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Hypertension and Brachydactyly Syndrome Associated With Vertebral Artery Malformation Caused by a PDE3A Missense Mutation.

PDE3A 错义突变引起的椎动脉畸形相关的高血压和短指畸形综合征。

  • 影响因子:2.49
  • DOI:10.1093/ajh/hpz151
  • 作者列表:"Fan P","Zhang D","Yang KQ","Zhang QY","Luo F","Lou Y","Liu YX","Zhang HM","Song L","Cai J","Wu HY","Zhou XL
  • 发表时间:2020-02-22

BACKGROUND:Hypertension and brachydactyly syndrome (HTNB), also called Bilginturan syndrome, is a rare autosomal dominant disorder characterized by severe salt-independent hypertension, a short stature, brachydactyly, and death from stroke before the age of 50 years when untreated. The purpose of the present study was to identify a PDE3A mutation leading to HTNB associated with vertebral artery malformation in a Chinese family. METHODS:Peripheral blood samples were collected from all subjects for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the PDE3A mutation. A comparative overview was performed in the probands with HTNB caused by PDE3A mutations. RESULTS:Genetic analysis identified a missense mutation in PDE3A, c.1346G>A, in the proband with HTNB. This mutation, resulting in p.Gly449Asp, was located in a highly conserved domain and predicted to be damaging by different bioinformatics tools. Cosegregation analyses showed that the proband inherited the identified mutation from her father. Antihypertensive therapy was effective for the proband. Comparative overview of HTNB probands with 9 different PDE3A mutations revealed phenotypic heterogeneity. CONCLUSIONS:Genetic screening can significantly improve the diagnosis of HTNB patients at an early age. Our study not only adds to the spectrum of PDE3A mutations in the Chinese population and extends the phenotype of HTNB patients to include vertebral malformation but also improves the awareness of pathogenesis in HTNB patients. We emphasize the importance of antihypertensive treatment and long-term follow-up to prevent stroke and adverse cardiovascular events.


背景: 高血压和短指畸形综合征 (HTNB),又称 Bilginturan 综合征,是一种罕见的常染色体显性遗传病,以严重的非盐依赖性高血压、身材矮小、短指畸形、 50 岁以前因中风而死亡时不予治疗。本研究的目的是在一个中国家族中确定一个导致 HTNB 相关椎动脉畸形的 PDE3A 突变。 方法: 采集所有受试者的外周血标本进行 DNA 提取。进行了新一代测序和 Sanger 测序以鉴定 PDE3A 突变。对 PDE3A 突变引起的 HTNB 先证者进行了比较概述。 结果: 遗传分析确定了 HTNB 先证者中 PDE3A 的一个错义突变,c.1346G> a。这种突变,导致 p.Gly449Asp,位于一个高度保守的结构域,并被不同的生物信息学工具预测具有破坏性。共遗传分析表明,先证者从她父亲那里继承了已鉴定的突变。对先证者降压治疗有效。具有 9 种不同 PDE3A 突变的 HTNB 先证者的比较概述揭示了表型异质性。 结论: 基因筛查可显著提高早期诊断 HTNB 患者的水平。我们的研究不仅增加了中国人群中 PDE3A 突变的谱,扩展了 HTNB 患者的表型,包括椎体畸形,而且提高了对 HTNB 患者发病机制的认识。我们强调降压治疗和长期随访对预防卒中和不良心血管事件的重要性。



作者列表:["Simard JF","Rossides M","Arkema EV","Svenungsson E","Wikström AK","Mittleman MA","Salmon JE"]

METHODS:BACKGROUND:Hypertensive disorders of pregnancy (HDP) increase cardiovascular disease (CVD) risk. Pregnancy morbidities, including preeclampsia, and CVD are common in systemic lupus erythematosus (SLE). Possible connections are important to explore. In a population-based cohort, we investigated whether HDP is associated with a higher risk of cardiovascular outcomes separately in SLE and non-SLE to examine the role of SLE. METHODS:We identified first singleton births in the Medical Birth Register (1987-2012) among mothers with SLE and a large general population comparison group. Discharge diagnoses for HDP, cardiovascular outcomes, and hypertension in the Patient Register were identified using ICD codes. We estimated adjusted hazard ratios and 95% confidence intervals (HR, 95% CI) of the association between HDP and outcomes, in separate models in women with and without SLE. We then evaluated additive and multiplicative effect modification using relative excess risk due to interaction and Cox models jointly accounting for SLE and HDP, respectively. Mediation analysis estimated the proportion of the association between SLE and outcome explained by HDP. RESULTS:HDP were more common in SLE pregnancies (20% vs 7%). In SLE, HDP were associated with a two-fold higher rate of cardiovascular outcomes and three-fold higher rate of incident hypertension. HDP mediated 20% of the latter association. In women without SLE, HDP was associated with higher hypertension incidence later in life. CONCLUSION:In women with and without SLE, HDP were associated with a three-fold higher rate of hypertension. In SLE, women with HDP developed cardiovascular outcomes twice as often as women without HDP.

