Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation.
Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation.
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DOI：
10.1002/mgg3.1794
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发表时间：
2021-10
影响因子：
2
通讯作者：
Kim H
中科院分区：
文献类型：
--
作者：
Choksi F;Weinsheimer S;Nelson J;Pawlikowska L;Fox CK;Zafar A;Mabray MC;Zabramski J;Akers A;Hart BL;Morrison L;McCulloch CE;Kim H
探讨EphB4和RASA1基因常见变异与脑海绵状血管畸形(CCM)疾病严重程度表型的相关性，包括颅内出血(ICH)、总病变数和大病变数。纳入脑血管畸形协会登记的家族性CCM病例(n=338)。在磁共振上对总病灶和大病灶(≥5 mm)进行计数；入选时通过病历评估脑出血的临床病史。样本在Affymetrix Axiom基因组范围的LAT1人类阵列上进行基因分型。我们使用脑出血的多变量Logistic回归(优势比，OR)和总的和大的病变计数的多变量线性回归(比例增加，PI)来检验七个常见变量(EphB4中的三个和RASA1中的四个)的相关性，并调整了年龄、性别和三个主成分。显着性基于多次比较的Bonferroni调整(0.007/7个变量=1,005)。EphB4变异与CCM严重程度表型无显著相关性。1个RASA1内含子变异(rs72783711A>；C)与脑出血显著相关(OR=91.82，95%CI=111.21-2.37，P=0.004)，名义上与较大的病变数相关(PI=111.17，95%CI=111.03-1.32，P=0.02)。在家族性CCM中，一种常见的RASA1变异可能与脑出血和大病变计数有关。EphB4变异与三种CCM严重表型中的任何一种都没有关联。我们调查了EphB4和RASA1的常见变异是否与家族性脑海绵状畸形(CCM)疾病严重表型相关，包括颅内出血(ICH)、总病变和大病变计数。EphB4变异与三种CCM严重表型中的任何一种都没有关联。然而，RASA1内含子变异与家族性CCM的脑出血和大病变计数显著相关，提示RAS-Erk通路可能在CCM疾病严重程度中发挥作用。
To investigate whether common variants in EPHB4 and RASA1 are associated with cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. Familial CCM cases enrolled in the Brain Vascular Malformation Consortium were included (n = 338). Total lesions and large lesions (≥5 mm) were counted on MRI; clinical history of ICH at enrollment was assessed by medical records. Samples were genotyped on the Affymetrix Axiom Genome‐Wide LAT1 Human Array. We tested the association of seven common variants (three in EPHB4 and four in RASA1) using multivariable logistic regression for ICH (odds ratio, OR) and multivariable linear regression for total and large lesion counts (proportional increase, PI), adjusting for age, sex, and three principal components. Significance was based on Bonferroni adjustment for multiple comparisons (0.05/7 variants = 0.007). EPHB4 variants were not significantly associated with CCM severity phenotypes. One RASA1 intronic variant (rs72783711 A>C) was significantly associated with ICH (OR = 1.82, 95% CI = 1.21–2.37, p = 0.004) and nominally associated with large lesion count (PI = 1.17, 95% CI = 1.03–1.32, p = 0.02). A common RASA1 variant may be associated with ICH and large lesion count in familial CCM. EPHB4 variants were not associated with any of the three CCM severity phenotypes. We investigated whether common variants in EPHB4 and RASA1 are associated with familial cerebral cavernous malformation (CCM) disease severity phenotypes, including intracranial hemorrhage (ICH), total and large lesion counts. EPHB4 variants were not associated with any of the three CCM severity phenotypes. However, an intronic RASA1 variant was significantly associated with ICH and large lesion count in familial CCM, suggesting that the Ras‐Erk pathway may play a role in CCM disease severity.
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影响因子：
7.7
作者：
Linck, Ethan;Battey, C. J.
通讯作者：
Battey, C. J.
影响因子：
8.8
作者：
Shenkar, Robert;Shi, Changbin;Awad, Issam A.
通讯作者：
Awad, Issam A.
影响因子：
4.4
作者：
Haghighi, Alireza;Fathi, Davood;Friedman, Bethany
通讯作者：
Friedman, Bethany
DOI：
10.1002/ajmg.a.61519
发表时间：
2020-05
期刊：
American journal of medical genetics. Part A
影响因子：
--
作者：
Manole AK;Forrester VJ;Zlotoff BJ;Hart BL;Morrison LA
通讯作者：
Morrison LA
影响因子：
9.8
作者：
Eerola, I;Boon, LM;Vikkula, M
通讯作者：
Vikkula, M