Abstract 53: Variation in DNA Mismatch Repair Genes Nominally Associated With Severity of Cerebral Cavernous Malformation Type 1
Introduction: Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by CCM1 mutations, and characterized by multiple brain lesions that can lead to intracerebral hemorrhage (ICH). In humans, CCM lesion genesis follows a two-hit mutation mechanism, where both germline and somatic mutations occur to inactivate the CCM1 protein. In mouse models, Ccm1+/- mice need to be crossed into a mismatch repair-deficient Msh2-/- or Trp53-/- background, which increases the overall rate of somatic mutations, to exhibit CCM lesions. We hypothesized that common variants in MSH2 and TP53 may modify CCM1 disease severity, as manifested by ICH and greater total or large lesion counts.
Methods: We analyzed 188 CCM1 patients all harboring the common Hispanic mutation (CHM, Q455X). ICH and lesion counts at enrollment were obtained by clinical assessment and MRI. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. After excluding variants with missing call rate >2%, minor allele frequency <1%, deviation from Hardy-Weinberg equilibrium (P<0.001), or in high linkage disequilibrium (r2≥0.8), 16 and 11 variants within +/- 5kb of MSH2 and TP53, respectively, were analyzed for association with ICH, total lesion count, and large lesion (≥5 mm) count using multivariable regression.
Results: No variant was associated with ICH or total lesion count. Two MSH2 variants (rs62139708 and rs17224794) were nominally associated with an increase in large lesion count independent of age and gender. Subjects carrying the minor allele at rs62139708 and at rs17224794 had 34% (P=0.024) and 63% more large lesions (P=0.039), respectively, compared to non-carriers. In contrast, subjects carrying the minor allele at TP53 rs8073498 had 19% fewer large lesions (P=0.046) than non-carriers at baseline.
Conclusions: Variants in MSH2 and TP53 contribute modestly to variability in large lesion count in CCM1 disease. As suggested by CCM1 mouse models, DNA mismatch repair genes may influence CCM lesion multiplicity and progression in the human disease.
Author Disclosures: H. Choquet: None. L. Pawlikowska: None. J. Nelson: None. C. McCulloch: None. A. Akers: None. Y. Khan: None. B. Hart: None. L. Morrison: None. H. Kim: None.
This research has received full or partial funding support from the American Heart Association, Western States - Alaska, Arizona, California, Hawaii, Idaho, Montana, Nevada, Oregon, Utah, Washington.
- © 2016 by American Heart Association, Inc.