Laboratorio de Genetica e Cardiologia Molecular, Faculdade Medicina da Universidade de São Paulo, Instituto do Coracao (InCor) HC.FMUSP, Av Dr Eneas C Aguiar 44, São Paulo, SP, 05403-000, Brazil.
Curr Hypertens Rep. 2018 May 19;20(6):48. doi: 10.1007/s11906-018-0852-4.
Blood pressure regulation in humans has long been known to be a genetically determined trait. The identification of causal genetic modulators for this trait has been unfulfilling at the least. Despite the recent advances of genome-wide genetic studies, loci associated with hypertension or blood pressure still explain a very low percentage of the overall variation of blood pressure in the general population. This has precluded the translation of discoveries in the genetics of human hypertension to clinical use. Here, we propose the combined use of resistant hypertension as a trait for mapping genetic determinants in humans and the integration of new large-scale technologies to approach in model systems the multidimensional nature of the problem.
New large-scale efforts in the genetic and genomic arenas are paving the way for an increased and granular understanding of genetic determinants of hypertension. New technologies for whole genome sequence and large-scale forward genetic screens can help prioritize gene and gene-pathways for downstream characterization and large-scale population studies, and guided pharmacological design can be used to drive discoveries to the translational application through better risk stratification and new therapeutic approaches. Although significant challenges remain in the mapping and identification of genetic determinants of hypertension, new large-scale technological approaches have been proposed to surpass some of the shortcomings that have limited progress in the area for the last three decades. The incorporation of these technologies to hypertension research may significantly help in the understanding of inter-individual blood pressure variation and the deployment of new phenotyping and treatment approaches for the condition.
人类的血压调节一直以来被认为是一种由基因决定的特征。至少可以说，确定这种特征的因果遗传调节剂的工作并不令人满意。尽管最近全基因组遗传研究取得了进展，但与高血压或血压相关的基因座仍然只能解释一般人群血压总体变异的很小一部分。这使得人类高血压遗传学方面的发现无法转化为临床应用。在这里，我们提出将耐药性高血压作为一种在人类中映射遗传决定因素的特征，并整合新的大规模技术，以模型系统来解决问题的多维性质。
遗传和基因组领域的新的大规模努力正在为增加和细化对高血压遗传决定因素的理解铺平道路。全基因组测序和大规模正向遗传筛选的新技术可以帮助优先考虑基因和基因途径，进行下游特征描述和大规模人群研究，并且可以通过更好的风险分层和新的治疗方法，指导药物设计将发现转化为应用。尽管在映射和鉴定高血压的遗传决定因素方面仍然存在重大挑战，但已经提出了新的大规模技术方法来克服过去三十年来限制该领域进展的一些缺点。将这些技术纳入高血压研究可能会极大地帮助我们理解个体间血压变异，并为该疾病部署新的表型和治疗方法。
