肺动脉高压患者外周血中BMPR2基因表达降低:病情严重程度的标志?

2022-06-27 刘少飞 MedSci原创

肺动脉高压(PAH)可由BMPR2基因的致病变体引起。虽然已知BMPR2蛋白表达水平在遗传性PAH(HPAH)患者的肺部组织中降低,但还缺乏评估更容易获得的血液样本中的表达及其临床相关性系统研究。

肺动脉高压(PAH)的特点是进行性肺血管重塑,导致肺血管阻力增加、右心室肥大,最终导致右心衰竭。截至目前,在遗传性PAH(HPAH)中已经描述了18个基因的不同致病种系变异,其中新的基因正在不断被发现。骨生成蛋白受体II型(BMPR2)基因突变,在约50-80%的HPAH患者和约15-20%的特发性PAH(IPAH)患者中被发现。这些致病变体以常染色体显性方式遗传,但外显率降低。因此,并非所有携带致病变体的家族成员都会出现明显的PAH。外显率降低的原因可能是野生型变异体在杂合子携带者中表达较高,或者需要额外的疾病诱因,如另一个致病变异体作为受影响患者的 "第二次打击"。在健康的肺组织中,BMPR2主要表达于内皮细胞。在PAH患者中,BMPR2的表达也可以在内皮细胞和丛状病变的肌成纤维细胞中检测到。然而,在BMPR2变异体携带者的肺内皮细胞中,BMPR2蛋白表达大大降低。与健康对照组相比,非变异体携带者的表达量减少不明显,但仍有很大的意义。

与BMPR2变异体破坏重要的分子通路相一致,变异体携带者的疾病严重性已被证明明显恶化。与非变异体携带者相比,具有BMPR2基因致病变异的HPAH患者具有诊断年龄早、血流动力学差、肺移植率高以及全因死亡率高等特点。因此,定期对表面上健康的BMPR2变异体携带者进行临床筛查,以尽早发现可能的疾病发生是很重要的。早期发现可以在早期阶段开始治疗,并可能导致更好的结果。由于PAH患者的肺部活检有很高的发病率和死亡率风险,该研究的目标是,首先,澄清BMPR2 mRNA和蛋白的血液表达水平在受影响的BMPR2变异体携带者中是否与非变异体携带者和健康对照者有差异;其次,旨在将BMPR2 mRNA和蛋白的血液表达水平与临床和实验室参数相关联。

研究设计

这是一项前瞻性、探索性、横断面研究,调查PAH患者和健康对照者血液中BMPR2的RNA和蛋白表达水平。大多数患者是在德国海德堡大学医院Thoraxklinik Heidelberg gGmbH的肺动脉高压中心诊断和治疗的。其中3名BMPR2变异体携带者在德国德累斯顿卡尔-古斯塔夫-卡洛斯大学医院接受治疗,4名在德国莱比锡大学医院接受治疗。如果进行常规抽血,则邀请年龄和性别匹配的健康对照组参加。

图1. 从2019年5月到2020年1月招募研究人群。筛选了110名参与者,并收集了其中的109份样本进行分析和纳入。BMPR2:骨形态发生蛋白受体II型,PAH:肺动脉高压,PVOD:肺静脉闭塞症。

 

BMPR2的特征和表达

23名变异体携带者的BMPR2基因的致病变体被描述为碱基对缺失(n = 7)或重复(n = 2)导致的框架移位、整个外显子缺失(n = 2)、整个外显子重复(n = 1)、剪接点变异(n = 6)或无意义(n = 5)变异。通过qPCR测量的全血中BMPR2 mRNA表达水平在BMPR2变异体携带者、非携带者和健康对照者之间存在明显差异(P < 0.0001,图2)。BMPR2变异体携带者的表达水平最低。与健康对照组相比,非携带者的BMPR2 mRNA表达量较低,没有统计学意义(p = 0.151,图2)。两个具有GDF2或SMAD9基因致病变体的IPAH患者的BMPR2 mRNA表达水平(分别为0.394和0.433)低于BMPR2非携带者组的平均值(0.445),尽管其数值高于BMPR2变体携带者组的平均值(0.353)。

图2. 全血中相对BMPR2 mRNA表达的平均值。

BMPR2 mRNA的表达与进一步的实验室和临床特征的相关性

BMPR2 mRNA的低表达与低肾小球滤过率、高血细胞比容和高尿素水平有微弱但明显的相关性(表2)。BMPR2 mRNA表达较低的患者通过右心导管检查和超声心动图测量的收缩期肺动脉压力(sPAP)明显较高,右心室壁厚度较大,肺血管阻力较大,心脏指数较低,6分钟步行距离较短。

研究讨论:

