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首页> 外文期刊>Journal of stroke and cerebrovascular diseases: The official journal of National Stroke Association >Association of Rare Nonsynonymous Variants in PKD1 and PKD2 with Familial Intracranial Aneurysms in a Japanese Population
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Association of Rare Nonsynonymous Variants in PKD1 and PKD2 with Familial Intracranial Aneurysms in a Japanese Population

机译：PKD1和PKD2中罕见的非同义变体与日本人群家族性颅内动脉瘤的关联

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Background: Autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious mutations in PKD1 (16p13.3) and PKD2 (4q21) often coexists with intracranial aneurysms (IAs). In this study, we investigated whether IAs without obvious renal diseases were also associated with these ADPKD genes. Methods: We performed next-generation sequencing of the ADPKD genes in 150 Japanese familial IA patients and age- and sex-matched 150 non-IA controls without obvious renal diseases. Rare coding variants for the following association analysis were defined according to allelic frequencies of less than .5% either in our controls or in the 1000 genomes database. Association with IA was evaluated using burden and variance component methods: the weighted-sum statistic (WSS) and the sequence kernel association test (SKAT), respectively. Results: A total of 44 rare candidate variants were confirmed by Sanger sequencing; 26 were identified from 33 patients, whereas 21 were identified from 20 controls. The candidate variants were all missense variants, except for 1 patient's nonsense variant (p.Q924X) in PKD2, and showed consistent association with IA in both burden and variance component tests (odds ratio [ OR] = 1.80; WSS, P = .026; SKAT, P = .044). This association was largely derived from the variants found in the extracellular structural domains of PKD1 (OR = 2.06; WSS, P = .030; SKAT, P = .029). Conclusion: ADPKD genes are susceptibility genes for IA even in patients without ADPKD.
机译：背景：由PKD1（16p13.3）和PKD2（4q21）的有害突变引起的常染色体显性多囊肾疾病（ADPKD）通常与颅内动脉瘤（IAs）共存。在这项研究中，我们调查了没有明显肾脏疾病的IA是否也与这些ADPKD基因相关。方法：我们对150例日本家族性IA患者以及年龄和性别匹配的150例无明显肾脏疾病的非IA对照者进行了ADPKD基因的下一代测序。在我们的对照或1000个基因组数据库中，根据小于0.5％的等位基因频率，定义了用于以下关联分析的罕见编码变体。使用负担和方差成分方法评估与IA的关联：分别是加权和统计（WSS）和序列核关联检验（SKAT）。结果：通过Sanger测序共确认了44种稀有候选变体。从33名患者中鉴定出26名，而从20名对照中鉴定出21名。候选变体均为错义变体，除了PKD2中的1位患者的无意义变体（p.Q924X）外，并且在负担和方差成分检验中均显示与IA一致（奇数比[OR] = 1.80; WSS，P = .026） ; SKAT，P = .044）。这种关联主要源自在PKD1的细胞外结构域中发现的变异体（OR = 2.06; WSS，P = .030; SKAT，P = .029）。结论：即使没有ADPKD的患者，ADPKD基因也是IA的易感基因。

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