Abstract：
Sickle cell anemia (SCA) is the most common cause of stroke in children. As it is a rare disease, studies investigating the association with complications like stroke in SCD have small sample sizes. Here, we performed a systematic review and meta-analysis of the studies exploring an association of genetic variants with stroke to get a better indication of their association with stroke. PubMed and Google Scholar were searched to identify studies that had performed an association analysis of genetic variants for the risk of stroke in SCA patients. After screening of eligible studies, summary statistics of association analysis with stroke and other general information were extracted. Meta-analysis was performed using the fixed effect method on the tool METAL and forest plots were plotted using the R program. The random effect model was performed as a sensitivity analysis for loci where significant heterogeneity was observed. 407 studies were identified using the search term and after screening 37 studies that cumulatively analyzed 11,373 SCA patients were included. These 37 studies included a total of 2,222 SCA patients with stroke, predominantly included individuals of African ancestry (N = 16). Three of these studies performed whole exome sequencing while 35 performed single nucleotide-based genotyping. Though the studies reported association with 132 loci, meta-analyses could be performed only for 12 loci that had data from two or more studies. After meta-analysis we observed that four loci were significantly associated with risk for stroke: -α3.7 kb Alpha-thalassemia deletion (P = 0.00000027), rs489347-TEK (P = 0.00081), rs2238432-ADCY9 (P = 0.00085), rs11853426-ANXA2 (P = 0.0034), and rs1800629-TNF (P = 0.0003396). Ethnic representation of regions with a high prevalence of SCD like the Mediterranean basin and India needs to be improved for genetic studies on associated complications like stroke. Larger genome-wide collaborative studies on SCD and associated complications including stroke need to be performed.
摘要：
镰状细胞性贫血（SCA）是儿童中风的最常见原因。因为它是一种罕见的疾病，调查SCD患者卒中等并发症的相关性的研究样本量较小.这里,我们对探索遗传变异与卒中关联的研究进行了系统综述和荟萃分析,以更好地表明其与卒中的关联.搜索PubMed和GoogleScholar，以确定对SCA患者中风风险的遗传变异进行关联分析的研究。筛选合格的研究后，提取与卒中关联分析的汇总统计量和其他一般信息。使用工具METAL的固定效应方法进行Meta分析，并使用R程序绘制森林地块。随机效应模型作为观察到显著异质性的基因座的敏感性分析。使用搜索词确定了407项研究，筛选后纳入了37项研究，累计分析了11,373名SCA患者。这37项研究共纳入2222例SCA卒中患者，主要包括非洲血统的个体（N=16）。这些研究中的三项进行了全外显子组测序，而35项进行了基于单核苷酸的基因分型。尽管研究报告与132个基因座相关，荟萃分析只能对12个来自两个或更多研究数据的基因座进行.荟萃分析后，我们观察到四个基因座与卒中风险显着相关：-α3.7kbα-地中海贫血缺失（P=0.00000027），rs489347-TEK(P=0.00081),rs2238432-ADCY9(P=0.00085),rs11853426-ANXA2（P=0.0034），和rs1800629-TNF(P=0.0003396)。需要改善地中海盆地和印度等SCD患病率高的地区的种族代表性，以进行中风等相关并发症的遗传研究。需要对SCD和包括卒中在内的相关并发症进行更大的全基因组协作研究。
