title: Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity.
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 that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count.
  
  
  METHODS
  Hispanic CCM1 patients (n=188) harboring the founder Q455X 'common Hispanic mutation' (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways.
  
  
  RESULTS
  At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean ± standard deviation (SD) of 60.1±115.0 (range 0-713) for total lesions and 4.9±8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE=0.31), 0.81 (SE=0.17), and 0.48 (SE=0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p≤0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p=0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count.
  
  
  CONCLUSIONS
  These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sample sizes are needed 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: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nelson
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; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics; D020786:Hemangioma, Cavernous, Central Nervous System / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics; D000075927:KRIT1 Protein; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D051117:Scavenger Receptors, Class A / Q000235:genetics; D012720:Severity of Illness Index; D051197:Toll-Like Receptor 4 / Q000235:genetics; D055815:Young Adult
chemical_list: C508598:IL4 protein, human; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D018950:Lipopolysaccharide Receptors; C495139:MSR1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D019947:Receptors, Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D051117:Scavenger Receptors, Class A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D015847:Interleukin-4; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II