Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome.
Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome.
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DOI：
10.1016/s0140-6736(11)61453-0
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发表时间：
2012-03-10
期刊：
影响因子：
168.9
通讯作者：
Tomaszewski, Maciej
中科院分区：
文献类型：
--
作者：
Charchar, Fadi J.;Bloomer, Lisa D. S.;Barnes, Timothy A.;Cowley, Mark J.;Nelson, Christopher P.;Wang, Yanzhong;Denniff, Matthew;Debiec, Radoslaw;Christofidou, Paraskevi;Nankervis, Scott;Dominiczak, Anna F.;Bani-Mustafa, Ahmed;Balmforth, Anthony J.;Hall, Alistair S.;Erdmann, Jeanette;Cambien, Francois;Deloukas, Panos;Hengstenberg, Christian;Packard, Chris;Schunkert, Heribert;Ouwehand, Willem H.;Ford, Ian;Goodall, Alison H.;Jobling, Mark A.;Samani, Nilesh J.;Tomaszewski, Maciej
冠状动脉疾病的发病率和患病率存在性别二态性——男性比同龄女性更容易受到影响。我们在性别不平等的背景下探讨了 Y 染色体在冠状动脉疾病中的作用。我们对来自三个队列的 3233 名生物学上无关的英国男性的 Y 染色体男性特异性区域的 11 个标记进行了基因分型：英国心脏基金会家庭心脏研究 (BHF-FHS)、苏格兰西部冠状动脉预防研究 (WOSCOPS) 和心脏病学研究。根据这些信息，每条 Y 染色体都被追溯到 13 个被定义为单倍群的古代谱系之一。然后，我们在横断面 BHF-FHS 和前瞻性 WOSCOPS 中检查了常见 Y 染色体单倍群与冠状动脉疾病风险之间的关联。最后，我们从心脏发生学研究中对英国男性的 Y 染色体对单核细胞和巨噬细胞转录组的影响进行了功能分析。在已确定的 9 个单倍群中，其中两个（R1b1b2 和 I）约占英国男性 Y 染色体变异的 90%。在 BHF-FHS 中，单倍群 I 的携带者患冠状动脉疾病的年龄调整风险比其他 Y 染色体谱系的男性高约 50%（比值比 1·75，95% CI 1·20–2·54，p=0·004）、WOSCOPS（1·45、1·08–1·95，p=0·012）以及两个人群的联合分析(1·56, 1·24–1·97, p=0·0002)。单倍群 I 与冠状动脉疾病风险增加之间的关联独立于传统的心血管和社会经济危险因素。心脏发生学研究中的巨噬细胞转录组分析显示，单倍群 I 和 Y 染色体其他谱系男性之间表现出强烈差异表达的 19 条分子通路通过与炎症和免疫相关的常见基因相互连接，其中一些与动脉粥样硬化有很强的相关性。人类 Y 染色体与欧洲血统男性患冠状动脉疾病的风险相关，可能是通过免疫和炎症的相互作用实现的。英国心脏基金会；英国国家健康研究所； LEW Carty 慈善基金；澳大利亚国家健康和医学研究委员会；欧盟第六框架计划；惠康信托。
A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity. We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study. Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis. The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation. British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.