Genetic Basis of Severe Malarial Anemia

描述（由申请人提供）：严重疟疾性贫血（SMA）是婴幼儿严重疟疾最常见的临床表现，在恶性疟原虫完全流行地区，3岁以下儿童的死亡率约为20%。SMA是一种多因素疾病，涉及红细胞破坏增加以及红细胞产生减少。尽管这些机制的病因可能涉及炎症介质的失调，但SMA的潜在分子基础在很大程度上仍不明确。目前的应用程序是一个竞争性的延续，以前资助的建议，以应对RFA，以迎接这一挑战。为了更好地了解调节SMA的因素，我们采取了一种基于遗传的方法，研究先天性炎症介质在调节肯尼亚西部疟疾传播全流行区儿童SMA的发展和结局中的作用。我们之前的申请集中于通过进行广泛的临床评价来定义SMA的复杂表型，以便可以确定导致不同结局的潜在基因。这些研究确定了许多与SMA易感性相关的新型炎症介质和免疫应答基因多态性。这些研究进一步表明，HIV-1暴露显著增强了急性疟疾期间SMA的发展。这一发现具有重要的公共卫生意义，因为20%的研究参与者暴露于HIV-1，这一比例与撒哈拉以南非洲的大部分地区相当。虽然我们成功地确定了促进SMA的因素，但由于严重贫血儿童的样本量较小，这些研究受到限制。生物技术的最新进展现在允许克服这些限制的具有成本效益的高通量遗传和免疫分析。由于疟疾是一种多基因疾病，需要探索更大的基因组，以成功地确定那些影响临床结果的变异。因此，在竞争性继续研究中，我们将研究一组全面但集中的先天免疫应答基因，我们假设这些基因在调节SMA的急性和纵向结局中很重要。这将允许构建似乎比个体多态性更好地预测复杂疾病结果的单倍型。该提案的主要目标是：1）确定基因型谱和单倍型结构，这些基因型谱和单倍型结构在疟疾作为单一疾病的儿童和暴露于HIV-1的儿童中调节SMA的发展和结局，以及2）鉴定在疟疾反复发作后介导针对SMA的保护性免疫的先天免疫应答基因。该提案的总体目标是确定SMA易感性的关键基因。成功实现这一目标将有助于确定哪些儿童需要有针对性的治疗干预。

DESCRIPTION (provided by applicant): Severe malarial anemia (SMA) is the most common clinical manifestation of severe malaria in infants and young children and causes ~ 20% mortality in children < 3 years in areas holoendemic for P. falciparum. SMA is a multifactorial disease involving increased erythrocyte destruction as well as decreased erythrocyte production. Although the etiology of these mechanisms likely involves dysregulation in inflammatory mediators, the underlying molecular basis of SMA remains largely undefined. The current application is a competing continuation of a previously funded proposal in response to an RFA to meet this challenge. To gain improved understanding of the factors that regulate SMA, we have taken a genetic-based approach that investigates the role of innate inflammatory mediators in conditioning the development and outcomes of SMA in children residing in a holoendemic area of malaria transmission in western Kenya. Our previous application focused on defining the complex phenotype of SMA by performing extensive clinical evaluations so that the underlying genes responsible for the varied outcomes could be established. These investigations identified a number of novel inflammatory mediators and polymorphisms within immune response genes associated with susceptibility to SMA. These studies further revealed that HIV-1 exposure significantly enhanced the development of SMA during acute malaria. This finding has important public health implications since 20% of the study participants were exposed to HIV-1, a rate comparable to that throughout much of sub-Saharan Africa. Although we successfully defined factors that promote SMA, these studies were limited due to small sample volumes available from severely anemic children. Recent advances in biotechnology now allow for cost-effective, high-throughput genetic and immunological analyses that overcome these limitations. Since malaria is a polygenic disease, exploration of a larger panel of genes is required to successfully identify those variants that condition clinical outcomes. As such, in the competing continuation, we will investigate a comprehensive, but focused panel of innate immune response genes we hypothesize to be important in conditioning acute and longitudinal outcomes of SMA. This will allow for construction of haplotypes which appear to be better predictors of complex disease outcomes than individual polymorphisms. The primary goals of this proposal are: 1) to determine the genotypic profiles and haplotypic structures that condition the development and outcomes of SMA in children with malaria as a single disease and in children exposed to HIV-1, and 2) to identify innate immune response genes that mediate protective immunity against SMA following repeated episodes of malaria. The overall goal of this proposal is to identify critical genes that underlie susceptibility to SMA. Successful accomplishment of this goal will aid in identifying those children in which targeted therapeutic interventions are required.