Novartis Foundation Symposium最新文献

英文中文

Gene-environment interaction in complex diseases: asthma as an illustrative case. 复杂疾病中的基因-环境相互作用:以哮喘为例。

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470696781.CH15

F. Martinez

Genetic studies of asthma have been plagued by a remarkable difficulty in constantly replicating results in different populations for most of the polymorphisms studied. This was true even when the quality of the study design and statistical power were not an issue. The most plausible explanation for these inconsistent results is that genetic polymorphisms, in most cases, do not directly influence risk for asthma but instead modulate the effect of environmental exposures on the inception and clinical expression of asthma and allergies. A better understanding of the genetics of asthma is thus inseparable from a better understanding of the mechanisms by which environmental factors increase the risk for asthma or protect against it.

哮喘的遗传研究一直被一个显著的困难所困扰，即在不同的人群中不断复制大多数所研究的多态性的结果。即使在研究设计的质量和统计能力不存在问题的情况下也是如此。对于这些不一致的结果，最合理的解释是，在大多数情况下，遗传多态性并不直接影响哮喘的风险，而是调节环境暴露对哮喘和过敏的开始和临床表现的影响。因此，更好地了解哮喘的遗传学与更好地了解环境因素增加或预防哮喘的机制是分不开的。

引用次数: 24

Use of monozygotic twins to investigate the relationship between 5HTTLPR genotype, depression and stressful life events: an application of Item Response Theory. 应用项目反应理论，利用同卵双胞胎研究5HTTLPR基因型与抑郁和应激性生活事件的关系。

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470696781.CH4

N. Wray, W. Coventry, M. James, G. Montgomery, L. Eaves, N. Martin

We examine the interaction between stressful life events (SLE) and genotypes for the length polymorphism of the serotonin receptor gene (5HTTLPR) on risk of depression. We hypothesize that if the interaction is real, monozygotic twin pairs (MZT) homozygous for the short allele (SS) will have a greater within pair variance in depression measures than MZT homozygous for the long allele (LL), as a reflection of their increased sensitivity to unknown environmental risk factors. Telephone interviews were used to assess symptoms of depression and suicidality on 824 MZT. Rather than using the interview items to calculate sum scores or allocate diagnostic classes we use Item Response Theory to model the contribution of each item to each individual's underlying liability to depression. SLE were also measured on the MZT assessed by mailed questionnaire on average 3.8 years previously, and these were used in follow-up analyses. We find no evidence for significant differences in within pair variance between 5HTTLPR genotypic classes and so can provide no support for interaction between these genotypes and the environment. The use of MZT provides a novel framework for examining genotype x environment interaction in the absence of measures on SLE.

我们研究了应激性生活事件(SLE)和5 -羟色胺受体基因(5HTTLPR)长度多态性与抑郁症风险的基因型之间的相互作用。我们假设，如果相互作用是真实的，短等位基因(SS)纯合的同卵双胞胎(MZT)比长等位基因(LL)纯合的同卵双胞胎(MZT)在抑郁测量中具有更大的对内方差，这反映了它们对未知环境危险因素的敏感性增加。通过电话访谈评估824 MZT患者的抑郁和自杀症状。我们没有使用访谈项目来计算总得分或分配诊断类别，而是使用项目反应理论来模拟每个项目对每个人潜在抑郁责任的贡献。通过邮寄问卷对SLE患者平均3.8年的MZT进行测量，并用于随访分析。我们没有发现5种httlpr基因型之间对内方差存在显著差异的证据，因此不能为这些基因型与环境之间的相互作用提供支持。MZT的使用为在缺乏SLE措施的情况下检查基因型x环境相互作用提供了一个新的框架。

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引用次数: 22

Introduction: whither gene-environment interactions? 引言:基因与环境的相互作用走向何方?

