title: Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation.
abstract: BACKGROUND
  Cerebral cavernous malformations (CCM) are enlarged vascular lesions affecting 0.1-0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age. The number of lesions varies widely for unknown reasons, even among carriers of similar ages with the same mutation. The purpose of this study was to investigate whether cardiovascular (CV) risk factors influence potential markers of familial CCM1 disease severity, such as lesion count and history of intracerebral hemorrhage.
  
  
  METHODS
  We analyzed baseline data from 185 Hispanic subjects, enrolled in the Brain Vascular Malformation Consortium study between June 2010 and March 2013. All subjects were carriers of the founder Q455X 'Common Hispanic Mutation' (CHM) in the KRIT1 gene, and had a clinical diagnosis of CCM or had an affected first- or second-degree relative with CCM. We performed a cross-sectional study, collecting detailed clinical information of CCM1-CHM subjects and cerebral susceptibility-weighted magnetic resonance imaging to assess lesion count. Linear or logistic regression analysis of log-lesion count or history of intracerebral hemorrhage and CV risk factors (age, gender, obesity, diabetes, hypertension, hyperlipidemia and smoking status) and related quantitative traits (body mass index, glycosylated hemoglobin levels, blood pressure, lipids levels and pack-years of cigarette smoking) was performed accommodating familial clustering.
  
  
  RESULTS
  CCM1-CHM subjects were mainly female (63.8%) and symptomatic at presentation (63.2%). Lesion count was highly variable (mean ± SD: 57.7 ± 110.6; range: 0-713); 90% of CCM1-CHM subjects had multiple lesions at enrollment. Age (p < 0.001) was positively correlated with lesion count and male gender (p = 0.035) was associated with a greater number of lesions. Obesity (p = 0.001) and higher body mass index (p = 0.002) were associated with fewer lesions. No association with hypertension was detected, however, systolic blood pressure (p = 0.002) was associated with fewer lesions. No significant association with lesion count was observed for diabetes, hyperlipidemia, smoking status or for related quantitative traits. History of intracerebral hemorrhage was not significantly associated with any CV risk factors, however, we found borderline associations of hemorrhage with obesity (p = 0.062), systolic blood pressure (p = 0.083) and pack-years of cigarette smoking (p = 0.055). After correction for multiple testing, age and obesity remained significantly associated with lesion count in CCM1-CHM subjects.
  
  
  CONCLUSIONS
  These results suggest that several CV risk factors explain some of the variability in lesion count in Hispanic CCM1-CHM subjects. Although age, gender, obesity, body mass index and systolic blood pressure may influence familial CCM1 disease severity, further longitudinal studies in larger sample sizes are essential to confirm these findings.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, Calif., USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Choquet
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nelson
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCulloch
authors.forename: Amy
authors.initials: A
authors.lastname: Akers
authors.forename: Beth
authors.initials: B
authors.lastname: Baca
authors.forename: Yasir
authors.initials: Y
authors.lastname: Khan
authors.forename: Blaine
authors.initials: B
authors.lastname: Hart
authors.forename: Leslie
authors.initials: L
authors.lastname: Morrison
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015992:Body Mass Index; D001921:Brain / Q000473:pathology; D002318:Cardiovascular Diseases / Q000208:ethnology*; D002543:Cerebral Hemorrhage / Q000209:etiology; D002648:Child; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D020786:Hemangioma, Cavernous, Central Nervous System / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008297:Male; D008800:Mexico / Q000208:ethnology; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins