Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system

Background: Polymorphisms in the proinflammatory cytokine interleukin (IL)-1β gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1β and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients. Method: Two IL-1β promoter SNPs (–511C→T, –31T→C) and 1 synonymous coding SNP in exon 5 at +3953C→T (Phe) were genotyped in 410 BAVM patients. We performed a survival analysis of time to subsequent ICH, censoring cases at first treatment, death or last follow-up. A Cox regression analysis was performed to obtain hazard ratios (HRs) for genotypes adjusted for age, sex, Caucasian race/ethnicity and hemorrhagic presentation. Results: Subjects with the –31 CC genotype (HR = 2.7; 95% CI 1.1–6.6; p = 0.029) or the –511 TT genotype (HR = 2.6; 95% CI 1.1–6.5; p = 0.039) had a greater risk of subsequent ICH compared with reference genotypes, adjusting for covariates. The +3953C→T SNP was not significantly associated with an increased ICH risk (p = 0.22). The IL-1β promoter polymorphisms were also associated with BAVM susceptibility among a subset of 235 BAVM cases and 255 healthy controls of Caucasian race/ethnicity (p < 0.001). Conclusion: IL-1β promoter polymorphisms were associated with an increased risk of ICH in BAVM clinical course and with BAVM susceptibility. These results suggest that inflammatory pathways, including the IL-1β cytokine, may play an important role in ICH.

Section: Discussionmentioning

confidence: 99%

Common Variants in Interleukin-1-Beta Gene Are Associated with Intracranial Hemorrhage and Susceptibility to Brain Arteriovenous Malformation

Kim¹,

Hysi²,

Pawlikowska³

et al. 2008

“…Diagnoses were made by brain imaging, including digital subtraction angiography in all cases. Patients with known autosomal dominant polycystic kidney disease, fibromuscular dysplasia or with additional cerebrovascular dysplasia were excluded [9]. …”

Section: Methodsmentioning

confidence: 99%

Polymorphisms of Homocysteine Metabolism Are Associated with Intracranial Aneurysms

Semmler¹,

Linnebank²,

Götz³

et al. 2008

Self Cite

Background: Impaired homocysteine metabolism is associated with a number of vasculopathies including extracranial aneurysms. We analyzed the possible association of nine genetic variants of homocysteine metabolism with the occurrence of intracranial aneurysms. Methods: Caucasian patients (n = 255) treated at two German hospitals for intracranial aneurysms and local controls (n = 348) were genotyped for the following polymorphisms: methionine synthase (MTR) c.2756A→G, methylenetetrahydrofolate reductase (MTHFR) c.677C→T, MTHFR c.1298A→C, cystathionine β-synthase (CBS) c.844_855ins68, CBS c.833T→C, dihydrofolate reductase (DHFR) c.594 + 59del19bp, glutathione S-transferase Ω-1 (GSTO1) c.428C→A, reduced folate carrier 1 (RFC1) c.80G→A and transcobalamin 2 (Tc2) c.776C→G. Results: The G-allele of the missense polymorphism Tc2 c.777C→G was found to be underrepresented in patients, suggesting that this variant may protect from the formation of cerebral aneurysms [odds ratio per two risk alleles (OR) 0.48; 95% confidence interval (CI) 0.30–0.77; p = 0.002]. We obtained borderline results for the G-allele of RFC1 c.80G→A (OR 1.64; 95% CI 1.01–2.65; p = 0.051) and the insertion allele of DHFR c.594 + 59del19bp (OR 1.61; 95% CI 1.00–2.60; p = 0.059), which were found to be overrepresented in patients. Conclusion: Polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms.

“…This association appears independent of the ALK1 genotype, which was previously shown to be associated with BAVM risk in two different BAVM cohorts [51,52]. These results suggest that ANGPTL4 polymorphisms may predispose individuals to BAVM and may represent a pathway independent of ALK1 (TGF-β signaling) for further study in BAVM pathogenesis.…”

Section: Discussionmentioning

confidence: 58%

“…After adjusting for age and sex, the risk of BAVM was 56% higher in A carriers compared to noncarriers (OR = 1.56; 95% CI = 1.01–2.41; p = 0.046; table 3). As a sensitivity analysis, we further adjusted for ALK-1 genotype, which we and others have previously reported as a significant genetic risk factor for BAVM susceptibility [51,52]. The ANGTPL4 rs11672433 A carrier association remained (OR = 1.56, 95% CI = 1.00–2.42, p = 0.051) after adjustment for age, sex and ALK1 IVS3–35 any A genotype.…”

Section: Resultsmentioning

confidence: 99%

Angiopoietin-Like 4 <i>(ANGPTL4)</i> Gene Polymorphisms and Risk of Brain Arteriovenous Malformations

Mikhak¹,

Weinsheimer²,

Pawlikowska³

et al. 2011

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.