Genomics of cardiovascular phenotypes in sickle cell disease

减去 摘要镰状细胞病是一种高发病率、高死亡率的遗传性疾病，具有公共卫生意义。 比率和有限的干预措施。基因组研究的进步提供了一个前所未有的机会 以综合方式应对慢性阻塞性肺病的健康挑战。心脏受累常见于镰状细胞 疾病(SCD)，并与增加的死亡率有关。心血管(CV)发病的主要原因 SCD的死亡率为慢性血管闭塞伴缺血和心功能不全、慢性溶血 慢性红细胞输注引起的贫血和继发性铁超载。这些最终会在 发展为心腔扩张，左心室(LV)质量代偿性增加 导致右室的室舒张功能不全、心律失常和肺动脉高压(PH) 功能障碍和猝死。此外，患有SCD的成年人的收缩压和平均动脉压显著高于对照组。 如果他们有肺动脉高压(PAH)，全身血压比那些没有PAH的人更高。这个 其中一些心血管异常的遗传易感性似乎也与 严重的SCD溶血。尽管一些基因变异被描述为与这两种PH相关 在SCD患者中，与这些ECHO-CV表型相关的遗传学研究尚未得到 在居住在非洲的SCD患者中报告。有必要透彻地了解 遗传多样性是非洲SCD患者CV表型异质性的基础。了解这些知识 因子将有助于识别在新疗法中可能被治疗操纵的基因和途径 接近了。这项研究的首要目标是确定与舒张压相关的常见遗传变异。 成人SCD患者的功能障碍和PH。这将通过三个相互关联的具体目标来实现。我们会 研究在尼日利亚和坦桑尼亚的一家4所机构登记的成年SCD患者的大量队列。具体来说，我们将 定义主要心脏回声-心血管表型(心脏扩张， 心脏指数、血压、舒张期功能障碍、三尖瓣反流速度(TRJV)和RV 功能障碍)(目标1)。我们将确定全基因组SNPs是否与溶血水平相关 将在该应用的配套项目中定义的细胞保护蛋白与特定的ECHO-CV相连 表型(目标2)。最后，我们将使用转基因镰刀鼠从功能上验证它们之间的关联 高血压患者细胞保护蛋白水平与舒张期功能不全、PH及相关系统性高血压的关系 SCD(目标3)。这个项目将是第一个与舒张期功能障碍和PH相关的遗传学特征。 在居住在非洲的SCD患者中。它将具有很高的翻译潜力，并可能提供机械性的见解 并提出了可用于临床翻译的新的治疗靶点。

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.