Project 4: Understanding the relationship between the gut microbiome, and cardiometabolic disease and aging in African populations.

由下一代测序提供的高质量、负担得起的测序已经 彻底改变了我们对人类微生物群的多样性和对健康的重要性的理解， 尤其是心脏新陈代谢状态。 在非洲，关于微生物组的研究相对较少，更少的是研究关联 心脏新陈代谢健康。许多非洲国家正在经历生活方式的转变(食物， 体力活动)，现在发现心脏代谢紊乱(肥胖、2型糖尿病)是一种严重的健康问题 挑战，重要的是要了解微生物群如何与这些疾病有关。 健康、人类基因、环境和微生物群之间的关系是复杂的。 杜加斯等人。(2016)最近呼吁“发展大型的、全球分布的、人类 微生物区系研究“以了解微生物组在流行病学转变中的作用。 AWI-Gen联盟处于有利地位，可以探索微生物群在流行病学中的作用 过渡。我们在四个非洲国家有六个站点：布基纳法索的Nanoro，加纳的Navrongo， 肯尼亚的内罗毕，南非的阿金库尔、迪克盖尔和索韦托。这些网站有不同的 具有显著遗传多样性的物理环境，处于非常不同的位置 流行病学转变。南非约翰内斯堡的索韦托反映了一个社会，它一直是 经过几代人的城市化，人们过着西方化的生活方式。有很高的 肥胖率和心脏代谢紊乱的比率。布基纳法索的Nanoro和Navrongo网站以及 加纳是农村社区，那里的流行病过渡刚刚开始，人们生活在那里。 传统的生活方式。肥胖水平很低--事实上，我们研究中的许多参与者 体重指数非常低。进一步将AWI-Gen作为镜头来探索两者之间的关系 微生物组状态和健康状态为：AWI-Gen第一阶段的所有参与者都将接受基因分型 在高质量的芯片阵列上；它们在AWI-Gen的第一阶段中得到了很好的表型，并将再次 第二阶段的表型；我们有良好的人力和设备基础设施来进行研究。 本项目将探讨四个关键问题： ·非洲人口不同阶段微生物群的多样性是什么？ 流行病学转型？我们将能够通过检查不同之处来探讨这个问题 不同的地点。 ·微生物群状态与心脏代谢健康有什么关系？我们的研究 在AWI-Gen的第一阶段和第二阶段，将收集有关心脏代谢健康和 我们的参与者的生活方式，我们将能够找到与微生物群状态的联系。 ·微生物群如何随着时间的推移而变化，特别是对经历荷尔蒙的女性来说 过渡？这项研究的一个组成部分将比较绝经前和绝经后的女性。少校 AWI-Gen的贡献将是收集可长期使用的基线数据 纵向研究。我们还将有权比较不同年龄段的女性。 ·宿主基因组和微生物组之间有什么关系？最近的研究表明，宿主 基因可以塑造微生物群。由于我们所有的参与者都将进行基因分型，我们可以探索一下这一点 问题。由于样本量的限制，我们不会进行全基因组研究，而是将重点放在 复制和特定感兴趣的基因。 研究的另一个重要目标是为今后的纵向研究奠定基础 微生物群在个体水平和群落水平上的变化。这些是 在AWI-Gen阶段2之后，我们和其他人可以探索的重要问题和帮助 支持未来的研究。 我们的抽样有两个重要的限制，以确保有足够的权力 回答我们的假设。(1)虽然我们会招聘男性和女性，但我们专注于女性。项目 3特别关注荷尔蒙转换的影响，我们希望有能力探索 微生物组的影响。此外，在一些网站上，女性似乎更有可能患上 高BMI。(2)艾滋病毒和疟疾等传染病在某些地方是地方病，可能会有 对微生物群有深远的影响(或许反之亦然)。然而，为了减少 可变性我们将把这些视为需要控制的协变量，而不是专门检查 这些都是假设中的。 我们建议的优势在于，我们将能够很好地向其他资助者申请 为嵌套项目提供额外资金，以便在以下时间框架内探讨这一问题和其他问题 AWI-Gen阶段2及以后。

The availability of quality, affordable sequencing offered by next generation sequencing has revolutionised our understanding of the diversity and importance of the human microbiome to health, and particularly to cardio- metabolic status. There are relatively few studies of the microbiome in Africa, and even fewer examining association with cardio- metabolic health. Many African countries going through transition of lifestyle (food, physical activity), now find cardio-metabolic disorders (obesity, type-2 diabetes) a serious health challenge, and it is important to understand how the microbiome is associated with these disorders. The relationship between health, human genetics, environment and the microbiome is complex. Dugas et al. (2016) have recently called for the “development of large, globally-distributed, human microbiota studies” to understand the role of the microbiome in epidemiological transition. The AWI-Gen consortium is well placed to explore the role of the microbiome in epidemiological transition. We have six sites in four African countries: Nanoro in Burkina Faso, Navrongo in Ghana, Nairobi in Kenya, and Agincourt, Dikgale and Soweto in South Africa. These sites have different physical environments with significant genetic diversity and are at very different places in epidemiological transition. Soweto in Johannesburg, South Africa reflects a society, which has been urbanized for several generations and in which people have a westernised lifestyle. There are high rates of obesity and cardio-metabolic disorders. The Nanoro and Navrongo sites in Burkina Faso and Ghana are rural communities, where epidemiological transition has just started and people live traditional lifestyles. Levels of obesity are low — indeed many participants in our studies have very low BMI. Further strengths of AWI-Gen as a lens to explore the relationship between microbiome status and health status are: all participants in phase 1 of AWI-Gen will be genotyped on a high quality chip array; they were finely phenotyped in phase 1 of AWI-Gen and will again be phenotyped in phase 2; and we have good human and equipment infrastructure for the study. This project will explore four key questions: • What is the diversity of the microbiome in African populations at different stages of epidemiological transition? We will be able to explore this question by examining differences at different sites. • What is the relationship between microbiome status and cardio-metabolic health? Our studies in phase 1 and 2 of AWI-Gen will collect detailed information about cardio-metabolic health and lifestyle of our participants, and we will be able to find associations with microbiome status. • How does the microbiome change over time and particularly for women going through hormonal transition? A component of the study will compare pre- and post-menopausal women. The major contribution of AWI-Gen will be to collect base-line data that can be used for long term longitudinal studies. We will also be powered to compare women in different age groups. • What is the relationship between host genome and microbiome? Recent work has shown that the host genetics can shape the microbiome. As all our participants will be genotyped we can explore this question. Due to sample size limitations, rather than doing a genome-wide study we will focus on replication and genes of specific interest. A further important objective of the study is to lay the basis for future longitudinal studies of how the microbiome changes at both the individual level and the community level. These are important questions that can be explored by us, and others, past the AWI-Gen phase 2 and help sustain future research. There are two important restrictions on our sampling, compromises to ensure sufficient power to answer our hypotheses. (1) Although we will recruit both men and women, we focus on women. Project 3 specifically looks at the effect of hormonal transition and we want to be powered to explore the effect of the microbiome. Also, at several sites women appear to be much more at risk of having high BMI. (2) Infectious diseases such as HIV and malaria are endemic at some sites and can have a profound effect on the microbiome (and perhaps vice- versa). However, in order to reduce variability we will treat these as covariates to be controlled, rather than specifically examining these in hypotheses. The strength of our proposal is that we will be in a good position to apply to other funders for additional funding for nested projects to explore this and other questions within the time-frame of AWI-Gen Phase 2 and beyond.