Genomics of cardiovascular phenotypes in sickle cell disease

提取 镰状细胞病（SCD）是一种遗传性疾病，具有高患病率、高死亡率和严重的公共卫生问题 率和有限的干预。基因组研究的进展为以下方面提供了前所未有的机会： 以综合方式应对SCD的健康挑战。镰状细胞病常见心脏受累 疾病（SCD），并与死亡率增加有关。心血管（CV）发病的主要原因 和死亡率是慢性血管闭塞伴缺血和心功能不全，慢性溶血性 贫血和慢性红细胞输注引起的继发性铁超负荷。这些最终在 心腔扩张和左心室（LV）质量代偿性增加;左心室 心室舒张功能障碍、心律失常和肺动脉高压（PH）导致右心室（RV） 功能障碍和猝死此外，患有SCD的成人具有显著更高的收缩压和平均收缩压。 如果他们有肺动脉高压（PAH），全身血压比那些没有PAH。的 某些CV异常的遗传易感性似乎也与 SCD严重溶血。虽然一些遗传变异已被描述为与PH 和心脏舒张功能障碍，与这些echo-CV表型相关的遗传学研究尚未被证实。 在居住在非洲的SCD患者中报告。有必要提供一个全面的了解， 遗传多样性是非洲SCD患者CV表型异质性的基础了解这些 这些因素将有助于确定可能在新的治疗中进行治疗操作的基因和途径， 接近。这项研究的首要目标是确定与舒张功能相关的常见遗传变异。 功能障碍和PH值。这将通过三个相互关联的具体目标来实现。我们将 研究了在尼日利亚和坦桑尼亚的4个机构登记的成人SCD患者的大队列。具体来说，我们将 定义主要回声心血管表型的全基因组遗传决定因素（心脏扩张， 心脏指数、血压、舒张功能不全、三尖瓣反流速度（TRJV）和RV 功能障碍）（目的1）。我们将确定是否全基因组的单核苷酸多态性与溶血水平 在本申请的配套项目中定义的细胞保护蛋白与特异性echo-CV相关， 表型（目标2）。最后，我们将使用转基因镰刀小鼠功能验证， 细胞保护蛋白水平与舒张功能障碍、PH和相对全身性高血压之间的关系 SCD（目标3）。该项目将是第一个表征与舒张功能障碍和PH相关的遗传学 在居住在非洲的SCD患者中。它将具有很高的翻译潜力，并可能提供机制的见解 并提出了可用于临床转化的新的治疗靶点。

ABTRACT Sickle cell disease (SCD) is a genetic disorder of public health significance with high prevalence, high mortality rate and limited interventions. Advancement in genomic research offers an unprecedented opportunity to address the health challenges of SCD in an integrated manner. Cardiac involvement is common in sickle cell disease (SCD) and is associated with increased mortality. The main causes of cardiovascular (CV) morbidity and mortality in SCD are chronic vaso-occlusion with ischemia and cardiac dysfunction, chronic hemolytic anaemia and secondary iron overload from chronic red blood cells transfusion. These culminate in the development of cardiac chamber dilation, and a compensatory increase in left ventricular (LV) mass; left ventricular diastolic dysfunction, dysrhythmia and pulmonary hypertension (PH) leading to right ventricular (RV) dysfunction, and sudden death. In addition, adults with SCD have significantly higher systolic and mean systemic blood pressures if they have pulmonary arterial hypertension (PAH), than in those without PAH. The genetic susceptibility to the development of some of these CV abnormalities also seems to be related to the severe hemolysis in SCD. Although some genetic variants have been described to be associated with both PH and diastolic dysfunction in SCD, genetic studies associated with these echo-CV phenotypes have not been reported in SCD patients who reside in Africa. There is a need to provide a thorough appreciation of the genetic diversity that underlies CV phenotypic heterogeneity in SCD patients in Africa. Knowledge of these factors will help to identify genes and pathways that might be therapeutically manipulated in novel treatment approaches. The overarching goal of this study is to identify common genetic variants associated with diastolic dysfunction and PH in adults with SCD. This will be achieved through three inter-related specific aims. We will study large cohorts of adult SCD patients enrolled in a 4 institution in Nigeria and Tanzania. Specifically we will define the genome-wide genetic determinants of major echo-cardiovascular phenotypes (cardiac dilation, cardiac index, blood pressure, diastolic dysfunction, tricuspid jet regurgitation velocity (TRJV) and RV dysfunction) (Aim 1). We will determine whether genome-wide SNPs associated with the level of hemolysis cytoprotective proteins to be defined in a companion project to this application are linked to specific echo-CV phenotypes (Aim 2). Finally, we will functionally validate using transgenic sickle mice, the associations between the level of cytoprotective proteins and diastolic dysfunction, PH and relative systemic hypertension in SCD (Aim 3). This project will be the first characterizing genetics associated with diastolic dysfunction and PH in SCD patients residing in Africa. It will have high translational potential and may provide mechanistic insight into cardiac disease in SCD and suggest new therapeutic targets that can be exploited for clinical translation.