Department of Neurology and Neurophysiology (E.M., C.S., A.H.), Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Germany.
Center for Genomic Medicine (E.M., M.K.G., M.M.U., J.R., P.N.), Massachusetts General Hospital, Boston.
Stroke. 2023 Apr;54(4):938-946. doi: 10.1161/STROKEAHA.122.041416. Epub 2023 Feb 15.
Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment.
We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation.
We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; <0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; <0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; =0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; =0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy.
Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.
未明确定义的中风病因阻碍了很大一部分年轻患者的最佳二级预防。我们探讨了针对不确定潜能的克隆性造血（CHIP）的基因筛查是否可以识别出需要特定治疗的骨髓前体病变或隐性骨髓肿瘤患者。
我们对 18 至 60 岁之间急性脑缺血的前瞻性队列患者的 56 个经常发生血液肿瘤突变的基因进行了靶向测序。CHIP 的患病率与年龄匹配的尼梅根生物医学研究（n=1604）和英国生物库（n=101678）的健康对照组进行了比较。怀疑有高风险 CHIP 或髓系肿瘤的患者被邀请进行进一步的血液学评估。
我们纳入了 248 例连续患者（39%为女性），其中 176 例（71%）为隐源性中风病因。51 例（21%）患者存在 CHIP，是普通人群的 3 倍（尼梅根生物医学研究为 7.7%对 2.6%，英国生物库为 11.9%对 4.1%；两者均 <0.001）。CHIP 患者年龄较大（中位数[四分位数范围]，53[50-59]岁比 51[41-56]岁；<0.001），颈动脉内膜中层厚度较高（0.68[0.58-0.80]mm 比 0.59[0.51-0.73]mm；=0.009），动脉粥样硬化负担较高（29.4%比 16.7%；=0.04）。我们邀请了 11 名患者（4.4%）进行进一步的血液学评估，其中 7 名患者的 CHIP 风险较高，2 名患者的新诊断为骨髓增生性肿瘤，需要进行细胞减少治疗。
我们在以不明病因为主的中风患者中使用针对髓系疾病的基因筛查，发现 CHIP 的患病率比普通人群高 3 倍。我们发现，高风险 CHIP 和以前隐性骨髓增生性肿瘤分别在 4.4%和 1%的患者中作为潜在的中风病因。我们的发现证明了基因筛查在年轻中风患者中的诊断和治疗效果。未来的研究应探讨 CHIP 在中风复发和最佳二级预防中的作用。
