title: Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations.
abstract: BACKGROUND
  Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH.
  
  
  RESULTS
  We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01-2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03-2.15; p(trend) = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ(2) = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ(2) = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases.
  
  
  CONCLUSIONS
  A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 94110, USA.
authors.forename: Bahar
authors.initials: B
authors.lastname: Mikhak
authors.forename: Shantel
authors.initials: S
authors.lastname: Weinsheimer
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lawton
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Zaroff
authors.forename: Stephen
authors.initials: S
authors.lastname: Sidney
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCulloch
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
mesh_terms: D000328:Adult; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000032:analysis / Q000235:genetics*; D002140:California; D016022:Case-Control Studies; D002533:Cerebral Angiography / Q000379:methods; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D016015:Logistic Models; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D044465:White People; D055815:Young Adult
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins