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.

摘要 镰状细胞病(SCD)是世界上最常见的遗传病。它在非洲最为流行。 通过新生儿筛查确定的新生儿预防青霉素降低了SCD的死亡率。不过，这个 在减少因其他原因造成的死亡方面，没有取得与之相匹配的进展。终末期器官 损害现在是西方SCD患者死亡的主要原因，它有望成为 一旦感染的预防和及时管理变得广泛，非洲的主要死亡原因 在非洲大陆实施。溶血释放的炎症分子，如血红素，会导致严重的 组织损伤，最终导致SCD的器官损伤。溶血可提高循环中的游离血红素水平 以及足以造成组织损伤的无细胞血红蛋白。我们之前的研究报告发表在 临床研究表明，循环中的血红素略有增加，但对转基因没有影响 具有镰状细胞特征的小鼠在一种常见的条件下会对患有SCD的小鼠的肺造成致命的损害 称为急性胸腔综合征(ACS)。我们的初步研究表明，循环中过量的血红素也会导致 转基因镰状细胞小鼠的急性肾损伤。总而言之，这些发现突出了可以 中和血红素作为SCD患者器官损害的潜在缓解药物 溶血。为了支持这一观点，我们以前报道过，(GT)n二核苷酸多态与 随着血红素加氧酶-1(HO-1)活性的增加，限制血红素降解速度的酶与 显著降低了急性冠脉综合征的发生率。还有其他四种关键的溶血细胞保护蛋白(HCPs)； 血凝素、α-1微球蛋白、铁蛋白和结合珠蛋白。我们认为这些HCP是急性疾病的修饰语 SCD中的器官损害。值得注意的是，以前还没有全基因组关联研究(GWAS) 确定影响三种直接解毒血红素的HCP水平的遗传因素；HO-1， 血凝素和α-1微球蛋白。提示在SCD患者中存在一种可变的细胞保护防御机制， 我们的初步研究显示，五种关键的HCP中的每一种都有广泛的水平(高达300倍的变化)。 加纳的SCD患者队列。我们将执行GWAS以确定与水平相关的变体 在加纳的两个大队列SCD患者中发现五个HCP，并在三个大的患者队列中重复我们的发现 在喀麦隆、尼日利亚和坦桑尼亚。这一地理覆盖范围将确保我们捕捉到 非洲大陆SCD患者中HCP的表达变化。然后我们将纵向跟随 这些队列旨在确定与HCP水平升高相关的变异是否能保护患者免受急性 血管闭塞危象和高溶血时的器官损害。这个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 在非洲大陆的时间，以帮助实现H3非洲财团的核心目标。