title: Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1.
abstract: BACKGROUND
  Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.
  
  
  METHODS
  Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 'common Hispanic mutation' (CCM1-CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.
  
  
  RESULTS
  The CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.
  
  
  CONCLUSIONS
  Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Choquet
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Orbassano, TO, Italy; CCM Italia Research Network (www.ccmitalia.unito.it).
authors.forename: Eliana
authors.initials: E
authors.lastname: Trapani
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Orbassano, TO, Italy; CCM Italia Research Network (www.ccmitalia.unito.it).
authors.forename: Luca
authors.initials: L
authors.lastname: Goitre
authors.affiliation: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy; CCM Italia Research Network (www.ccmitalia.unito.it).
authors.forename: Lorenza
authors.initials: L
authors.lastname: Trabalzini
authors.affiliation: Angioma Alliance, Durham, NC, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Akers
authors.affiliation: Department of Neurosurgery, Spedali Civili and University of Brescia, Brescia, Italy; CCM Italia Research Network (www.ccmitalia.unito.it).
authors.forename: Marco
authors.initials: M
authors.lastname: Fontanella
authors.affiliation: Department of Radiology, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Blaine L
authors.initials: BL
authors.lastname: Hart
authors.affiliation: Department of Neurology University of New Mexico, Albuquerque, NM, USA; Department of Pediatrics, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Morrison
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Orbassano, TO, Italy; CCM Italia Research Network (www.ccmitalia.unito.it). Electronic address: francesco.retta@unito.it.
authors.forename: Saverio Francesco
authors.initials: SF
authors.lastname: Retta
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D020786:Hemangioma, Cavernous, Central Nervous System / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012720:Severity of Illness Index
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D003577:Cytochrome P-450 Enzyme System; D020782:Matrix Metalloproteinases
keywords: Cerebral Cavernous Malformation (CCM); Cerebrovascular disease; Cytochrome P450 (CYP); Disease severity; Familial Cerebral Cavernous Malformation type 1; Free radicals; Genetic markers set association study; Inter-individual variability in disease susceptibility and outcome; Intracerebral hemorrhage; KRIT1/CCM1; Matrix metalloproteinase (MMP); Oxidative stress; Reactive oxygen species (ROS); Vascular brain lesions