多组学在慢性病病因学研究中的应用及其进展

慢性病流行病学的主要目的之一是探索疾病病因。多组学通常包括在脱氧核糖核酸复制、转录、翻译、翻译后修饰的过程中,产生的全部基因(基因组学)、基因表达的广泛变化(表观遗传组学)、核糖核酸(转录组学)和蛋白质(蛋白质组学),以及下游的小分子代谢产物(代谢组学)。多组学检测技术为包括基因组、转录组、蛋白质组在内的组学测定提供技术支持,系统流行病学为利用多组学开展病因研究提供理论与方法支持。多组学研究既揭示了分子间的相互作用网络,又从微观病因学层面有助于因果推断。随着国际公开数据、分析平台与协作组的指数级增长,多组学研究资源将更加丰富,所研究的深度与广度也将得到大幅扩展。本文将详细介绍多组学在慢性病病因学研究中的应用及近三年的研究进展、多组学对慢性病流行病学研究的意义和价值、为大规模队列研究带来的机遇与挑战、中国在多组学病因学研究的优势与问题及多组学研究展望。     

暴露组学的概念与应用

暴露组学作为基因组学的补充是指从妊娠开始贯穿整个人生的环境暴露(包括生活方式因素)。暴露源包括外源(污染、辐射、饮食等)和内源(炎症、感染、微生物等)。继全基因组关联研究(GWAS)之后发展的全暴露组关联研究(EWAS)的目的是对在未知方式下暴露的评估。EWAS方法通过比较患者和健康受试者暴露组的分析结果,确定有效的生物标志物,进而利用这些生物标志物来阐明暴露-效应关系(生化流行病学)、暴露和人体动力学来源(暴露生物学),以及作用机制(系统生物学)。"自下而上"和"自上而下"的方法在识别个体暴露上都具有科学价值。"自上而下"法用于揭示人类疾病的未知暴露源,而"自下而上"法是用于分析外暴露以及建立干预与预防的方法。生物标志物不仅可以用于研究外暴露,也可以用于研究内暴露。内暴露组学采用组学的方法进行研究,如基因组学、蛋白质组学、表观基因组学、代谢组学、转录组学、加合物组学等。人类生命早期暴露组学(HELIX)项目是近期启动的描述欧洲人群的早期暴露以及揭示组学标志物和儿童时期健康关系的第一次尝试。该文介绍了其研究方法、工具、思路及其重要意义,同时总结了暴露组学从概念到应用可能面临的挑战。     

代谢组流行病学研究进展

近年来，基于代谢组学技术平台和数据分析方法的快速发展，作为系统流行病学的重要分支——代谢组流行病学正获得越来越多的关注。代谢组流行病学有助于更好地描述暴露特征，反映环境-基因相互作用的效应，阐明暴露与疾病的"黑箱"机制，并发现新的生物标志物。本文简要介绍代谢组流行病学研究的定义、方法、研究进展及展望。     

暴露组与暴露组学

人类复杂疾病主要是由环境因素或者环境与遗传因素相互作用所致.自人类基因组计划开展以来,有关遗传因索与复杂疾病发病关系的研究进展非常迅速,相比之下,环境暴露与复杂疫病关系的研究却没有得到应有的重视和发展.暴露组与暴露组学的提出,为推动环境因素与人类健康之间关系的研究提供了新思路.     

代谢组学在心血管代谢疾病病因研究中的应用进展

代谢组学是采用高通量组学技术对所有代谢物进行鉴定和定量的生命科学研究, 近年来在心血管代谢疾病的病因研究中得到广泛应用。作为系统流行病学的一个重要组成部分, 代谢组学从代谢改变的视角提供了病因探索的新思路。代谢组学的研究问题包括分析代谢物与心血管代谢疾病的关联、发现新型生物标志物和构建疾病风险预测模型等。本文从物质类别出发详细介绍代谢组学在2型糖尿病、心血管疾病、高血压和亚临床动脉粥样硬化病因研究中的应用进展, 并提出展望。     

