Genetic determinants of hemolysis modifying defense in sickle cell disease

镰状细胞病溶血改变防御的遗传决定因素

基本信息

批准号：
10000996
负责人：
Solomon Fiifi Ofori-Acquah
金额：
$ 25.62万
依托单位：
UNIVERSITY OF GHANA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000996
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Africa African Blood Coagulation Disorders Cameroon Cause of Death Cells Cessation of life Chronic Clinic Clinical Complement Data Dinucleoside Phosphates Ensure Enzymes Ferritin Functional disorder Genetic Genetic Determinism Genetic Diseases Genetic Identity Genetic Polymorphism Genetic Variation Genetic study Genome Genomics Geography Ghana Haplotypes Haptoglobins Heart Heme Hemoglobin Hemolysis Hemopexin Hospitalization Hypoxia Immune System Diseases Individual Inflammatory Infusion procedures Journals Kidney Kidney Diseases Link Liver Longitudinal cohort Lung Methodology Modeling Monitor Mus Neonatal Screening Nigeria Organ Patients Penicillins Pharmacology Phenotype Plasma Population Prevention Prophylactic treatment Proteins Publications Pulmonary Hypertension Reporting Risk Role SNP array Sampling Studies Scientist Sickle Cell Sickle Cell Anemia Sickle Cell Trait Site Suggestion Tanzania Testing Time Transgenic Organisms Variant acute chest syndrome alpha-1-microglobulin care outcomes case control clinical investigation cohort design experimental study genetic variant genome wide association study heme oxygenase-1 infection management insight mortality neonate organ injury protein expression rare variant sickling standard care tissue injury vaso-occlusive crisis

项目摘要

ABSTRACT Sickle cell disease (SCD) is the commonest genetic disorder in the World. It is most prevalent in Africa. Penicillin prophylaxis in neonates identified by newborn screening has reduced mortality in SCD. However, this progress has not been matched by advancements in reducing deaths due to other causes. End-stage organ damage is now the leading cause of death among SCD patients in the West and it is poised to become the major cause of death in Africa once prevention and prompt management of infections becomes widely implemented on the continent. Inflammatory molecules such as heme released from hemolysis cause severe tissue injury that ultimately causes organ damage in SCD. Hemolysis raises circulating levels of free heme and cell-free hemoglobin sufficiently to cause tissue injury. Our prior studies reported in the Journal of Clinical Investigations showed that a modest elevation of circulating heme that has no impact on transgenic sickle cell trait mice causes a lethal damage to the lungs in littermates with SCD in a condition commonly called acute chest syndrome (ACS). Our preliminary studies show that excess circulating heme can also cause acute kidney injury (AKI) in transgenic sickle cell mice. Together these findings highlight proteins that can neutralize heme as potential alleviators of the organ damage seen in SCD patients who develop hyper- hemolysis. In support of this idea, we reported previously that a (GT)n dinucleotide polymorphism associated with increased activity of heme oxygenase-1 (HO-1), the rate limiting heme degradation enzyme is linked to significantly lower rates of ACS. There are four other key hemolysis cytoprotective proteins (HCPs); hemopexin, alpha-1 microglobulin, ferritin and haptoglobin. We reason that these HCPs are modifiers of acute organ damage in SCD. Remarkably, there has not previously been a genome-wide association study (GWAS) to identity the genetic factors that influence the level of the three HCPs that directly detoxify heme; HO-1, hemopexin and alpha-1 microglobin. Suggestive of a variable cyto-protective defense among SCD patients, our preliminary studies show a wide range of levels (up to 300-fold variation) for each of the five key HCPs in a cohort of SCD patients in Ghana. We will perform a GWAS to identify variants associated with the level of the five HCPs in two large cohorts SCD patients in Ghana, and replicate our findings in three large patient cohorts in Cameroon, Nigeria and Tanzania. This geographical coverage will ensure that we capture the genetics of variable HCP expression among SCD patients across the African continent. We will then longitudinally follow these cohorts to determine whether variants associated with raised HCP level protect patients from acute organ damage during vaso-occlusive crisis and hyper hemolysis. This project will provide a unique opportunity for African scientists to study genomics of SCD, including experiments using transgenic SCD mice for the first time on the continent, to help fulfill the central objective of the H3Africa consortium.

抽象的镰状细胞病（SCD）是世界上最常见的遗传性疾病。它在非洲最为流行。通过新生儿筛查发现，对新生儿进行青霉素预防可以降低 SCD 的死亡率。然而，这在减少其他原因造成的死亡方面取得的进展并未与进展相匹配。终末期器官目前，损害已成为西方 SCD 患者死亡的主要原因，并且有望成为一旦感染预防和及时管理得到广泛应用，将成为非洲主要死亡原因在非洲大陆实施。溶血释放的血红素等炎症分子会导致严重的 SCD 中最终导致器官损伤的组织损伤。溶血提高游离血红素的循环水平和无细胞血红蛋白足以引起组织损伤。我们之前的研究发表在《Journal of 临床研究表明，循环血红素的适度升高对转基因没有影响镰状细胞性状小鼠在患有 SCD 的同窝小鼠中通常会造成肺部致命损伤称为急性胸部综合征（ACS）。我们的初步研究表明，过量的循环血红素也会导致转基因镰状细胞小鼠的急性肾损伤（AKI）。这些发现共同强调了蛋白质可以中和血红素作为潜在的减轻 SCD 患者器官损伤的药物溶血。为了支持这个想法，我们之前报道了与（GT）n二核苷酸多态性相关的随着血红素加氧酶-1 (HO-1) 活性的增加，限速血红素降解酶与 ACS 发生率显着降低。还有其他四种关键的溶血细胞保护蛋白 (HCP)；血红素、α-1 微球蛋白、铁蛋白和触珠蛋白。我们推断这些 HCP 是急性发作的调节剂 SCD 中的器官损伤。值得注意的是，此前还没有进行过全基因组关联研究（GWAS）确定影响直接解毒血红素的三种 HCP 水平的遗传因素； HO-1, 血红素和 α-1 微球蛋白。提示 SCD 患者存在不同的细胞保护防御，我们的初步研究表明，五个关键 HCP 中的每一个的水平范围很广（高达 300 倍的变化）。加纳的 SCD 患者队列。我们将进行 GWAS 来识别与病毒水平相关的变异在加纳的两个大型 SCD 患者队列中，有 5 名 HCP 进行了研究，并在三个大型患者队列中重复了我们的研究结果喀麦隆、尼日利亚和坦桑尼亚。这种地理覆盖范围将确保我们捕捉到基因非洲大陆 SCD 患者中 HCP 的表达存在差异。然后我们将纵向跟踪这些队列旨在确定与 HCP 水平升高相关的变异是否可以保护患者免受急性血管闭塞危象和过度溶血期间的器官损伤。该项目将提供一个独特的机会非洲科学家研究 SCD 基因组学，包括首次使用转基因 SCD 小鼠进行实验非洲大陆的时间，帮助实现 H3Africa 联盟的中心目标。