Sturiale Carmelo Lucio, Fontanella Marco Maria, Gatto Ilaria, Puca Alfredo, Giarretta Igor, D'Arrigo Sonia, Lofrese Giorgio, Rainero Innocenzo, Gallone Salvatore, Pinessi Lorenzo, Ducati Alessandro, Maira Giulio, Pola Roberto
Institute of Neurosurgery, Catholic University School of Medicine, Rome, Italy.
Cerebrovasc Dis. 2014;37(4):290-5. doi: 10.1159/000360752. Epub 2014 May 7.
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.
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.
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.
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.
染色体位点9p21是多种心血管和脑血管疾病的新型遗传标志物。在最近的一项研究中，我们已经证明染色体9p21上的单核苷酸多态性（SNP）rs1333040C>T与散发性脑动静脉畸形（BAVMs）之间存在关联。在此，我们将分析扩展至染色体9p21上的另一个SNP（rs7865618A>G），并增加了样本量，纳入了来自两个不同意大利神经外科中心的BAVMs病例。
我们研究了206例散发性BAVMs患者和171名未受影响的对照者。从外周血中分离基因组DNA，分别使用BsmI和MspI限制性内切酶通过PCR-RFLP评估rs1333040C>T和rs7865618A>G多态性。对于每个SNP，我们进行了显性、隐性和加性遗传模型分析。
rs1333040的三种可能基因型（TT、TC和CC）在病例组和对照组之间的分布存在统计学差异（p = 0.0008）。在显性模型（p = 0.013）和隐性模型（p = 0.012）中，TT基因型均与BAVMs显著相关。在加性模型中，T等位基因与BAVMs显著相关（p = 0.002）。rs7865618的三种可能基因型（GG、AG和AA）在病例组和对照组之间的分布也存在统计学差异（p = 0.005），在显性模型（p = 0.032）、隐性模型（p = 0.007）和加性模型（p = 0.009）中，GG基因型和G等位基因均与BAVMs显著相关。我们还检测到大型病灶的BAVMs与rs7865618的GG基因型和G等位基因以及rs1333040的TT基因型之间存在显著关联。相反，深部静脉引流与rs1333040的TT基因型和rs7865618的GG基因型相关。出血的发生与rs1333040的TT基因型和T等位基因相关，而癫痫发作的存在似乎与rs7865618的GG基因型相关。
9p21区域的SNP，除了作为冠状动脉疾病、中风和颅内动脉瘤的遗传标志物外，还与散发性BAVMs相关。这些结果扩展并强化了9p21染色体区域作为脑血管疾病常见危险因素的作用。
