背景:中风是全球范围内的主要死亡原因,缺乏改善预后的有效治疗方法。本研究的目的是确定缺血性卒中后功能结局的新治疗靶点。
结果:可药用基因的顺式表达数量性状基因座数据用作工具变量。主要结果是缺血性卒中后3个月的改良Rankin量表评分,评估为二分变量(3-6对0-2),也作为序数变量。药物靶点孟德尔随机化,Steiger滤波分析,并进行了共定位分析。此外,进行了全表型孟德尔随机化分析,以确定药物靶基因在遗传水平上的安全性。在超过2600个可药用基因中,16个基因的遗传预测表达(ABCC2,ATRAID,BLK,CD93,CHST13,NR1H3,NRBP1,PI3,RIPK4,SEMG1,SLC22A4,SLC22A5,SLCO3A1,TEK,TLR4和WNT10B)显示出与序数改良的Rankin量表(P<1.892×10-5)或不良功能结局(改良的Rankin量表3-6对0-2,P<1.893×10-5)的因果关系。Steiger滤波分析提示潜在的方向稳定性(P<0.05)。共定位分析进一步支持ABCC2、NRBP1、PI3和SEMG1基因预测表达与缺血性卒中后功能结局之间的关联。此外,全表型孟德尔随机化显示了针对ABCC2,NRBP1,PI3和SEMG1的治疗的其他有益适应症和几乎没有潜在的安全性问题,但这些结果的稳健性受到低功率的限制。
结论:本研究揭示了改善缺血性卒中后功能结局的4个候选治疗靶点,而潜在的机制需要进一步调查。
BACKGROUND: Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke .
RESULTS: Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (ABCC2, ATRAID, BLK, CD93, CHST13, NR1H3, NRBP1, PI3, RIPK4, SEMG1, SLC22A4, SLC22A5, SLCO3A1, TEK, TLR4, and WNT10B) demonstrated the causal associations with ordinal modified Rankin Scale (P<1.892×10-5) or poor functional outcome (modified Rankin Scale 3-6 versus 0-2, P<1.893×10-5). Steiger filtering analysis suggested potential directional stability (P<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of ABCC2, NRBP1, PI3, and SEMG1 with functional outcome after ischemic stroke. Furthermore, phenome-wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting ABCC2, NRBP1, PI3, and SEMG1, but the robustness of these results was limited by low power.
CONCLUSIONS: The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.