Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke.
Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke.
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DOI：
10.1111/bpa.12620
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Vanakker OM
中科院分区：
文献类型：
--
作者：
De Vilder EYG;Cardoen S;Hosen MJ;Le Saux O;De Zaeytijd J;Leroy BP;De Reuck J;Coucke PJ;De Paepe A;Hemelsoet D;Vanakker OM
缺血性卒中在世界范围内引起高死亡率和发病率。它是由不完全已知的环境和遗传风险因素的复杂相互作用造成的。我们研究了ABCC 6基因作为缺血性卒中的候选危险因素，因为在常染色体隐性遗传病弹性假黄瘤中，由双等位基因致病性ABCC 6变异体引起的缺血性卒中发病率增加，杂合子携带者的心血管风险较高，以及ABCC 6功能障碍在心肌缺血中的既定作用。我们建立了一个已知的致病性ABCC 6变异体的分离（p。[Arg 1314 Gln]）在相对年轻时患有缺血性中风和/或心血管疾病的多代大家族中的缺血性中风患者的11/19个家族成员中的表达。在424例缺血性卒中患者和250例健康对照的独立病例对照研究中，缺血性卒中患者队列中致病性ABCC 6变异的频率是正常对照的4.9倍（P = 0.036; 95%CI 1.11-21.33）。为了研究ABCC 6缺陷在脑中的细胞后果，对Abcc 6缺陷小鼠和野生型对照中的脑切片进行免疫染色。在Abcc 6-/-小鼠中鉴定了Bmp 4和Eng的上调和Alk 2的下调，表明细胞凋亡和血管生成增加。由于这两个过程都是在缺血中诱导的，我们认为促缺血状态可以解释携带致病性ABCC 6变体的患者患缺血性卒中的风险较高，因为这可能降低这些患者发生急性缺血事件的阈值。总之，本研究确定了ABCC 6杂合子变异体作为缺血性卒中的危险因素。此外，Abcc 6-/-小鼠脑中Bmp（Bmp 4，Alk 2）和Tgfβ（Eng）信号传导的失调可导致促缺血状态，降低发生急性缺血事件的阈值。这些数据证明了ABCC 6基因的分子分析在诊断为隐源性缺血性卒中患者中的重要性。
Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia. We established segregation of a known pathogenic ABCC6 variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case-control study in 424 ischemic stroke patients and 250 healthy controls, pathogenic ABCC6 variants were 4.9 times more frequent (P = 0.036; 95% CI 1.11–21.33) in the ischemic stroke patient cohort. To study cellular consequences of ABCC6 deficiency in the brain, immunostaining of brain sections in Abcc6-deficient mice and wild-type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified in Abcc6–/– mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro-ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenic ABCC6 variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygous ABCC6 variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfβ (Eng) signaling in the brain of Abcc6–/– mice could lead to a pro-ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of the ABCC6 gene in patients diagnosed with cryp togenic ischemic stroke.
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影响因子：
8.3
作者：
KRUPINSKI, J;KALUZA, J;WANG, JM
通讯作者：
WANG, JM
影响因子：
2.9
作者：
Andrikovics, H;Pongrácz, E;Tordai, A
通讯作者：
Tordai, A
影响因子：
--
作者：
Hornstrup, Louise S.;Tybjaerg-Hansen, Anne;Frikke-Schmidt, Ruth
通讯作者：
Frikke-Schmidt, Ruth
影响因子：
30.8
作者：
Helgadottir, A;Manolescu, A;Stefansson, K
通讯作者：
Stefansson, K
DOI：
10.1016/s1357-2725(97)00135-0
发表时间：
1998-04-01
影响因子：
4
作者：
Andrews, NC
通讯作者：
Andrews, NC