Doctoral Dissertation Research: Genetic Adaptation to Disease: Tuberculosis Susceptibility in Native South Americans

长期以来，生物人类学家一直对疾病易感性的种群差异问题感兴趣，但在宿主-病原体共同进化的研究中，美洲原住民社区的代表性一直较低。鉴于古病理学中一个长期悬而未决的争议涉及新大陆结核病的起源，将这些群体纳入其中对于了解这种疾病的演变及其对土著社区的历史和当前影响至关重要。自欧洲人接触以来，美洲原住民人口中的结核病发病率一直很高，美洲原住民的极端易感性传统上被认为是哥伦布前结核病的证据，但最近的研究证实，在欧洲人接触之前，新大陆就存在这种疾病。因此，必须将美洲原住民群体的易感性作为一种潜在的适应其他环境因素的机制来考察。对世界其他人群进行的研究的越来越多的证据表明，宿主遗传和环境的复杂相互作用在确定结核病易感性方面发挥着重要作用。例如，在迄今研究的亚洲、非洲和欧洲人群中，多个基因与易感性有关，这些基因因人群而异。本论文研究了宿主遗传和环境因素在巴拉圭AChE地区结核病易感性中的作用。其他人群中与结核病相关的候选基因(维生素D受体、天然耐药相关巨噬细胞蛋白和甘露糖结合凝集素)将被分析与结核病有关。该项目的科学价值在于，它是第一次对美洲原住民进行大规模研究，将广泛的系谱、人口统计和流行病学数据纳入其中，以检查结核病易感性的遗传和环境原因。数据集的纵向性质将允许检查美洲原住民人口相对于欧洲人的高发病率的潜在遗传原因。在更广泛的层面上，这个项目可以作为检查其他美洲原住民群体中可能涉及类似基因的结核病易感性的模型。这里提出的研究可以通过识别与尚未检查的美洲原住民群体中的结核病易感性有关的基因，来增加关于人类群体及其病原体共同进化的越来越多的信息。这项研究的更广泛影响可以分为两个阶段。在个人层面，将培训一名研究生和一名本科生助理。在人口层面上，AChE可能会对健康和经济产生影响，也许还有其他南美原住民社区，他们在这类研究中的代表性不足。土著社区的疾病易感性不仅仅是一个生物学问题：高发病率会导致社会混乱和经济生产力的损失。关于疾病易感性的遗传和环境原因的信息可能是未来公共卫生战略的关键。

Biological anthropologists have long been interested in the question of population differences in disease susceptibility, but Native American communities have historically been underrepresented in research on host-pathogen co-evolution. Given that a longstanding, unresolved controversy in paleopathology concerns the origin of New World tuberculosis, inclusion of these groups is of utmost importance to the understanding of the evolution of this disease and its historical and current impact on native communities. Tuberculosis incidence in Native American populations since European contact has been high, and extreme susceptibility of Native Americans was traditionally considered evidence against pre-Columbian tuberculosis, but recent studies confirm presence of the disease in the New World prior to European contact. Thus, susceptibility of Native American groups must be examined as a potential adaptive mechanism to other environmental factors. Mounting evidence from research performed on other world populations indicates that a complex interplay of host genetics and the environment play an important role in determining tuberculosis susceptibility. In Asian, African and European populations studied to date, for example multiple genes are involved in susceptibility, and these genes differ by population. This dissertation examines the role of host genetics and environmental factors in tuberculosis susceptibility in the Ache of Paraguay. Candidate genes associated with tuberculosis in other populations (vitamin D receptor, natural resistance-associated macrophage protein, and mannose binding lectin) will be analyzed for linkage to tuberculosis. The scientific merit of this project is that it is the first large-scale study of Native Americans to incorporate extensive pedigree, demographic and epidemiological data to examine genetic and environmental causes of tuberculosis susceptibility. The longitudinal nature of the data set will allow examination of the underlying genetic causes of the high case rates in Native American populations relative to European ones. At a broader level, this project can serve as a model for examining susceptibility to TB in other Native American groups in that similar loci may be involved. The research proposed here can add to the growing body of information on the co-evolution of human populations and their pathogens by identifying loci that are involved in TB susceptibility in an as yet unexamined Native American group.The broader impact of this research can be divided into two stages. At an individual level, a graduate student, and an undergraduate assistant will be trained. At the level of the population, there may be health and economic consequences for Ache and perhaps other native South American communities, who have been underrepresented in this type of research. Disease susceptibility in native communities is more than a biological question: high rates of disease lead to social disruption and loss of economic productivity. Information about genetic vs. environmental causes of disease susceptibility may be key for future public health strategies.