半胱氨酸改变的变异是老年人群中风的危险因素。

Cysteine-Altering Variants Are a Risk Factor for Stroke in the Elderly Population.

机构信息

Department of Clinical Genetics, Leiden University Medical Center, the Netherlands (R.J.H., J.W.R., S.A.J.L.O.).

Geisinger Genomic Medicine Institute, Danville, PA (T.N.P.).

出版信息

Stroke. 2020 Dec;51(12):3562-3569. doi: 10.1161/STROKEAHA.120.030343. Epub 2020 Nov 9.

DOI:10.1161/STROKEAHA.120.030343

PMID:33161844

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7678653/

Abstract

BACKGROUND AND PURPOSE

Cysteine altering variants, which have previously been exclusively associated with the rare hereditary small vessel disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, have a population frequency of 1:300 worldwide. Using a large population database, and taking genotype as a starting point, we aimed to determine whether individuals harboring a cysteine altering variant have a higher load of small vessel disease markers on brain magnetic resonance imaging than controls, as well as a higher risk of stroke and cognitive impairment.

METHODS

A cross-sectional study using integrated clinical, neuroimaging, and whole-exome sequencing data of 92 456 participants from the Geisinger DiscovEHR initiative cohort. The case group consisted of individuals harboring a cysteine altering variant (n=118). The control group consisted of randomly selected age- and sex-matched individuals who did not have any nonsynonymous variants in (n=184). Medical records including brain magnetic resonance imagings were evaluated for clinical and neuroimaging findings associated with small vessel disease. Group comparisons were done using Fisher exact test and ordinal logistic regression models. Risk of stroke was assessed using Cox regression.

RESULTS

Of the 118 cases, 39.0% were men, mean age 58.1±16.9 years; 12.6% had a history of stroke, compared with 4.9% of controls. The risk of stroke was significantly increased after age 65 years (hazard ratio, 6.0 [95% CI, 1.4-26.3]). Dementia, mild cognitive impairment, migraine with aura and depression were equally prevalent in cases and controls. Twenty-nine cases (25%) and 45 controls (24%) had an available brain magnetic resonance imaging. After age 65 years, cases had a higher white matter lesion burden and more lacunes. A severe small vessel disease phenotype compatible with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy was rarely seen.

CONCLUSIONS

Cysteine altering variants are an important contributor to the risk of stroke, lacunes, and white matter hyperintensities in the elderly population.

摘要

背景与目的

半胱氨酸改变变体以前仅与罕见的遗传性小血管疾病脑常染色体显性动脉病伴皮质下梗死和白质脑病相关，其在全球的人群频率为 1:300。利用大型人群数据库，并以基因型为起点，我们旨在确定携带半胱氨酸改变变体的个体在脑磁共振成像上是否比对照组具有更高的小血管疾病标志物负荷，以及更高的中风和认知障碍风险。

方法

这是一项使用 Geisinger DiscovEHR 计划队列中 92456 名参与者的综合临床、神经影像学和全外显子组测序数据的横断面研究。病例组由携带半胱氨酸改变变体的个体（n=118）组成。对照组由年龄和性别匹配且无任何非同义变体的随机选择的个体组成（n=184）。评估了病历包括脑磁共振成像，以确定与小血管疾病相关的临床和神经影像学发现。使用 Fisher 精确检验和有序逻辑回归模型进行组间比较。使用 Cox 回归评估中风风险。

结果

在 118 例病例中，39.0%为男性，平均年龄 58.1±16.9 岁；12.6%有中风病史，而对照组为 4.9%。65 岁后中风风险显著增加（危险比，6.0 [95%CI，1.4-26.3]）。病例组和对照组的痴呆、轻度认知障碍、有先兆偏头痛和抑郁症的发生率相同。29 例（25%）和 45 例对照组（24%）有可用的脑磁共振成像。65 岁后，病例组的白质病变负荷更高，腔隙更多。罕见出现符合脑常染色体显性动脉病伴皮质下梗死和白质脑病的严重小血管疾病表型。