Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10⁻⁶). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

中文翻译：

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影响髓过氧化物酶水平升高的遗传变异会增加中风的风险

原发性脑出血和腔隙性缺血性中风是进行性脑微血管疾病的急性表现。当前的范例表明，动脉粥样硬化是响应各种环境挑战引起的内皮损伤而沉淀的慢性，动态，炎症性疾病。髓过氧化物酶在血管炎症的发生和发展中起着核心作用，但是先前的研究尚未将髓过氧化物酶与中风风险联系起来。我们假设髓过氧化物酶水平的遗传决定因素影响血管不稳定的发展，导致原发性脑出血和腔隙性中风的风险增加。我们使用了来自三项研究的1409例原发性脑出血病例和1624例对照的发现队列，来自NINDS-SiGN的12 577例缺血性中风病例和25 643例对照的扩展队列，以及来自METASTROKE联盟的10 307例缺血性中风病例和29 326例对照的验证队列，并进行了全基因组基因分型，以检验这一假设。遗传风险评分反映了髓过氧化物酶水平的升高，是从15种常见的单核苷酸多态性构建的，该多态性是根据先前对循环髓过氧化物酶水平的全基因组研究确定的（P <5×10 ^-6）。该遗传风险评分在多变量回归模型中用作独立变量，用于与原发性脑出血和缺血性中风亚型相关。我们使用固定效应的荟萃分析汇总了各个研究的估计值。我们还在174名原发性脑内出血幸存者的预期队列中使用了Cox回归模型，以与脑内出血复发相关联。我们介绍了髓过氧化物酶升高单核苷酸多态性对每个风险等位基因中风风险的影响，相当于一个等位基因在髓过氧化物酶中增加了遗传风险评分。循环髓过氧化物酶水平升高的遗传决定因素与原发性脑出血风险相关（比值比为1.07，P= 0.04）和复发性脑出血风险（危险比1.45，P = 0.006）。在缺血性卒中亚型的分析中，髓过氧化物酶增加的遗传风险评分仅与腔隙性亚型密切相关（优势比，1.05，P= 0.0012）。这些结果表明，增加髓过氧化物酶水平的常见遗传变异会增加原发性脑出血和腔隙性中风的风险，这直接暗示了髓过氧化物酶途径与脑小血管疾病的发病机制有关。由于遗传变异不受环境暴露的影响，因此这些结果为脊髓过氧化物酶在脑血管疾病进展中的因果关系提供了新的支持，而不是旁观者的作用。此外，这些结果支持了将慢性炎症作为潜在的可改变的中风风险机制的理论基础，并表明免疫靶向疗法可用于治疗和预防脑血管疾病。