Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk
Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk
复制标题
DOI：
10.1073/pnas.1117137108
复制
发表时间：
2011-12-06
影响因子：
11.1
通讯作者：
Guenel, Murat
中科院分区：
文献类型：
--
作者：
Yasuno, Katsuhito;Bakircioglu, Mehmet;Guenel, Murat
颅内动脉瘤（IA）的形成和破裂的发病机制是复杂的，与遗传因素的显着贡献。我们先前报道了基于欧洲发现和日本复制队列的全基因组关联研究，其中5，891例病例和14，181例对照确定了5个疾病相关位点。这些研究是基于检测发现队列中包含后验关联概率（PPA）大于0.5的SNP的基因组区域的复制。为了确定额外的IA风险基因座，我们在发现队列中追踪了PPA在0.1和0.5之间的14个基因座。使用两个独立的日本队列对来自这些基因座的25个SNP进行基因分型，并通过荟萃分析将来自发现和复制队列的结果合并。结果显示IA与染色体4q31.23上的rs6841581显著相关，紧邻A型内皮素受体的5'端，P = 2.2 × 10（-8）[比值比（OR）= 1.22，PPA = 0.986]。我们还观察到染色体12 q22（OR = 1.16，P = 1.1 × 10（-7），PPA = 0.934）和20p12.1（OR = 1.20，P = 6.9 × 10（-7），PPA = 0.728）上的其他两个区域的关联证据显著增加。虽然内皮素信号转导已被假设在各种心血管疾病中发挥作用超过二十年，我们的研究结果是独特的，提供了遗传证据与IA的显着关联，并表明内皮素通路的操纵可能有重要的意义，预防和治疗IA。
The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5' of the endothelin receptor type A with P = 2.2 x 10(-8) [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 x 10(-7), PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 x 10(-7), PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.