多组学整合分析的设计及统计方法在肿瘤流行病学研究中的应用

生物技术飞速发展为我们提供了大量生物系统中来自不同层面的组学数据,包括基因组学、转录组学、蛋白质组学、代谢组学和表观遗传学等。基于单组学数据的肿瘤研究日益成熟,而多组学数据研究的整合工作刚刚起步。肿瘤是一个复杂的调控系统,利用单一组学数据研究的局限性愈发显著,对多种层次和来源的高通量、多组学数据的整合分析势在必行。本文综述了近年来肿瘤方面组学的研究以及组学数据整合方面的研究现状,着重讨论研究设计和整合策略。     

代谢组学在毒理学研究中的应用

代谢组学是关于生物内源代谢物整体及其变化规律的科学。代谢组学方法源于毒理学研究,并促进了毒理学的研究进程。代谢组学不仅能为毒性的筛选提供快速和准确的方法,也为毒性作用机制研究提供了动态的研究技术,还为毒性生物标志物研究提供了新的方法。本文简要综述了代谢组学技术及其在毒理学研究中的应用进展。     

重视开展儿科领域内代谢组学研究

代谢组学是近年来飞速发展的一个前沿研究领域。在医学领域里已经开展了对癌症、代谢性疾病、肥胖和营养学的应用研究,成功地找到了具有指示意义的生物标志物,促进了早期诊断和及时治疗。本文就从代谢组学及其简史、代谢组学方法学的基本指向、儿科代谢组学研究、代谢组学的哲学指向等四个方面做一介绍。     

毒理学机制研究与"组学"

毒理学机制研究是环境与职业卫生相关疾病控制领域的重要方面。随着科学技术的进步，毒理学机制研究有了较大发展。近年来，“组学”在毒理学机制研究中的应用引起界内学者的普遍关注。“组学”，如基因组学（Genomics）和蛋白质组学（Pmteomics），是生命科学的前沿，具有以“通量化”的优势，但同时具有局限性，不仅在检测成本、定量、标准化等方面尚需完善，在能否回答基因间精细关系等科学问题方面也存在明显的不足。针对某些情况下“组学”概念及技术被不恰当使用的问题，Pognan曾尖锐地指出：基因组学，蛋白质学，毒理代谢组学，希望不是“时髦组学”。     

食物组学——现代食物科学和营养学研究的新方法

食物组学为近几年出现的新兴学科,借助基因组学、转录组学、蛋白质组学和代谢组学等组学技术研究食物和营养领域问题,解决现代食物科学和营养研究中有关食物安全性、溯源性、质量、新食物、转基因食物、功能性食物、营养制品等有关问题。本文综述了食物组学在蛋白质、碳水化合物、脂类、维生素、微量元素等方面研究应用。     

Epidemiology, social medicine, environmental medicine--a plea for a difficult but necessary integration

The origins of environmental medicine date back more than 2000 years. The increasing incidence of environmental disease together with successful research into their etiology and pathogenesis have caused an impetus for this discipline in quantitative terms. A growing interest of patients, but also of politicians and parts of the industry in actual or suspected environmental risk factors for health have given rise to controversies--rendering the development of a rational, quality-oriented environmental medicine difficult, if not impossible. Given these controversies surrounding environmental health issues formal demarcations between the traditional disciplines (environmental) epidemiology, social medicine, occupational medicine, and environmental medicine become obsolete. Instead, a common agenda with respect to research, quality assurance, risk communication, and prevention as well as patient counselling and policy advising calls for a conceptual and institutional integration of these disciplines.     

Prisoners of the proximate: loosening the constraints on epidemiology in an age of change.

