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

Abstract

Background: The chromosomal locus 9p21 is a novel genetic marker for a variety of cardiovascular and cerebrovascular diseases. In a recent study, we have demonstrated an association between the single nucleotide polymorphism (SNP) rs1333040C>T on chromosome 9p21 and sporadic brain arteriovenous malformations (BAVMs). Here, we extended our analysis to an additional SNP on chromosome 9p21 (rs7865618A>G) and increased our sample size including BAVMs from two different Italian neurosurgical centers. Methods: We studied 206 patients with sporadic BAVMs and 171 unaffected controls. Genomic DNA was isolated from peripheral blood and the rs1333040C>T and rs7865618A>G polymorphisms were assessed by PCR-RFLP using the BsmI and MspI restriction endonucleases, respectively. For each SNP, we performed dominant, recessive, and additive genetic models. Results: The distribution of the three possible genotypes of rs1333040 (TT, TC and CC) was statistically different between cases and controls (p = 0.0008). The TT genotype was significantly associated with BAVMs both in the dominant (p = 0.013) and recessive (p = 0.012) models. The T allele was significantly associated with BAVMs in the additive model (p = 0.002). Also the distribution of the three possible genotypes of rs7865618 (GG, AG and AA) was statistically different between cases and controls (p = 0.005), and the GG genotype and G allele were significantly associated with BAVMs in the dominant (p = 0.032), recessive (p = 0.007), and additive models (p = 0.009). We also detected a significant association between BAVMs with large nidus size and the GG genotype and G allele of rs7865618 and the TT genotype of rs1333040. A deep venous drainage was instead associated with the TT genotype of the rs1333040 and the GG genotype of the rs7865618. The occurrence of bleeding was associated with the TT genotype and T allele of rs1333040, while the presence of seizures appeared associated with the GG genotype of rs7865618. Conclusions: SNPs of the 9p21 region, in addition to be genetic markers for coronary artery disease, stroke, and intracranial aneurysms, are associated with sporadic BAVMs. These results extend and strengthen the role of the 9p21 chromosomal region as a common risk factor for cerebrovascular diseases.

Genome-wide association study of sporadic brain arteriovenous malformations

“…[29] Interestingly, CDKN2B–AS1 is a non-coding RNA located within the CDKN2A–CDKN2B gene cluster on 9p21, the strongest genetic locus for cardiovascular diseases and linked to intracranial aneurysm. [32] More recently, the 9p21 SNP rs1333040 has been associated with BAVM,[15, 33] and replicated in our discovery cohort (Phase 1). However, this genetic association appears to be explained by the presence of BAVM-associated aneurysms.…”

“…[10][11][12][13][14][15] Of these, 57 SNPs were successfully genotyped in the replication cohort (call rate >96.9%). Samples with >10% missing genotypes were excluded, resulting in 608 cases and 744 controls.…”

“…Several common single nucleotide polymorphisms (SNPs) have been reported to be associated with BAVM. [10][11][12][13][14][15] Here, we report an estimate of heritability of BAVM and results from the first genomewide association study (GWAS) of common SNPs in Caucasian patients with BAVM, initiated by the Genetics of Arteriovenous Malformation (GEN-AVM) Consortium, a major international effort to better understand the genetics of BAVM.…”

Association ofCDKN2B-AS1rs1333049 with Brain Diseases: A Case-control Study and a Meta-analysis

“…SNP rs1333049 in CDKN2B-AS1 was located on chromosome 9p21.3, which was considered as the most widely and consistently replicated risk locus for cardiovascular and CDs. 29) Previous study showed that CDKN2B-AS1 polymorphism significantly associated with the risk of glioma by affecting the gliomagenesis. 35) The CDKN2B - AS1 polymorphism rs1333040 was located on the risk locus chromosome 9p21.3, and showed high linkage disequilibrium with rs1333049 (0.81≤r 2 ≤0.97) in previous studies.…”

Pathobiology of Cerebral Arteriovenous Malformations: Correlating Genetic Polymorphisms to Clinical Presentation and Nidus Angioarchitecture

“…I have read with interest a recent article in Cerebrovascular Diseases by Sturiale et al, entitled ‘Association between polymorphisms rs1333040 and rs7865618 of chromosome 9p21 and sporadic brain arteriovenous malformations' [1]. The authors analyzed single nucleotide polymorphisms (SNP) on the p21 locus of chromosome 9 in 206 patients with cerebral arteriovenous malformations (AVM), using 171 patients without intracranial vascular malformations as controls.…”