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470696781.CH1

M. Rutter

Discussion Appendix General discussion I Role of gene-stress interactions in gene-finding studies Discussion Practice and public policy in the era of gene-environment interactions Discussion Gene-environment interaction and the metabolic syndrome Discussion General discussion II Longitudinal studies of gene-environment interaction in common diseases-good value for money? Discussion Gene-environment interactions in breast cancer Discussion Unbiased forward genetics and systems biology approaches to understanding how gene-environment interactions work to predict susceptibility and outcomes of infections

讨论附录一般性讨论1基因-应激相互作用在基因发现研究中的作用讨论基因-环境相互作用时代的实践与公共政策讨论基因-环境相互作用与代谢综合征讨论一般性讨论II常见病基因-环境相互作用的纵向研究-物有所值?讨论无偏见的正向遗传学和系统生物学方法来理解基因-环境相互作用如何预测感染的易感性和结果

引用次数: 8

Unbiased forward genetics and systems biology approaches to understanding how gene-environment interactions work to predict susceptibility and outcomes of infections. 无偏见的正向遗传学和系统生物学方法，了解基因-环境相互作用如何预测易感性和感染的结果。

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470696781.CH12

M. Kotb, Nourtan Fathey, R. Aziz, Sarah Rowe, Robert W. Williams, Lu Lu

Like most human diseases, infectious diseases are effected by complex genetic traits and multiple, interactive environmental and inherent host factors. By linking specific genotypes to disease susceptibility phenotypes we can identify the genetic basis for inter-individual differences in disease susceptibility as well as gain insight into how gene-environment interactions influence infection outcomes. Our research has focused on delineating interactive pathways and molecular events modulating host resistance or susceptibility to specific pathogens. Our model system has been that of Group A Streptococcus infections that can manifest in starkly different ways and cause distinct diseases in genetically distinct individuals. We have extended our work to other pathogens, including those with a potential of causing major, global biological threats. In as much as it is quite difficult to conduct certain infectious disease studies in humans, there has been a critical need for small animal models for infectious diseases. Appreciating the limitations of existing models, we developed several novel and complementary mouse models that are ideal for use in systems genetics studies of complex diseases. These models not only allow biological validation of known genetic associations, but importantly they afford an unbiased tool for discovering novel genes and pathways contributing to disease outcomes, under different environments.

像大多数人类疾病一样，传染病受到复杂的遗传特征和多种相互作用的环境和固有宿主因素的影响。通过将特定基因型与疾病易感性表型联系起来，我们可以确定疾病易感性个体间差异的遗传基础，并深入了解基因-环境相互作用如何影响感染结果。我们的研究主要集中在描述相互作用的途径和分子事件调节宿主对特定病原体的抗性或易感性。我们的模型系统是A群链球菌感染，它可以以截然不同的方式表现出来，并在基因不同的个体中引起不同的疾病。我们已将工作扩展到其他病原体，包括那些可能造成重大全球生物威胁的病原体。由于在人类身上进行某些传染病研究相当困难，因此迫切需要传染病的小动物模型。考虑到现有模型的局限性，我们开发了几种新的和互补的小鼠模型，这些模型非常适合用于复杂疾病的系统遗传学研究。这些模型不仅允许对已知的遗传关联进行生物学验证，而且重要的是，它们为发现在不同环境下导致疾病结果的新基因和途径提供了公正的工具。

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引用次数: 4

Gene-environment interaction: overcoming methodological challenges. 基因-环境相互作用:克服方法论挑战。

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470696781.CH2

R. Uher

While interacting biological effects of genes and environmental exposures (G x E) form a natural part of the causal framework underlying disorders of human health, the detection of G x E relies on inference from statistical interactions observed at population level. The validity of such inference has been questioned because the presence or absence of statistical interaction depends on measurement scale and statistical model. Furthermore, the feasibility of G x E research is threatened by the fact that tests of statistical interaction require large samples and their power is substantially reduced by unreliability in the assessments of genes, environmental exposures and pathology. It is demonstrated that concerns about statistical models and scaling can be addressed by integration of observational and experimental data. Judicious selection of genes and environmental factors should limit multiple testing. To overcome the challenge of low statistical power, it is suggested to maximize the reliability of measurement, integrate prior knowledge under Bayesian framework and facilitate pooling of data across studies by use of standardized stratified reporting. Consistencies and discrepancies among studies can be exploited for methodological analysis and model specification.

