Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections.
Recurrent chromosome 16p13.1 duplications are a risk factor for aortic dissections.
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DOI：
10.1371/journal.pgen.1002118
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发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
GenTAC Investigators
中科院分区：
文献类型：
--
作者：
Kuang SQ;Guo DC;Prakash SK;McDonald ML;Johnson RJ;Wang M;Regalado ES;Russell L;Cao JM;Kwartler C;Fraivillig K;Coselli JS;Safi HJ;Estrera AL;Leal SM;LeMaire SA;Belmont JW;Milewicz DM;GenTAC Investigators
16p13.1 区域的染色体缺失或相互重复与多种神经精神疾病有关，例如自闭症、精神分裂症、癫痫和注意力缺陷多动障碍 (ADHD)。在这项研究中，我们研究了复发性基因组拷贝数变异（CNV）与胸主动脉瘤和夹层（TAAD）的关联。通过使用 SNP 阵列进行筛选和比较基因组杂交微阵列进行验证，我们在 765 名成年发病 TAAD 的欧洲血统患者中发现了 8 名患者存在 16p13.1 重复，而在 4,569 名种族匹配的对照中则有 4 名患者出现了 16p13.1 重复（P = 5.0×10−5，OR = 12.2）。该研究结果在 467 名欧洲血统 TAAD 患者的独立队列中得到了重复（P = 0.005，OR = 14.7）。与无重复的患者相比，有 16p13.1 重复的患者更有可能出现第二个罕见的 CNV (P = 0.012) 并出现主动脉夹层 (P = 0.010)。在 130 名家族性 TAAD 患者中，有 2 名发现了 16p13.1 的重复，但这些重复并不与家族中的 TAAD 分离。 MYH11 是一种已知易患 TAAD 的基因，位于 16p13.1 的重复区域，与对照主动脉相比，在 16p13.1 重复的 TAAD 患者的主动脉组织中发现 MYH11 表达增加。这些数据表明，除了已确定的神经精神疾病风险之外，染色体 16p13.1 重复还会带来 TAAD 风险。它还表明，复发性 CNV 可能易患涉及多个器官系统的疾病，这一观察对于理解复发性 CNV 在人类疾病中的作用至关重要，并且这一发现对于涉及多个基因的其他复发性 CNV 可能是常见的。胸主动脉瘤和急性主动脉夹层（TAAD）已成为美国第十五大死因。 TAAD 可以以常染色体显性方式在家族中遗传，ACTA2 和 MYH11（编码平滑肌收缩单位两个主要成分的基因）的突变导致大约 15% 的家族性 TAAD。然而，大多数 TAAD 患者没有明确的综合征或主动脉疾病家族史，并且尚未确定导致这些散发病例的遗传因素。为了确定复发性基因组拷贝数变异 (CNV) 是否与 TAAD 发病机制有关，我们对 765 名成人发病的 TAAD 患者进行了 CNV 筛查，并在 1% 的 TAAD 病例中发现了复发性 16p13.1 重复，而对照组这一比例为 0.09%。 16p13.1重复涉及9个基因，包括MYH11。 16p13.1 的这种反复重复也已被确定与神经精神疾病有关，特别是精神分裂症和注意力缺陷多动障碍。我们的研究表明，16p13.1 的反复重复会带来神经精神疾病和 TAAD 的风险，这一发现对于涉及多个基因的其他复发性 CNV 可能很常见。
Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10−5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes. Thoracic aortic aneurysms and acute aortic dissections (TAAD) have ranked as high as the fifteenth leading cause of death in the United States. TAAD can be inherited in families in an autosomal dominant manner, and mutations in ACTA2 and MYH11, genes encoding two major components of the smooth muscle contractile unit, are responsible for approximately 15% of familial TAAD. However, the majority of patients with TAAD do not have an identified syndrome or family history of aortic disease, and genetic factors predisposing to these sporadic cases have not been identified. To determine whether recurrent genomic copy number variants (CNVs) contribute to TAAD pathogenesis, we screened 765 patients with adult-onset TAAD for CNVs and identified recurrent 16p13.1 duplications in 1% of TAAD cases compared with 0.09% of controls. The 16p13.1 duplication involves 9 genes, including MYH11. This recurrent duplication of 16p13.1 has also been determined to be associated with neuropsychiatric conditions, specifically schizophrenia and attention-deficit hyperactivity disorder. Our study suggests that recurrent duplications of 16p13.1 confer a risk for both neuropsychiatric diseases and TAAD, a finding that may be common to other recurrent CNVs involving multiple genes.
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