title: 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.
authors.affiliation: Institute of Neurosurgery, Catholic University School of Medicine, Rome, Italy.
authors.forename: Carmelo Lucio
authors.initials: CL
authors.lastname: Sturiale
authors.forename: Marco Maria
authors.initials: MM
authors.lastname: Fontanella
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gatto
authors.forename: Alfredo
authors.initials: A
authors.lastname: Puca
authors.forename: Igor
authors.initials: I
authors.lastname: Giarretta
authors.forename: Sonia
authors.initials: S
authors.lastname: D'Arrigo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lofrese
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.forename: Salvatore
authors.initials: S
authors.lastname: Gallone
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pinessi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ducati
authors.forename: Giulio
authors.initials: G
authors.lastname: Maira
authors.forename: Roberto
authors.initials: R
authors.lastname: Pola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012306:Risk; D055815:Young Adult