虽然基因和环境暴露的相互作用的生物效应(gx E)构成人类健康疾病的因果框架的自然组成部分，但gx E的检测依赖于从在人口水平上观察到的统计相互作用的推断。这种推断的有效性受到质疑，因为统计相互作用的存在与否取决于测量尺度和统计模型。此外，gx E研究的可行性受到以下事实的威胁:统计相互作用的测试需要大量样本，而基因、环境暴露和病理评估的不可靠性大大降低了其效力。研究表明，对统计模型和尺度的关注可以通过观测数据和实验数据的整合来解决。明智的选择基因和环境因素应该限制多重测试。为了克服统计能力低的挑战，建议最大限度地提高测量的可靠性，在贝叶斯框架下整合先验知识，并通过标准化分层报告促进跨研究数据的汇集。研究之间的一致性和差异可以用于方法学分析和模型规范。

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引用次数: 28

Pancreatic pathology in type 1 diabetes in human. 人类1型糖尿病的胰腺病理。

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470697405.CH2

A. Foulis

In type 1 autoimmune diabetes there is a selective destruction of insulin-secreting beta cells. Around the time of clinical presentation, insulitis, a chronic inflammatory infiltrate of the islets affecting primarily insulin containing islets, is present in the majority of cases. The inflammatory infiltrate consists primarily of T lymphocytes; CD8 cells outnumber CD4 cells, there are fewer B lymphocytes and macrophages are relatively scarce. beta cell death may involve the Fas apoptotic pathway since they have been shown to express Fas, infiltrating T lymphocytes express Fas-L and apoptotic beta cells have been described. Hyperexpression of class I MHC by all the endocrine cells in many insulin-containing islets is a well recognized phenomenon, characteristic of the disease. It has been argued that this is an earlier event than insulitis within a given islet and appears to be due to secretion of interferon alpha by beta cells within that islet. A recent study has found evidence of Coxsackie virus infection in beta cells in three out of six pancreases of patients with recent-onset type 1 diabetes. Coxsackie viruses are known to induce interferon alpha secretion by beta cells and this could initiate the sequence of events that culminates in their autoimmune destruction.

在1型自身免疫性糖尿病中，胰岛素分泌β细胞被选择性破坏。在临床表现前后，大多数病例存在胰岛素炎，一种慢性炎症浸润胰岛，主要影响含胰岛素的胰岛。炎性浸润主要由T淋巴细胞组成;CD8细胞多于CD4细胞，B淋巴细胞较少，巨噬细胞相对稀少。β细胞死亡可能涉及Fas凋亡途径，因为它们已被证明表达Fas，浸润性T淋巴细胞表达Fas- l和凋亡的β细胞已被描述。在许多含胰岛素的胰岛中，所有内分泌细胞高表达I类MHC是一种公认的现象，是本病的特征。有人认为，这是一个比胰岛内的胰岛素炎更早的事件，似乎是由于胰岛内的β细胞分泌干扰素α。最近的一项研究发现，在新近发病的1型糖尿病患者的6例胰腺中，有3例的β细胞感染柯萨奇病毒。已知柯萨奇病毒诱导β细胞分泌α干扰素，这可能引发一系列事件，最终导致自身免疫破坏。

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引用次数: 26

Practice and public policy in the era of gene-environment interactions. 基因-环境相互作用时代的实践与公共政策。

Novartis Foundation Symposium

Pub Date : 2008-08-12 DOI: 10.1002/9780470696781.CH7

K. Dodge

This chapter argues that implications of the gene-environment interaction revolution for public policy and practice are contingent on how the findings get framed in public discourse. Frame analysis is used to identify the implications of the ways in which findings are cast. The frame of 'defective group' perpetuates racial and class stereotypes and limits policy efforts to redress health disparities. Furthermore, empirical evidence finds it inaccurate. The frame of'defective gene' precludes the adaptive genetic significance of genes. The frame of 'individual genetic profile' offers individualized health care but risks misapplication in policies that place responsibility for disease prevention on the individual to the policy relief of industry and toxic environments. Framing the interaction in terms of 'defective environments' promotes the identification of harmful environments that can be regulated through policy. The 'therapeutic environment' frame offers hope of discovering interventions that have greater precision and effectiveness but risks dis-incentivizing the pharmaceutical industry from discovering drug treatments for 'obscure' gene-environment match groups. Can a more accurate and helpful framing of the gene-environment interaction be identified? Findings that genes shape environments and that environments alter the gene pool suggest a more textured and symbiotic relationship that is still in search of an apt public framing.

