., S.C.A.d.J., G.P., H.M.d.R.), Department of Medical Genetics, Center of Molecular Medicine (D.K.), Laboratory of Clinical Chemistry and Haematology, Division Laboratories and Pharmacy (G.P.), and Department of Cardiology, Division Heart and Lungs (F.W.A.), University Medical Center Utrecht, The Netherlands; Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom (J.E., M.T.); Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom (M.T.); Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (F.W.A.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
Circ Cardiovasc Genet. 2017 Aug;10(4):e001544. doi: 10.1161/CIRCGENETICS.116.001544.
Recent studies found an immune regulatory role for Y chromosome and a relationship between loss of Y chromosome (LOY) in blood cells and a higher risk of cancer and mortality. Given involvement of immune cells in atherosclerosis, we hypothesized that LOY is associated with the severity of atherosclerotic plaque characteristics and outcome in men undergoing carotid endarterectomy.
LOY was quantified in blood and plaque from raw intensity genotyping data in men within the Athero-Express biobank study. Plaques were dissected, and the culprit lesions used for histology and the measurement of inflammatory proteins. We tested LOY for association with (inflammatory) atherosclerotic plaque phenotypes and cytokines and assessed the association of LOY with secondary events during 3-year follow-up. Of 366 patients with carotid endarterectomy, 61 exhibited some degree of LOY in blood. LOY was also present in atherosclerotic plaque lesions (n=8/242, 3%). LOY in blood was negatively associated with age (β=-0.03/10 y; =0.07; =1.6×10) but not with cardiovascular disease severity at baseline. LOY in blood was associated with a larger atheroma size (odds ratio, 2.15; 95% confidence interval, 1.06-4.76; =0.04); however, this association was not significant after correction for multiple testing. LOY was independently associated with secondary major cardiovascular events (hazard ratio=2.28; 95% confidence interval, 1.11-4.67; =0.02) in blood when corrected for confounders.
In this hypothesis-generating study, LOY in blood is independently associated with secondary major cardiovascular events in a severely atherosclerotic population. Our data could indicate that LOY affects secondary outcome via other mechanisms than inflammation in the atherosclerotic plaque.
近期研究发现Y染色体具有免疫调节作用，且血细胞中Y染色体缺失（LOY）与癌症风险增加及死亡率升高之间存在关联。鉴于免疫细胞参与动脉粥样硬化的发生发展，我们推测LOY与接受颈动脉内膜切除术的男性患者动脉粥样硬化斑块特征的严重程度及预后相关。
在Athero-Express生物样本库研究中，通过原始强度基因分型数据对男性血液和斑块中的LOY进行定量分析。对斑块进行解剖，将罪犯病变用于组织学检查及炎症蛋白测量。我们检测LOY与（炎症性）动脉粥样硬化斑块表型及细胞因子的相关性，并评估LOY与3年随访期间继发事件的相关性。在366例接受颈动脉内膜切除术的患者中，61例血液中存在一定程度的LOY。LOY也存在于动脉粥样硬化斑块病变中（n = 8/242，3%）。血液中的LOY与年龄呈负相关（β = -0.03/10岁；P = 0.07；t = 1.6×10），但与基线时的心血管疾病严重程度无关。血液中的LOY与较大的动脉粥样硬化斑块大小相关（比值比，2.15；95%置信区间，1.06 - 4.76；P = 0.04）；然而，在进行多重检验校正后，这种相关性并不显著。校正混杂因素后，血液中的LOY与继发的主要心血管事件独立相关（风险比 = 2.28；95%置信区间，1.11 - 4.67；P = 0.02）。
在这项探索性研究中，血液中的LOY与严重动脉粥样硬化人群继发的主要心血管事件独立相关。我们的数据可能表明，LOY通过不同于动脉粥样硬化斑块炎症的其他机制影响继发结局。