"Modern epidemiology" has a primary orientation to the study of multiple risk factors for chronic noncommunicable diseases. If epidemiologists are to understand the determinants of population health in terms that extend beyond proximate, individual-level risk factors (and their biological mediators), they must learn to apply a social-ecologic systems perspective. The mind-set and methods of modern epidemiology entail the following four main constraints that limit engagement in issues of wider context: 1) a preoccupation with proximate risk factors; 2) a focus on individual-level versus population-level influences on health; 3) a typically modular (time-windowed) view of how individuals undergo changes in risk status (i.e., a life-stage vs. a life-course model of risk acquisition); and 4) the, as yet, unfamiliar challenge of scenario-based forecasting of health consequences of future, large-scale social and environmental changes. The evolution of the content and methods of epidemiology continues. Epidemiologists are gaining insights into the complex social and environmental systems that are the context for health and disease; thinking about population health in increasingly ecologic terms; developing dynamic, interactive, life-course models of disease risk acquisition; and extending their spatial-temporal frame of reference as they perceive the health risks posed by escalating human pressures on the wider environment. The constraints of "the proximate" upon epidemiology are thus loosening as the end of the century approaches.     

Cancer risk and the complexity of the interactions between environmental and host factors: HENVINET interactive diagrams as simple tools for exploring and understanding the scientific evidence

Background

Development of graphical/visual presentations of cancer etiology caused by environmental stressors is a process that requires combining the complex biological interactions between xenobiotics in living and occupational environment with genes (gene-environment interaction) and genomic and non-genomic based disease specific mechanisms in living organisms. Traditionally, presentation of causal relationships includes the statistical association between exposure to one xenobiotic and the disease corrected for the effect of potential confounders.

Methods

Within the FP6 project HENVINET, we aimed at considering together all known agents and mechanisms involved in development of selected cancer types. Selection of cancer types for causal diagrams was based on the corpus of available data and reported relative risk (RR). In constructing causal diagrams the complexity of the interactions between xenobiotics was considered a priority in the interpretation of cancer risk. Additionally, gene-environment interactions were incorporated such as polymorphisms in genes for repair and for phase I and II enzymes involved in metabolism of xenobiotics and their elimination. Information on possible age or gender susceptibility is also included. Diagrams are user friendly thanks to multistep access to information packages and the possibility of referring to related literature and a glossary of terms. Diagrams cover both chemical and physical agents (ionizing and non-ionizing radiation) and provide basic information on the strength of the association between type of exposure and cancer risk reported by human studies and supported by mechanistic studies. Causal diagrams developed within HENVINET project represent a valuable source of information for professionals working in the field of environmental health and epidemiology, and as educational material for students.

Introduction

Cancer risk results from a complex interaction of environmental exposures with inherited gene polymorphisms, genetic burden collected during development and non genomic capacity of response to environmental insults. In order to adopt effective preventive measures and the associated regulatory actions, a comprehensive investigation of cancer etiology is crucial. Variations and fluctuations of cancer incidence in human populations do not necessarily reflect environmental pollution policies or population distribution of polymorphisms of genes known to be associated with increased cancer risk. Tools which may be used in such a comprehensive research, including molecular biology applied to field studies, require a methodological shift from the reductionism that has been used until recently as a basic axiom in interpretation of data. The complexity of the interactions between cells, genes and the environment, i.e. the resonance of the living matter with the environment, can be synthesized by systems biology. Within the HENVINET project such philosophy was followed in order to develop interactive causal diagrams for the investigation of cancers with possible etiology in environmental exposure.

Results

Causal diagrams represent integrated knowledge and seed tool for their future development and development of similar diagrams for other environmentally related diseases such as asthma or sterility. In this paper development and application of causal diagrams for cancer are presented and discussed.

     

Social factors in the etiology of chronic disease: an overview

Our intention in this introductory article is to emphasize what we consider to be certain critical points in the current state of research into the social epidemiology of chronic disease. As will be outlined, these critical points need to be considered in future research. To begin with we provide a mild critique of research in this area which has had its tradition specified by social epidemiology, a term which has recently come into favor to describe research concerned with social factors in the etiology of chronic disease. Next we briefly summarize critical available evidence on an etiological relationship between social factors and cardiovascular disease, cancer and multiple disease outcomes. Following this a major emphasis will be placed on issues which directly relate to problems of methodology in social factors assessment. Finally, an emphasis will be given to the critical question of mechanisms which need to be clarified in this type of multivariate research.     

