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性疾病。它在非洲最为流行。 通过新生儿筛查确定的新生儿青霉素预防可降低SCD的死亡率。但这 在减少其他原因造成的死亡方面，进展并不相称。终末期器官 损伤现在是西方SCD患者死亡的主要原因， 一旦预防和及时管理感染成为非洲的主要死因， 在大陆上实施。溶血释放的血红素等炎症分子会导致严重的 组织损伤最终导致SCD中的器官损伤。溶血增加了循环中游离血红素的水平 以及足以导致组织损伤的无细胞血红蛋白。我们之前的研究报告在《医学杂志》上发表， 临床研究表明，循环血红素的适度升高对转基因小鼠没有影响， 镰状细胞性状小鼠在患有SCD的同窝仔中对肺部造成致命损伤， 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 急性肾损伤（阿基）的转基因镰状细胞小鼠。这些发现共同强调了蛋白质， 中和血红素，作为发生高血压的SCD患者器官损伤的潜在缓解剂 溶血为了支持这一观点，我们先前报道了一个（GT）n二核苷酸多态性与 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的发生率显著降低。还有四种其他关键的溶血细胞保护蛋白（HCP）; 血红素结合蛋白、α-1微球蛋白、铁蛋白和触珠蛋白。我们推断这些HCP是急性 SCD中的器官损伤。值得注意的是，以前还没有全基因组关联研究（GWAS） 为了鉴定影响直接解毒血红素的三种HCP水平的遗传因素; HO-1， 血红素结合蛋白和α-1微球蛋白。提示SCD患者中存在可变的细胞保护性防御， 我们的初步研究表明，在一个国家，五种关键HCP中的每一种都有很大的水平差异（高达300倍的变化）。 加纳的SCD患者队列。我们将执行GWAS以识别与 在加纳的两个大的SCD患者队列中的5名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的基因， 在整个非洲大陆的SCD患者中，HCP的表达是可变的。然后我们将纵向跟踪 这些队列，以确定与HCP水平升高相关的变异是否可保护患者免于急性 血管闭塞危象和高溶血时的器官损伤。这个项目将提供一个独特的机会 非洲科学家研究SCD的基因组学，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非洲联盟的中心目标。