Abstract DP225: Inflammation and Angiogenic Biomarkers Associated With Familial Cerebral Cavernous Malformation, Hereditary Hemorrhagic Telangiectasia and Sturge-Weber Syndrome

Introduction: Circulating plasma protein biomarkers may distinguish between related diseases that share common disease mechanisms, such as neuroinflammation and angiogenesis. We aimed to compare inflammatory and angiogenic protein levels between three rare vascular diseases that all have a brain vascular malformation phenotype: familial Cerebral Cavernous Malformation (FCCM), Hereditary Hemorrhagic Telangiectasia (HHT), and Sturge-Weber Syndrome (SWS). Methods: We measured plasma levels of 22 proteins related to inflammation and angiogenesis in 428 individuals enrolled in the Brain Vascular Malformation Consortium (BVMC), including 472 blood samples (216 FCCM, 206 HHT and 50 SWS), using the Angiome multiplex ELISA biomarker panel. Protein levels were assayed in two batches, measured in duplicate, log-transformed and averaged for analysis. We compared biomarker levels between diseases using multivariable linear regression, adjusting for age at blood collection, sex, and assay batch ; cluster-robust standard errors accounted for within-person correlation and Bonferroni-correction for multiple testing. Exponentiated coefficients are reported as Proportional Increase (PI) for protein levels between groups. Results: All 22 proteins were successfully measured in the 472 samples: 216 FCCM (42% male, median age 47 years), 206 HHT (48% male, median age 42 years), and 50 SWS (46% male, median age 18 years). As expected, HHT cases with endoglin mutations had ~50% lower endoglin levels. In CCM compared to HHT, we observed higher levels of endoglin (PI=1.45, P<0.001), GP130 (PI=1.26, P<0.001) and IL10 (PI=1.31, P=0.048), and lower levels of IL6R (PI=0.85, P<0.001) and IL1B (PI=0.38, P<0.001). In CCM compared to SWS cases, we observed a higher level of TIE2 (PI=1.31, P=0.002) and lower levels of IL6R (PI=0.80, P<0.001) and IL6 (PI=0.57, P=0.035). In HHT compared to SWS, we observed a higher level of VEGFR1 (PI=1.50, P=0.032) and lower levels of endoglin (PI=0.67, P<0.001) and IL6 (PI=0.55, P=0.039). Conclusions: We identified several circulating plasma biomarkers with a role in inflammation and angiogenesis that differ between FCCM, HHT and SWS cohorts, including endoglin, GP130, IL1B, IL10, IL6, IL6R, TIE2, and VEGFR1. These proteins may play a role in specific underlying disease mechanisms.