Background:Ischemic stroke is a devastating complication affecting children with sickle cell anemia. Genetic factors are likely to be important in determining the risk of stroke but are poorly defined.Methods:We have studied a cohort of 19 children who had an overt ischemic stroke before 4 years of age. We predicted genetic determinants of stroke would be more prominent in this group. We performed whole exome sequencing on this cohort and applied 2 hypotheses to our variant filtering. First, we looked for strong, potentially mono- or oligogenic variants for ischemic stroke, and second, we considered that more common polygenic variants will be enriched in our cohort. Candidate variants emerging from both strategies were validated in a cohort of 283 patients with sickle cell anemia and known pediatric cerebrovascular outcomes. We used principal component analysis in this cohort to control for relatedness and population substructure.Results:Our primary finding was that the Apoliprotein E genotypes ε2/ε4 and ε4/ ε4, defined by the interplay of rs7412 and rs429358, were associated with increased stroke risk, with an odds ratio of 4.35 ([95% CI, 1.85–10.0] P=0.0011) for ischemic stroke in the validation cohort. We also found that rs2297518 in NOS (NO synthase) 2 (odds ratio, 2.25 [95% CI, 1.21–4.19]; P=0.014) and rs2230123 in signal transducer and activator of transcription (odds ratio, 2.60 [95% CI, 1.30–5.20]; P=0.009) both had increased odds ratios for ischemic stroke, although these two variants were below the threshold for statistical significance after correction for multiple testing.Conclusions:These data identify new loci for future functional investigations into cerebrovascular disease in sickle cell anemia. Based on African population reference allele frequencies, the Apoliprotein E genotypes would be present in about 10% of children with sickle cell anemia and represent a genetic risk factor that is potentially modifiable by both dietary and pharmaceutical manipulation of its dyslipidemic effects.

中文翻译：

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4 岁前患有镰状细胞贫血和中风的患者的遗传分析表明 APOE 具有重要作用。

背景：缺血性中风是影响镰状细胞性贫血儿童的毁灭性并发症。遗传因素可能对确定中风的风险很重要，但定义不明确。方法：我们研究了一组 19 名 4 岁前患有明显缺血性中风的儿童。我们预测中风的遗传决定因素在这一组中会更加突出。我们对该队列进行了全外显子组测序，并将 2 个假设应用于我们的变异过滤。首先，我们为缺血性中风寻找强的、潜在的单基因或寡基因变异，其次，我们认为更常见的多基因变异将在我们的队列中得到丰富。从这两种策略中出现的候选变异在 283 名患有镰状细胞性贫血和已知的小儿脑血管结局的患者队列中得到验证。rs7412和rs429358与中风风险增加相关，验证队列中缺血性中风的比值比为 4.35（[95% CI，1.85–10.0] P =0.0011）。我们还发现NOS（NO 合酶）2 中的rs2297518（优势比，2.25 [95% CI，1.21–4.19]；P =0.014）和信号转导和转录激活因子中的rs2230123 （优势比，2.60 [95% CI， 1.30–5.20]；P=0.009) 两者都增加了缺血性中风的比值比，尽管这两个变体在多次测试校正后低于统计显着性阈值。结论：这些数据为未来镰状细胞性贫血脑血管疾病的功能研究确定了新的位点。根据非洲人口参考等位基因频率，载脂蛋白 E 基因型将存在于大约 10% 的镰状细胞性贫血儿童中，并且代表一种遗传风险因素，可能通过饮食和药物控制其血脂异常影响来改变。