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Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral
Foram Choksi1, Shantel Weinsheimer2,3, Jeffrey Nelson2
1Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
Insights
A common RASA1 gene variant is linked to increased risk of intracranial hemorrhage and larger lesions in familial cerebral cavernous malformation (CCM). EPHB4 gene variants showed no association with CCM severity.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Cerebral cavernous malformation (CCM) is a complex vascular disorder.
- Genetic factors significantly influence CCM development and severity.
- Investigating specific gene variants can elucidate disease mechanisms.
Purpose of the Study:
- To determine if common variants in EPHB4 and RASA1 genes are associated with CCM disease severity.
- To evaluate the impact of these variants on intracranial hemorrhage (ICH) and lesion burden.
Main Methods:
- Genotyping of 7 common variants in EPHB4 and RASA1 in 338 familial CCM cases.
- Assessing ICH history and quantifying total and large (≥5mm) MRI lesions.
- Utilizing multivariable logistic and linear regression models for association analyses.
Main Results:
- One intronic RASA1 variant (rs72783711 A>C) showed a significant association with ICH.
- This RASA1 variant was also nominally associated with a higher count of large lesions.
- No significant associations were found between EPHB4 variants and CCM severity phenotypes.
Conclusions:
- A common RASA1 variant may contribute to ICH and lesion progression in familial CCM.
- EPHB4 variants do not appear to influence the studied CCM severity phenotypes.
- RASA1 warrants further investigation in the context of CCM pathogenesis.
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.
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