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: 7143195
• 负责人: David E Reich
• 金额: $ 25.43万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143195
• 关键词: Africa; clinical research; genes; genetics; malaria

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（由申请人提供）：尽管目前已鉴定出 18 种基因变异可赋予对严重疟疾的抵抗力（主要是在西非人中），但多项研究中仅重复了其中的一个子集。在这里，我们建议评估罗人对疟疾的遗传易感性，罗人是东非人口，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遗传变异将导致新的药物靶点，但迄今为止的几种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疟疾抗性基因来寻找新的易感性变异。该项目的第一阶段将进行疟疾易感性的复制研究。我们将在 539 例罗氏病例和 477 例匹配对照中研究先前与疟疾耐药性相关的 18 种基因变异。对于出现这些变异的九个基因，我们还将创建针对罗群体的“单倍型图谱”，并识别频率> 5％的所有单倍型，并评估其中是否有任何一个与疟疾抵抗力相关。这些基因的单倍型分析非常重要，因为它将使我们能够识别仅存在于东非的新风险变异，而东非的研究还很少。第二阶段将寻找与疟疾抗性相关的九个基因的自然选择历史。我们最近发布了一项协议来搜索受自然选择影响的基因组区域。我们用它来建立 CD40 配体和 G6PD（以前与疟疾抗性相关的两个基因）选择的证据。我们现在建议使用相同的方案来寻找东非人与疟疾抗性相关的所有九个基因的自然选择证据。作为第二个选择测试，我们还将比较罗族和马赛族的疟疾抗性单倍型频率，马赛族与罗族一样起源于尼罗河，但历史上生活在低疟疾环境中。尽管种族背景相似，但与罗人和马赛人相比，发现频率差异很大的单倍型，这表明存在疟疾抗性基因。第三阶段将进行疟疾抗性基因的试点全基因组扫描。以前与疟疾抗性相关的所有基因都是通过“候选基因”方法鉴定的，其中少数被特别认为对疟疾发病机制具有重要意义的基因进行了相关性测试。然而，一些最有趣的药物靶点可能存在于尚未测试的大量基因中。我们建议开展首次全基因组关联扫描，以寻找疟疾抗性基因，使用 Affymetrix 基因芯片技术扫描多达 200 名罗族严重疟疾病例、200 名健康罗族对照和 100 名健康马赛人的 50,000 个变异组。我们不仅要寻找罗族病例和对照之间频率的差异，还要寻找罗族和马赛族之间频率显着不同的地区，尽管他们的种族起源相似，这表明罗族在过去几千年中选择了抗疟疾。