这项研究显示,与健康对照组相比,具有(可能)致病性BMPR2变异体的PAH患者外周血中测得的BMPR2 mRNA水平明显降低。非变异体携带者显示出BMPR2 mRNA表达水平降低的趋势。此外,该研究首次揭示了在血细胞中测得的较低的BMPR2 mRNA表达水平与血液动力学和实验室参数的较差值之间存在明显的相关性。特别是,BMPR2 mRNA的低表达与血流动力学恶化和运动能力降低的显著相关性表明,这种分析可作为反映潜在病理机制的疾病严重程度的标志。

研究不足之处:

由于时间上的限制,本研究没有招募无症状的BMPR2变异体携带者。因此,我们将在随后的更大规模的前瞻性研究中评估BMPR2变异体携带者和未受影响携带者的表达差异。此外,样本量不够大,无法研究不同类型的致病变体(如无义变体或框移变体)患者之间的表达水平差异。蛋白质BMPR2的表达在我们患者的血清中没有显示出明显不同的水平。这也可能是由于BMPR2是一种跨膜蛋白的性质,它在血清中的存在水平应该较低。最后,该研究只包括一个时间点的测量。需要进一步研究纵向测量,不仅为稳定期患者的病内测量提供一个范围,而且要确定治疗变化或临床恶化时BMPR2 mRNA的表达变化。

参考文献:

Theobald V, Benjamin N, Seyfarth HJ, Halank M, Schneider MA, Richtmann S, Hinderhofer K, Xanthouli P, Egenlauf B, Seeger R, Hoeper MM, Jonigk D, Grünig E, Eichstaedt CA. Reduction of BMPR2 mRNA Expression in Peripheral Blood of Pulmonary Arterial Hypertension Patients: A Marker for Disease Severity? Genes (Basel). 2022 Apr 26;13(5):759. doi: 10.3390/genes13050759. PMID: 35627145.

 

