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

• 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
• 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

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疾病。它在非洲最普遍。 通过新生儿筛查确定的新生儿中的青霉素预防症中的SCD死亡率降低。但是，这个 由于其他原因减少死亡的进步，进步尚未匹配。末期器官 现在损害是西方SCD患者死亡的主要原因，并有望成为 一旦预防和迅速管理感染的迅速管理，非洲的主要死亡原因广泛 在非洲大陆实施。炎性分子（例如溶血释放的血红素）导致严重 组织损伤最终导致器官损伤。溶血提高循环的自由血红素水平 和无细胞的血红蛋白足以引起组织损伤。我们先前在《杂志》中报道的研究 临床研究表明，对转基因没有影响的循环血红素的升高 镰状细胞性状小鼠在SCD中对同窝窝中的鸡肉造成致命损害 称为急性胸部综合征（ACS）。我们的初步研究表明，过多的循环血红素也可能导致 转基因镰状细胞小鼠中的急性肾损伤（AKI）。这些发现共同突出了可以 中和血红素是在患有超级损害的器官损害的潜在减轻者 溶血。为了支持这个想法，我们先前报道了（GT）N二核苷酸多态性相关 随着血红素氧酶-1（HO-1）的活性增加，速率限制血红素降解酶与 AC的速率明显降低。还有其他四个关键的溶血细胞保护蛋白（HCP）。 血红素，α-1微球蛋白，铁蛋白和触觉球蛋白。我们认为这些HCP是急性的修饰符 SCD中的器官损坏。值得注意的是，以前没有一项全基因组关联研究（GWAS） 识别影响直接排毒血红素的三个HCP水平的遗传因素； ho-1， 血红素和α-1微珠蛋白。暗示SCD患者中的细胞保护性防御可变， 我们的初步研究表明，在A 加纳的SCD患者队列。我们将执行GWAS来识别与该水平相关的变体 在加纳的两名大型SCD患者中，有五个HCP，并在三个大型患者队列中复制我们的发现 在喀麦隆，尼日利亚和坦桑尼亚。这种地理覆盖范围将确保我们捕获 非洲大陆的SCD患者的HCP表达可变。然后，我们将纵向跟随 这些队列以确定与HCP水平升高相关的变体是否保护患者免受急性 有机体损害在血管熟悉的危机和超溶血。该项目将提供独特的机会 为了使非洲科学家研究SCD的基因组学，包括使用转基因SCD小鼠进行的实验 在整个大陆上的时间，以帮助实现H3africa联盟的核心目标。