The epidemiology of pesticide exposure and cancer: A review

Cancer is a multifactorial disease with contributions from genetic, environmental, and lifestyle factors. Pesticide exposure is recognized as an important environmental risk factor associated with cancer development. The epidemiology of pesticide exposure and cancer in humans has been studied globally in various settings. Insecticides, herbicides, and fungicides are associated with hemopoetic cancers, and cancers of the prostate, pancreas, liver, and other body systems. The involvement of pesticides in breast cancer has not yet been determined. In developing countries, sufficient epidemiologic research and evidence is lacking to link pesticide exposure with cancer development. Agricultural and industrial workers are high-risk groups for developing cancer following pesticide exposure. Children of farm workers can be exposed to pesticides through their parents. Maternal exposure to pesticides can pose a health risk to the fetus and the newborn. The organophosphates are most the commonly used compounds, but the organochlorines are still permitted for limited use in developing countries. Pesticide exposure, independently or in synergism with modifiable risk factors, is associated with several types of cancer.     

Individual predisposition to lung neoplasm--the role of genes involved in metabolism of carcinogens

Molecular epidemiology of lung cancer analyses relationship between environment and individual susceptibility. Studying biomarkers of risk at the molecular level allows better understanding of chemical carcinogenesis processes and makes possible early detection of the disease as well as helps its prevention. Risk biomarkers include genetic polymorphism of CYP, GST and NAT genes that participate in metabolic biotransformation of various endo- and exogenous compounds including carcinogens. Exposure to potentially carcinogenic environmental factors plays an important role in etiology of lung cancer, which remains a leading cause of cancer death worldwide. This review presents current knowledge about molecular basis and impact of individual variations in carcinogen metabolism on lung cancer risk.     

Scope and strategies of Genetic Epidemiology: Analysis of articles published in Genetic Epidemiology, 1984–1991

Genetic epidemiology is a relatively new discipline that seeks to unravel the role of genetic factors and their interactions with environmental factors in the etiology of diseases, using population and family study approaches. To characterize the overall direction and emphasis of research strategies used in this field, we reviewed original research articles published in the journal Genetic Epidemiology since its inception in 1984 until the end of 1991. Of 259 published original articles, 92 (35%) focused primarily on methodologic/statistical developments, most commonly in the area of linkage analysis/gene mapping, and 167 (65%) articles were applied or data-derived. Only 42 articles (16%) were population studies, and 217 (84%) were family studies. Most family studies dealt with genetic analysis of pedigree data using segregation and linkage analyses. Of the 137 applied family studies, 73 (53%) were drawn from well-defined populations, and only 40 (29%) considered specific environmental factors in their analyses. These findings clearly indicate a rapid growth in the methodologic and statistical aspects of genetic epidemiology, and in the emphasis on family-based studies and genetic analysis methods. Further developments in genetic epidemiology will require greater integration of epidemiologic approaches of study design and analyses into population and family studies of disease etiology. © 1993 Wiley-Liss, Inc.     

Human breast biomonitoring and environmental chemicals: use of breast tissues and fluids in breast cancer etiologic research

