Ruhl A Parker, Jeffries Neal, Yang Yu, Brooks Steven D, Naik Rakhi P, Pecker Lydia H, Mott Bryan T, Winkler Cheryl A, Armstrong Nicole D, Zakai Neil A, Gutierrez Orlando M, Judd Suzanne E, Howard Virginia J, Howard George, Irvin Marguerite R, Cushman Mary, Ackerman Hans C
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
medRxiv. 2023 May 22:2023.03.15.23286908. doi: 10.1101/2023.03.15.23286908.
People with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene ( deletion would be associated with reduced risk of incident ischemic stroke.
We evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determine copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of copy number on time to first ischemic stroke.
Four-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years' follow-up. copy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66.
Although a reduction in copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.
与其他种族的人相比，具有非洲血统的人中风风险更高，且中风风险的遗传度也更高。鉴于一氧化氮（NO）在中风中的重要性，以及最近有证据表明α珠蛋白会限制血管内皮细胞释放一氧化氮，我们推测α珠蛋白基因（ 缺失与缺血性中风发病风险降低有关。
我们在全国性的前瞻性中风地理和种族差异原因（REGARDS）队列中评估了8947名自我报告有非洲血统的参与者。缺血性中风发病定义为经病历证实的非出血性中风伴局灶性神经功能缺损持续≥24小时，或经病历证实的局灶性或非局灶性神经功能缺损且影像学检查呈阳性。使用液滴数字PCR分析基因组DNA以确定 拷贝数。采用多变量Cox比例风险回归来估计 拷贝数对首次缺血性中风发生时间的风险比（HR）。
在中位（IQR）11.0（5.7，14.0）年的随访期间，479名（5.3%）参与者发生了缺血性中风。 拷贝数范围为2至6：368名（4%）-α/-α、2480名（28%）-α/αα、6014名（67%）αα/αα、83名（1%）ααα/αα和2名（<1%）ααα/ααα。 拷贝数与缺血性中风的校正后HR为1.04；95%CI为0.89，1.21；p = 0.66。
虽然预计 拷贝数减少会增加人类血管内皮中的内皮一氧化氮信号传导，但在这个大型美国黑人队列中， 拷贝数与缺血性中风发病无关。
