A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension.
A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension.
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DOI：
10.1186/s12890-017-0400-z
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发表时间：
2017-04-07
影响因子：
3.1
通讯作者：
Matsuda F
中科院分区：
文献类型：
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作者：
Higasa K;Ogawa A;Terao C;Shimizu M;Kosugi S;Yamada R;Date H;Matsubara H;Matsuda F
肺动脉高压（PAH）是一种严重的肺部疾病，只有少数有效的治疗方法。家族性PAH病例通常被认为是一种常染色体显性疾病，但该疾病的不完全外显率使得根据孟德尔遗传模式识别致病变异变得困难。为了阐明PAH的复杂遗传基础，我们获得了来自9个遗传性PAH家族的17名受试者的全外显子组或基因组测序数据，并对9名指数患者和300名无PAH的对照组进行了基于基因的关联分析。BMPR2罕见变异的负担显著增加了该疾病的风险（p = 6.0 × 10−8）。9个家族中有8个携带了4个先前报道的单核苷酸变异和4个新的插入/删除基因变异。其中一个新变异是6.5千碱基的大缺失。在剩下的一个家庭中，患者携带钾通道成员KCNK3的致病变异，这是亚洲人群中首次发现的通道病的复制性变异。罕见致病变异的多样性表明，利用来自越来越多样本的全基因组测序数据进行基于基因的关联分析，对于追踪遗传异质性和开发适当的基因检测小组至关重要。本文的在线版本（doi:10.1186/s12890-017-0400-z）包含补充材料，可供授权用户使用。
Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance. To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls. A burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10−8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population. The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing. The online version of this article (doi:10.1186/s12890-017-0400-z) contains supplementary material, which is available to authorized users.