Angiopoietin-Like 4 <i>(ANGPTL4)</i> 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. Methods and 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 (χ² = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ² = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases. Conclusion: A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.

Association between Polymorphisms rs1333040 and rs7865618 of Chromosome 9p21 and Sporadic Brain Arteriovenous Malformations

“…The vast majority of the studies that have so far investigated the genetic base of sporadic BAVMs have focused on SNPs of genes involved in angiogenesis and inflammation [14,15,16]. However, most of these studies have provided controversial and inconsistent results and a recent meta-analysis carried out by our research team has demonstrated a statistically significant association with BAVMs only for the IVS3-35A>G polymorphism of the ALK1 gene (ACVRL1) [14], consistent with the notion that ACVRL1 mutations are involved in the formation of arteriovenous dysplasia in patients with hereditary hemorrhagic telangiectasia [17].…”

Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment

“…37 Some specific molecules affected by SNPs are TGF-b, an extracellular glycosylated protein that suppresses the effects of interleukins and is critical in de novo AVM formation; 32 brain-derived neurotrophic factor (BDNF), a protein that supports survival, development, and function of neurons; 55 interleukin-6 (IL-6), which contributes to vascular wall instability by stimulating the release of MMP; 32,33,38 and angiopoietin-like 4 (ANGPTL4), a glycoprotein believed to be involved in angiogenesis (Table 1). 31 Vascular endothelial growth factor is a critical signaling molecule that regulates angiogenesis and is typically suppressed in normal adult vasculature. VEGF has a potent mitotic effect and is highly expressed in children with recurrent AVMs.…”

Susceptibility loci for sporadic brain arteriovenous malformation; a replication study and meta-analysis

“…The ANGPTL4 protein has been suggested to have a proangiogenic as well as an antiangiogenic effect 9 20. Suppression of angiogenesis may occur via the Raf/MEK/ERK1/2 MAP kinase pathway in endothelial cells 9 20.…”

“…Suppression of angiogenesis may occur via the Raf/MEK/ERK1/2 MAP kinase pathway in endothelial cells 9 20. Recent evidence from studies in knock-out mice showed that ANGPTL4 deficiency resulted in dysfunctional angiogenesis in retinal vessels and increased vessel permeability because of improper maturation 21.…”