Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation

Abstract Background 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. Methods Familial CCM cases enrolled in the Brain Vascular Malfo...

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Autores principales:	Foram Choksi, Shantel Weinsheimer, Jeffrey Nelson, Ludmila Pawlikowska, Christine K. Fox, Atif Zafar, Marc C. Mabray, Joseph Zabramski, Amy Akers, Blaine L. Hart, Leslie Morrison, Charles E. McCulloch, Helen Kim
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	cerebral cavernous malformation EPHB4 Ras‐Erk/Ras‐MAPK signaling RASA1 vascular malformation Genetics QH426-470
Acceso en línea:	https://doaj.org/article/9f363bcd55e644af80ceef59a0f22455
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spelling	oai:doaj.org-article:9f363bcd55e644af80ceef59a0f224552021-11-10T16:39:23ZAssessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation2324-926910.1002/mgg3.1794https://doaj.org/article/9f363bcd55e644af80ceef59a0f224552021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1794https://doaj.org/toc/2324-9269Abstract Background 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. Methods 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). Results 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). Conclusion 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.Foram ChoksiShantel WeinsheimerJeffrey NelsonLudmila PawlikowskaChristine K. FoxAtif ZafarMarc C. MabrayJoseph ZabramskiAmy AkersBlaine L. HartLeslie MorrisonCharles E. McCullochHelen KimWileyarticlecerebral cavernous malformationEPHB4Ras‐Erk/Ras‐MAPK signalingRASA1vascular malformationGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cerebral cavernous malformation EPHB4 Ras‐Erk/Ras‐MAPK signaling RASA1 vascular malformation Genetics QH426-470
spellingShingle	cerebral cavernous malformation EPHB4 Ras‐Erk/Ras‐MAPK signaling RASA1 vascular malformation Genetics QH426-470 Foram Choksi Shantel Weinsheimer Jeffrey Nelson Ludmila Pawlikowska Christine K. Fox Atif Zafar Marc C. Mabray Joseph Zabramski Amy Akers Blaine L. Hart Leslie Morrison Charles E. McCulloch Helen Kim Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation
description	Abstract Background 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. Methods 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). Results 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). Conclusion 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.
format	article
author	Foram Choksi Shantel Weinsheimer Jeffrey Nelson Ludmila Pawlikowska Christine K. Fox Atif Zafar Marc C. Mabray Joseph Zabramski Amy Akers Blaine L. Hart Leslie Morrison Charles E. McCulloch Helen Kim
author_facet	Foram Choksi Shantel Weinsheimer Jeffrey Nelson Ludmila Pawlikowska Christine K. Fox Atif Zafar Marc C. Mabray Joseph Zabramski Amy Akers Blaine L. Hart Leslie Morrison Charles E. McCulloch Helen Kim
author_sort	Foram Choksi
title	Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation
title_short	Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation
title_full	Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation
title_fullStr	Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation
title_full_unstemmed	Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation
title_sort	assessing the association of common genetic variants in ephb4 and rasa1 with phenotype severity in familial cerebral cavernous malformation
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/9f363bcd55e644af80ceef59a0f22455
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Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation

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