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createdName=docwu2019, createdTime=Sat Nov 05 08:24:13 CST 2022, time=2022-11-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1808670, encodeId=0a8718086e04a, content=<a href='/topic/show?id=eade820e7c0' target=_blank style='color:#2F92EE;'>#肺动脉高压患者#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=82077, encryptionId=eade820e7c0, topicName=肺动脉高压患者)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5b0e350, createdName=naiwu77, createdTime=Wed Aug 03 16:24:13 CST 2022, time=2022-08-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1229053, encodeId=8c5e1229053f6, content=学习了,谢谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7c592194322, createdName=1209e435m98(暂无昵称), createdTime=Mon Jun 27 23:25:33 CST 2022, time=2022-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223816, encodeId=d2fc122381617, content=学到了<a href='/topic/show?id=23e3454e353' target=_blank style='color:#2F92EE;'>#学习#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=131, replyNumber=1, topicName=null, topicId=null, topicList=[TopicDto(id=45473, encryptionId=23e3454e353, topicName=学习)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4e2b8180400, createdName=ms3000001364860097, createdTime=Wed Jun 01 11:09:39 CST 2022, time=2022-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1224077, encodeId=789512240e7f4, content=欢迎关注肺动脉高压研究进展, beContent=null, objectType=article, channel=null, level=null, likeNumber=65, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=[AttachmentDto(url=https://img.medsci.cn/comment/20220602/a915adf507c54b488b6b3dcc29a79272.jpg, type=image, width=258, height=258)], authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210922/abdffc3f4cb6439aa9fa85372323b9ec/5f4b4012b21a4508af5a117375a9f3e2.jpg, createdBy=1bd41976717, createdName=SophylioJerry, createdTime=Thu Jun 02 16:17:24 CST 2022, time=2022-06-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1348145, encodeId=9f65134814588, content=<a href='/topic/show?id=d61b418860a' target=_blank style='color:#2F92EE;'>#基因表达#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41886, encryptionId=d61b418860a, topicName=基因表达)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=395f25, createdName=bioon1, createdTime=Wed Jun 01 12:24:13 CST 2022, time=2022-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1578593, encodeId=d47c15e85935f, content=<a href='/topic/show?id=fd724282021' target=_blank style='color:#2F92EE;'>#外周血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42820, encryptionId=fd724282021, topicName=外周血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a31916414168, createdName=ms3994565386320060, createdTime=Wed Jun 01 12:24:13 CST 2022, time=2022-06-01, status=1, ipAttribution=)]
    2023-04-14 HNYYM
  4. [GetPortalCommentsPageByObjectIdResponse(id=2145963, encodeId=65c821459637c, content=师兄写得好, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d2098301191, createdName=ms3000001395116270, createdTime=Sun Jul 02 15:53:00 CST 2023, time=2023-07-02, status=1, ipAttribution=北京), GetPortalCommentsPageByObjectIdResponse(id=1765186, encodeId=0c851e65186cc, content=<a href='/topic/show?id=df00e086653' target=_blank style='color:#2F92EE;'>#病情#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70866, encryptionId=df00e086653, topicName=病情)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Fri Mar 24 15:24:13 CST 2023, time=2023-03-24, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=1578593, encodeId=d47c15e85935f, content=<a href='/topic/show?id=fd724282021' target=_blank style='color:#2F92EE;'>#外周血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42820, encryptionId=fd724282021, topicName=外周血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a31916414168, createdName=ms3994565386320060, createdTime=Wed Jun 01 12:24:13 CST 2022, time=2022-06-01, status=1, ipAttribution=)]
  5. [GetPortalCommentsPageByObjectIdResponse(id=2145963, encodeId=65c821459637c, content=师兄写得好, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d2098301191, createdName=ms3000001395116270, createdTime=Sun Jul 02 15:53:00 CST 2023, time=2023-07-02, status=1, ipAttribution=北京), GetPortalCommentsPageByObjectIdResponse(id=1765186, encodeId=0c851e65186cc, content=<a href='/topic/show?id=df00e086653' target=_blank style='color:#2F92EE;'>#病情#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70866, encryptionId=df00e086653, topicName=病情)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Fri Mar 24 15:24:13 CST 2023, time=2023-03-24, status=1, ipAttribution=), 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createdName=1209e435m98(暂无昵称), createdTime=Mon Jun 27 23:25:33 CST 2022, time=2022-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223816, encodeId=d2fc122381617, content=学到了<a href='/topic/show?id=23e3454e353' target=_blank style='color:#2F92EE;'>#学习#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=131, replyNumber=1, topicName=null, topicId=null, topicList=[TopicDto(id=45473, encryptionId=23e3454e353, topicName=学习)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4e2b8180400, createdName=ms3000001364860097, createdTime=Wed Jun 01 11:09:39 CST 2022, time=2022-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1224077, encodeId=789512240e7f4, content=欢迎关注肺动脉高压研究进展, beContent=null, objectType=article, channel=null, level=null, likeNumber=65, replyNumber=0, topicName=null, topicId=null, topicList=[], 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GetPortalCommentsPageByObjectIdResponse(id=1578593, encodeId=d47c15e85935f, content=<a href='/topic/show?id=fd724282021' target=_blank style='color:#2F92EE;'>#外周血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42820, encryptionId=fd724282021, topicName=外周血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a31916414168, createdName=ms3994565386320060, createdTime=Wed Jun 01 12:24:13 CST 2022, time=2022-06-01, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=2145963, encodeId=65c821459637c, content=师兄写得好, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d2098301191, createdName=ms3000001395116270, createdTime=Sun Jul 02 15:53:00 CST 2023, time=2023-07-02, status=1, ipAttribution=北京), GetPortalCommentsPageByObjectIdResponse(id=1765186, encodeId=0c851e65186cc, content=<a href='/topic/show?id=df00e086653' target=_blank style='color:#2F92EE;'>#病情#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=70866, encryptionId=df00e086653, topicName=病情)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=778d36, createdName=柳叶一刀, createdTime=Fri Mar 24 15:24:13 CST 2023, time=2023-03-24, status=1, ipAttribution=), 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GetPortalCommentsPageByObjectIdResponse(id=1578593, encodeId=d47c15e85935f, content=<a href='/topic/show?id=fd724282021' target=_blank style='color:#2F92EE;'>#外周血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=42820, encryptionId=fd724282021, topicName=外周血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a31916414168, createdName=ms3994565386320060, createdTime=Wed Jun 01 12:24:13 CST 2022, time=2022-06-01, status=1, ipAttribution=)]
    2022-06-27 1209e435m98(暂无昵称)

    学习了,谢谢分享

    0

  7. 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    2022-06-01 ms3000001364860097

    学到了#学习#

    1

    展开1条回复
  8. 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createdName=1209e435m98(暂无昵称), createdTime=Mon Jun 27 23:25:33 CST 2022, time=2022-06-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1223816, encodeId=d2fc122381617, content=学到了<a href='/topic/show?id=23e3454e353' target=_blank style='color:#2F92EE;'>#学习#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=131, replyNumber=1, topicName=null, topicId=null, topicList=[TopicDto(id=45473, encryptionId=23e3454e353, topicName=学习)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4e2b8180400, createdName=ms3000001364860097, createdTime=Wed Jun 01 11:09:39 CST 2022, time=2022-06-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1224077, encodeId=789512240e7f4, content=欢迎关注肺动脉高压研究进展, beContent=null, objectType=article, channel=null, level=null, likeNumber=65, replyNumber=0, topicName=null, topicId=null, topicList=[], 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  9. 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  10. 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