Genetic Basis of Severe Malarial Anemia

描述（由申请人提供）：严重疟疾贫血（SMA）是婴幼儿重症疟疾最常见的临床表现，在恶性疟原虫全流行地区，导致3岁以下儿童20%的死亡率。SMA是一种多因素疾病，涉及红细胞破坏增加和红细胞生成减少。尽管这些机制的病因可能涉及炎症介质的失调，但SMA的潜在分子基础仍未明确。当前的应用程序是先前资助的提案的竞争性延续，以响应RFA来应对这一挑战。为了更好地了解调节SMA的因素，我们采用了一种基于遗传学的方法，研究了先天炎症介质在调节肯尼亚西部疟疾传播全流行地区儿童SMA的发展和结果中的作用。我们之前的应用侧重于通过进行广泛的临床评估来定义SMA的复杂表型，以便确定导致不同结果的潜在基因。这些研究发现了许多新的炎症介质和与SMA易感性相关的免疫反应基因中的多态性。这些研究进一步表明，HIV-1暴露显著增强急性疟疾期间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小，这些研究受到限制。生物技术的最新进展使得成本效益高、高通量的遗传和免疫学分析能够克服这些限制。由于疟疾是一种多基因疾病，因此需要探索更大范围的基因，以成功地确定影响临床结果的变异。因此，在竞争的延续中，我们将研究一个全面的，但集中的先天免疫反应基因小组，我们假设这些基因在调节SMA的急性和纵向结果中很重要。这将允许构建单倍型，单倍型似乎比个体多态性更能预测复杂疾病的结果。本研究的主要目标是：1)确定疟疾患儿和暴露于HIV-1的儿童中SMA的发展和预后的基因型和单倍型结构；2)确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导致SMA易感性的关键基因。这一目标的成功实现将有助于确定需要有针对性的治疗干预措施的儿童。

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.