Genetics and genomics of pulmonary arterial hypertension.
Genetics and genomics of pulmonary arterial hypertension.
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DOI：
10.1016/j.jacc.2009.04.015
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发表时间：
2009-06-30
影响因子：
24
通讯作者：
Chung, Wendy K.
中科院分区：
文献类型：
--
作者：
Machado, Rajiv D.;Eickelberg, Oliver;Elliott, C. Gregory;Geraci, Mark W.;Hanaoka, Masayuki;Loyd, James E.;Newman, John H.;Phillips, John A., III;Soubrier, Florent;Trembath, Richard C.;Chung, Wendy K.
肺动脉高压 (PAH) 是一种罕见疾病，可能是遗传性 (HPAH)、特发性 (IPAH)，或与药物毒素暴露或其他医疗状况有关。家族性病例早已被认识到，通常是由于 2 型骨形态发生蛋白受体基因 (BMPR2) 突变，或者更不常见的是，转化生长因子-β 超家族的其他 2 个成员，激活素样激酶 I 型 (ALK1) 和内皮糖蛋白 (ENG)，它们与遗传性出血性毛细血管扩张症相关。此外，大约 20% 的 IPAH 患者携带 BMPR2 突变。我们总结了与 IPAH/HPAH 相关的 BMPR2 突变，其中大多数突变对于每个家族来说都是独特的，并且推测会导致功能丧失。我们回顾了在 IPAH/HPAH、芬氟拉明暴露以及与先天性心脏病相关的 PAH 中 BMPR2 中错义变异和未知意义变异的发现。 BMPR2 突变的临床检测是可用的，并且可以向 HPAH 和 IPAH 患者提供，但应先进行遗传咨询，因为终生外显率仅为 10%–20%，而且目前尚无已知的有效预防措施。家族突变的识别对于生殖计划和识别非突变携带者的家庭成员非常有价值，因此不需要终身监测。随着基因组技术的进步和国际合作的努力，将进行全基因组关联研究，以确定 HPAH 的其他基因、BMPR2 外显率的遗传修饰剂以及 IPAH 的遗传易感性。此外，BMPR2突变携带者的合作研究应该能够识别环境调节剂、疾病发生和进展的生物标志物以及临床药物开发中疗效终点的替代标志物，从而为PAH预防试验提供宝贵的资源。
Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognised and are usually due to mutations in Bone Morphogenetic Protein Receptor type 2 gene (BMPR2), or, much less commonly, 2 other members of the transforming growth factor-beta superfamily, Activin-like Kinase-Type I (ALK1) and Endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. We provide a summary of BMPR2 mutations associated with IPAH/HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counselling, since lifetime penetrance is only 10%–20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance, and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.
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影响因子：
10
作者：
Chaouat, A;Coulet, F;Humbert, M
通讯作者：
Humbert, M
影响因子：
3.9
作者：
Aldred, Micheala A.;Vijayakrishnan, Jairam;Trembath, Richard C.
通讯作者：
Trembath, Richard C.
影响因子：
8.8
作者：
Cogan, JD;Vnencak-Jones, CL;Loyd, JE
通讯作者：
Loyd, JE
影响因子：
37.8
作者：
Elliott, C. Gregory;Glissmeyer, Eric W.;Ward, Kenneth
通讯作者：
Ward, Kenneth
影响因子：
3.3
作者：
Fujiwara, Maya;Yagi, Hisato;Saji, Tsutomu
通讯作者：
Saji, Tsutomu