遗传关联研究可以揭示生物学和治疗目标,但对中风恢复的关注有限。StRONG(Stroke,压力,康复,和遗传学)是一个前瞻性的,纵向(1年),在美国28个卒中中心进行的成人卒中基因研究.主要目的是检查候选遗传变异与(1)运动/功能结果和(2)压力相关结果的关联。
■对于电动机/功能端点,3个候选基因变异(ApoEε4,BDNF[脑源性神经营养因子],和多巴胺多基因评分)分析与握力变化(3个月基线)的相关性,功能(3个月中风影响量表-日常生活活动),情绪(3个月患者健康问卷-8),和认知(12个月电话-蒙特利尔认知评估)。对于与压力相关的结果,7个变体(5-羟色胺转运体基因连锁启动子区,ACE[血管紧张素转换酶],催产素受体,FKBP5[FKBP脯氨酸异构酶5],FAAH[脂肪酸酰胺水解酶],BDNF,和COMT[儿茶酚-O-甲基转移酶])在6个月和12个月时评估与创伤后应激障碍([PTSD];PTSD初级护理量表)和抑郁症(患者健康问卷-8)的相关性;检查与压力相关的基因作为卒中后压力水平的函数。统计模型(线性,负二项式,或泊松回归)基于反应变量分布;所有包括卒中严重程度,年龄,性别,和祖先为协变量。其次探讨了中风亚型。数据经Holm-Bonferroni校正。二次复制分析检测rs1842681多态性(在GISCOME研究[缺血性卒中功能结局的遗传学]中鉴定)是否与STRONG中3个月修改的Rankin量表评分相关。
■763名参与者的年龄为63.1±14.9(平均值±SD)岁,美国国立卫生研究院卒中量表初始评分中位数为4分(四分位距,2-9);3个月时,n=515的结果数据可用,6个月时n=500,12个月时n=489。中风后1年,rs6265(BDNF)变异与认知较差相关(电话-蒙特利尔认知评估得分低0.9分,P=1×10-5)。对于与压力相关的结果,rs4291(ACE)和rs324420(FAAH)是卒中后压力增加与1年抑郁和PTSD症状升高相关的危险因素(P<0.05)。而rs4680(COMT)将卒中后压力与较低的1年抑郁和PTSD相关。当考虑中风亚型时,结果没有变化。强烈复制的GISCOME:rs1842681与较低的3个月改良Rankin量表评分相关(P=3.2×10-5)。
■这项研究确定了与认知功能的遗传关联,抑郁症,中风后1年和PTSD。PTSD和抑郁症状的遗传易感性根据中风后压力的大小而变化,强调生活经验在恢复中的关键作用。一起,结果提示,遗传关联研究提供了对人类中风恢复生物学的见解。
UNASSIGNED: Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic
study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes.
UNASSIGNED: For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME
study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG.
UNASSIGNED: The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P=1×10-5). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (P<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (P=3.2×10-5).
UNASSIGNED: This
study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.