Extensive research indicates that the etiology of breast cancer is complex and multifactorial and may include environmental risk factors. Breast cancer etiology and exposure to xenobiotic compounds, diet, electromagnetic fields, and lifestyle have been the subject of numerous scientific inquiries, but research has yielded inconsistent results. Biomonitoring has been used to explore associations between breast cancer and levels of environmental chemicals in the breast. Research using breast tissues and fluids to cast light on the etiology of breast cancer is, for the most part, predicated on the assumption that the tissue or fluid samples either contain measurable traces of the environmental agent(s) associated with the cancer or that they retain biological changes that are biomarkers of such exposure or precursors of carcinogenic effect. In this paper, we review breast cancer etiology research utilizing breast biomonitoring. We first provide a brief synopsis of the current state of understanding of associations between exposure to environmental chemicals and breast cancer etiology. We then describe the published breast cancer research on tissues and fluids, which have been used for biomonitoring, specifically human milk and its components, malignant and benign breast tissue, nipple aspirate fluid (NAF) and breast cyst fluid. We conclude with a discussion on recommendations for biomonitoring of breast tissues and fluids in future breast cancer etiology research. Both human milk and NAF fluids, and the cells contained therein, hold promise for future biomonitoring research into breast cancer etiology, but must be conducted with carefully delineated hypotheses and a scientifically supportable epidemiological approach.     

The promise of molecular epidemiology in defining the association between radiation and cancer

Molecular epidemiology involves the inclusion in epidemiologic studies of biologic measurements made at a genetic and molecular level and aims to improve the current knowledge of disease etiology and risk. One of the goals of molecular epidemiology studies of cancer is to determine the role of environmental and genetic factors in initiation and progression of malignancies and to use this knowledge to develop preventive strategies. This approach promises extraordinary opportunities for revolutionizing the practice of medicine and reducing risk. However, this will be accompanied by the need to address and resolve many challenges, such as ensuring the appropriate interpretation of molecular testing and resolving associated ethical, legal, and social issues. Traditional epidemiologic approaches determined that exposure to ionizing radiation poses significantly increased risk of leukemia and several other types of cancer. Such studies provided the basis for setting exposure standards to protect the public and the workforce from potentially adverse effects of ionizing radiation. These standards were set by using modeling approaches to extrapolate from the biological effects observed in high-dose radiation studies to predicted, but mostly unmeasurable, effects at low radiation doses. It is anticipated that the addition of the molecular parameters to the population-based studies will help identify the genes and pathways characteristic of cancers due to radiation exposure of individuals, as well as identify susceptible or resistant subpopulations. In turn, the information about the molecular mechanisms should aid to improve risk assessment. While studies on radiogenic cancers are currently limited to only a few candidate genes, the exponential growth of scientific knowledge and technology promises expansion of knowledge about identity of participating genes and pathways in the future. This article is meant to provide an introductory overview of recent advances in understanding of carcinogenesis at the molecular level, with an emphasis of the aspects that may be of use in establishing the association between radiation and cancer.     

The future of epidemiology

A decade ago there was considerable debate about the appropriate objectives and paradigms of modern epidemiologic research. One concern put forth in these debates was that "risk factor epidemiology" might be forcing our field to focus more on individuals and less on populations and public health. Today, most epidemiologists acknowledge that public health is influenced by both population-level and individual-level determinants. Ecologic studies are valuable tools for generating hypotheses and addressing group-level determinants of disease risk. Traditional risk factor studies and genomic studies have helped establish the multifactorial concept of disease causation. Individual-level studies also have provided the biomedical community with hypotheses that have stimulated research into disease mechanisms that have led to reductions in morbidity and mortality for diseases such as HIV/AIDS, cardiovascular disease, and cancer. Current debates about the role of genomic data in epidemiology and public health mirror the debates about risk factor epidemiology one decade ago. Genomic variation is measured at the individual level, but how this variation is maintained in human populations is a group-level (population) phenomenon that is worthy of epidemiologic investigation in its own right. Multilevel epidemiology seeks to understand multiple levels of inference, from genes to individuals to populations and could combine hypothesis-driven research with aspects of data mining. Multilevel epidemiology calls for the study of health and disease determinants defined at the population level and individual level for a more comprehensive strategy to understanding human disease etiology. With the continued development of multilevel statistical methods and the advent of data mining, the technical constraints of the past will become less relevant to the next generation of epidemiologists who wish to embrace a more multilevel epidemiology.