翻译标题与摘要 下载文献
作者列表:["Zhang J","Gong WY","Liu M","Zhou W","Rao J","Li YQ","Wu JH","Luo D","Wang C","Peng H"]

METHODS:BACKGROUND:'Neuronal precursor cell expressed developmentally down-regulated 4-like' (NEDD4L) is considered a candidate gene for hypertension-both functionally and genetically-through the regulation of the ubiquitination of the epithelial sodium channel (ENaC). This study explores the relationship between genetic variation in NEDD4L and hypertension with chronic kidney disease (CKD) in the southeastern Han Chinese population. METHODS:We recruited 623 CKD patients and measured ambulatory blood pressure monitoring (ABPM), and the rs4149601 and rs2288774 polymorphisms in NEDD4L were genotyped using qPCR. RESULTS:For rs4149601, significant differences in genotype frequencies in an additive model (GG vs GA vs AA) were observed between normotensive patients and hypertensive patients when hypertension was classified into ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension (P = 0.038, 0.005 and 0.006, respectively). In a recessive model (GG+GA vs AA), the frequency of the AA genotype of rs4149601 in the hypertension groups were all higher than that in the normotensive groups. The genotype distribution of rs2288774 did not differ significantly between the normotensive and hypertensive patients. In both the full cohort and the propensity score matching (PSM) cohort, the AA genotype of rs4149601 (compared to the GG+GA genotype group) was independently correlated with ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension by multivariate logistic regression analysis. CONCLUSIONS:The present study indicates that the AA genotype of rs4149601 associates with hypertension in CKD. Consequently, the rs4149601 A allele might be a risk factor for hypertension with CKD.

翻译标题与摘要 下载文献
作者列表:["Gyamfi J","Allegrante JP","Iwelunmor J","Williams O","Plange-Rhule J","Blackstone S","Ntim M","Apusiga K","Peprah E","Ogedegbe G"]

METHODS:BACKGROUND:The burden of hypertension in many low-and middle-income countries is alarming and requires effective evidence-based preventative strategies that is carefully appraised and accepted by key stakeholders to ensure successful implementation and sustainability. We assessed nurses' perceptions of a recently completed Task Shifting Strategy for Hypertension control (TASSH) trial in Ghana, and facilitators and challenges to TASSH implementation. METHODS:Focus group sessions and in-depth interviews were conducted with 27 community health nurses from participating health centers and district hospitals involved in the TASSH trial implemented in the Ashanti Region, Ghana, West Africa from 2012 to 2017. TASSH evaluated the comparative effectiveness of the WHO-PEN program versus provision of health insurance for blood pressure reduction in hypertensive adults. Qualitative data were analyzed using open and axial coding techniques with emerging themes mapped onto the Consolidated Framework for Implementation Research (CFIR). RESULTS:Three themes emerged following deductive analysis using CFIR, including: (1) Patient health goal setting- relative priority and positive feedback from nurses, which motivated patients to make healthy behavior changes as a result of their health being a priority; (2) Leadership engagement (i.e., medical directors) which influenced the extent to which nurses were able to successfully implement TASSH in their various facilities, with most directors being very supportive; and (3) Availability of resources making it possible to implement the TASSH protocol, with limited space and personnel time to carry out TASSH duties, limited blood pressure (BP) monitoring equipment, and transportation, listed as barriers to effective implementation. CONCLUSION:Assessing stakeholders' perception of the TASSH implementation process guided by CFIR is crucial as it provides a platform for the nurses to thoroughly evaluate the task shifting program, while considering the local context in which the program is implemented. The feedback from the nurses informed barriers and facilitators to implementation of TASSH within the current healthcare system, and suggested system level changes needed prior to scale-up of TASSH to other regions in Ghana with potential for long-term sustainment of the task shifting intervention. TRIAL REGISTRATION:Trial registration for parent TASSH study: NCT01802372. Registered February 27, 2013.