Abstract T P154: Association of Common Variants in Immune Response Genes with Severity of Familial Cerebral Cavernous Malformation Type 1

Abstract

Objective: Familial Cerebral Cavernous Malformation type 1 (fCCM1) is an autosomal dominant disease caused by KRIT1 mutations and characterized by brain lesions, which increase in number over time for unknown reasons. Inflammation and altered expression of immune response genes have been observed in human CCM lesions. We investigated whether common variants in immune response genes are associated with fCCM1 disease severity, as manifested by greater lesion burden. Methods: Lesion burden was assessed on susceptibility-weighted MR imaging for 178 fCCM1 subjects, all carriers of the founder common Hispanic mutation (CHM, Q455X in KRIT1 ) and recruited as part of the Brain Vascular Malformation Consortium study. We selected 321 variants in 12 immune response genes up-regulated in human CCM lesions and represented on the Affymetrix Axiom® Genome-Wide LAT-1 Human Array. Linear regression analyses under an additive model were performed to assess association of genotype with log-lesion burden residuals, after adjustment for age at enrollment and gender. P -values were generated using 100,000 permutations to account for family structure and multiple testing. Results: Lesion burden (range: 0-713; mean ± SD: 60.5 ± 116.3) was highly variable. The minor alleles at rs2272022 ( CD200 ), rs75223220 ( CD68 ), rs57767447 and rs12587347 ( IGH ), and rs13053345 ( IGL ) were associated with more lesions (≥32%, P <0.05) at baseline, independent of age and gender. The minor alleles at rs7639471 ( CD200 ), rs9901675 ( CD68 ), rs5759959 ( GUSP11 ), rs10147756 and rs7144404 ( IGH ), and rs987710 ( IGL ) were associated with fewer lesions (≤45%, P <0.05). Variants in CD247 , CD3G , HLA-DRB1 , IGJ , LOC390714 , MS4A1 and SDC1 were not significantly associated with lesion burden. Conclusions: Several common variants in immune response genes are associated with lesion burden in fCCM1-CHM subjects. Further studies are needed to confirm whether CD200, CD68, GUSP11, IGH and IGL genes influence fCCM1 disease severity.