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

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, 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

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.

Keywords: EPHB4; RASA1; Ras-Erk/Ras-MAPK signaling; cerebral cavernous malformation; vascular malformation.

Conflict of interest statement

The authors have declared that no competing interests exist.

© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

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