Associating genetic variation to resistance to severe malaria in East Africa

将遗传变异与东非对严重疟疾的抵抗力联系起来

• 批准号: 7267964
• 负责人: David E Reich
• 金额: $ 20.57万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267964
• 关键词: Affect; Africa; African; CD40 Ligand; Candidate Disease Gene; Collection; Drug Delivery Systems; Environment; Ethnic Origin; Foundations; Frequencies; G6PD gene; Gene Chips; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Glucosephosphate Dehydrogenase; Haplotypes; Human; Lead; Life; Malaria; Maps; Natural History; Natural Selections; Nature; Pathogenesis; Phase; Population; Predisposition; Protocols documentation; Publishing; Research Personnel; Resistance; Risk; Sample Size; Sampling; Scanning; Technology; Testing; Variant; case control; genetic variant; genome wide association study; interest; programs

DESCRIPTION (provided by applicant): Although 18 genetic variants have now been identified as conferring resistance to severe malaria, mostly in west Africans, only a subset have been replicated in multiple studies. Here we propose to assess genetic susceptibility to malaria in the Luo, an East African population from an ethnic background very different from the populations in which most of the associations were previously identified. We hypothesize that identifying genetic variation affecting susceptibility to malaria will lead to new drug targets, but that several of the candidate variants so far may not be real and thus need to be replicated. We also propose to search for new susceptibility variants, via the first whole-genome scan for malaria resistance genes. The first phase of this project will be to carry out a replication study for malaria susceptibility. We will study the 18 genetic variants previously associated to malaria resistance in 539 Luo cases and 477 matched controls. For the nine genes in which these variants occur, we will also create "haplotype maps" specific for the Luo population, and identify all the haplotypes of >5 percent frequency and assess whether any of them are associated to malaria resistance. The haplotype analysis in these genes is significant because it will allow us to identify new risk variants present only in East Africa, where few studies have been done. The second phase will be to search for a history of natural selection at nine genes associated with malaria resistance. We recently published a protocol to search for regions of the genome that have been affected by natural selection. We used this to establish evidence for selection at CD40 ligand and G6PD (two genes previously associated with malaria resistance). We now propose to use the same protocol to search for evidence of natural selection at all nine genes associated with malaria resistance in east Africans. As a second test for selection, we will also compare the frequencies of the malaria resistance haplotypes in the Luo to those in the Masai, a population that is also of Nilotic in origin like the Luo, but has historically lived in a low-malaria environment. The finding of a haplotype that is very different in frequency comparing the Luo and Masai, despite the similar ethnic background, would suggest the presence of a malaria resistance gene. The third phase will be to carry out a pilot whole-genome scan for malaria resistance genes. All the genes that were previously associated to resistance fo malaria were identified by the "candidate gene" approach, where a handful of genes that were specifically believed to be significant for malaria pathogenesis, were tested for association. However, it may be that some of the most interesting drug targets are in the mass of genes that have not yet been tested. We propose to carry out the first whole-genome association scan to find malaria resistance genes, using Affymetrix gene-chip technology to scan a panel of 50,000 variants in up to 200 Luo severe malaria cases, 200 healthy Luo controls, and 100 healthy Masai. We will search not only for differences in frequencies between Luo cases and controls, but also for regions that are strikingly different in frequency between the Luo and Masai despite their similar ethnic origin, suggesting selection for malaria resistance in Luo in the past few thousand years.

描述(申请人提供)：尽管现已确定18个基因变异对严重疟疾具有抵抗力，主要是在西非人中，但在多项研究中只复制了一个子集。在这里，我们建议评估罗族人对疟疾的遗传易感性，这是一个东非人口，其种族背景与之前发现的大多数关联的人口非常不同。我们假设，识别影响疟疾易感性的基因变异将导致新的药物靶点，但到目前为止，几个候选变异可能不是真实的，因此需要复制。我们还建议通过首次全基因组扫描寻找疟疾抗性基因，寻找新的易感变异。该项目的第一阶段将开展疟疾易感性的复制研究。我们将在539例Luo病例和477名配对对照中研究与疟疾耐药性相关的18个基因变异。对于发生这些变异的9个基因，我们还将创建罗族特有的“单倍型图谱”，识别&gt；5%频率的所有单倍型，并评估其中是否有与疟疾抗性有关的单倍型。这些基因的单倍型分析具有重要意义，因为它将使我们能够识别只在东非存在的新风险变异，那里的研究很少。第二阶段将在9个与疟疾抗药性相关的基因上寻找自然选择的历史。我们最近发布了一项协议，以搜索基因组中受自然选择影响的区域。我们利用这一点建立了CD40配体和G6PD(两个以前与疟疾抗药性相关的基因)进行选择的证据。我们现在建议使用同样的方案在东非人的所有9个与疟疾抗药性相关的基因中寻找自然选择的证据。作为第二个选择测试，我们还将比较罗人和马赛人的抗疟疾单倍型频率，马赛人也与罗人一样起源于尼罗河人，但历史上一直生活在低疟疾环境中。尽管罗族和马赛族有着相似的种族背景，但发现的单倍型在频率上与罗族和马赛族相比差异很大，这表明存在一种抗疟疾基因。第三阶段将进行试点全基因组扫描，寻找抗疟疾基因。所有以前与疟疾抗药性有关的基因都是通过“候选基因”方法确定的，在这种方法中，一些被特别认为对疟疾发病机制具有重要意义的基因被测试关联。然而，一些最有趣的药物靶点可能存在于大量尚未测试的基因中。我们计划开展第一次全基因组联合扫描来发现疟疾抗性基因，使用Affymetrix基因芯片技术扫描多达200例重症疟疾患者、200例健康的罗族对照和100名健康的马赛人的50,000个变异。我们不仅将寻找罗族病例和对照之间的频率差异，而且还将寻找罗族和马赛族尽管种族来源相似，但在频率上存在显著差异的地区，这表明过去几千年来罗族对疟疾的抗性是有选择的。