本章认为，基因-环境相互作用革命对公共政策和实践的影响取决于这些发现如何在公共话语中得到框架。框架分析用于确定研究结果的表达方式的含义。“缺陷群体”的框架使种族和阶级陈规定型观念永久化，并限制了纠正健康差距的政策努力。此外，经验证据发现它是不准确的。“缺陷基因”的框架排除了基因的适应性遗传意义。“个人基因图谱”的框架提供了个性化的医疗保健，但有可能在将预防疾病的责任放在个人身上的政策中被误用，从而导致对工业和有毒环境的政策救济。用“有缺陷的环境”来定义这种相互作用，促进了对可以通过政策加以调节的有害环境的识别。“治疗环境”框架为发现更精确和更有效的干预措施提供了希望，但也有可能使制药行业不愿意为“模糊的”基因-环境匹配群体发现药物治疗方法。能否找到一个更准确、更有用的基因与环境相互作用的框架?基因塑造环境和环境改变基因库的研究结果表明，一种更为复杂和共生的关系仍在寻找合适的公共框架。

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引用次数: 3

Role of gene-stress interactions in gene-finding studies. 基因-应激相互作用在基因发现研究中的作用。

Novartis Foundation Symposium

Pub Date : 2008-03-01 DOI: 10.1002/9780470696781.CH6

H. Snieder, Xiaoling Wang, V. Lagou, B. Penninx, H. Riese, C. Hartman

Identification of genetic variants underlying common complex traits and diseases can be viewed as a three-stage process that jump-started with the sequencing of the human genome. The second phase, characterization of genetic variants in different human populations, has shown major progress in recent years. The increased availability of single nucleotide polymorphisms (SNPs) has already spawned two important developments in genetic association studies. Increasingly, rather than focusing on one or two functional SNPs, candidate gene studies consider all variants within the gene jointly. The second development is that of the whole genome association study. This chapter illustrates two distinct ways in which gene-stress interactions may aid such gene finding studies. We have recently shown for heart rate variability--an index of autonomic dysfunction related to both psychopathology and cardiovascular disease--that exposure to an acute stressful challenge in a standardized lab setting may produce a more heritable endophenotype, facilitating identification of underlying genes. The second example shows how the creation of a cumulative index of chronic stress based on multiple questionnaire- and interview-based measures of stress exposure may be applied in a genome-wide association study of (high) blood pressure to find genes that only come to expression in stressful environments. We conclude that investigation ofgene-environment interactions in the context of both gene- and genome-wide association studies may offer important advantages in gene finding efforts for complex traits and diseases.

共同复杂特征和疾病的遗传变异鉴定可以看作是一个从人类基因组测序开始的三个阶段的过程。第二阶段，不同人群的遗传变异特征，近年来取得了重大进展。单核苷酸多态性(SNPs)的增加已经在遗传关联研究中产生了两个重要的发展。候选基因研究越来越多地考虑基因内的所有变异，而不是专注于一个或两个功能snp。二是全基因组关联研究的进展。本章阐述了基因-应激相互作用可能有助于基因发现研究的两种不同方式。我们最近的研究表明，心率变异性(一种与精神病理学和心血管疾病相关的自主神经功能障碍指标)在标准化实验室环境中暴露于急性应激挑战可能会产生更具遗传性的内表型，从而促进潜在基因的识别。第二个例子显示了基于多重问卷调查和基于访谈的压力暴露测量的慢性压力累积指数的创建如何应用于(高)血压的全基因组关联研究，以发现只在压力环境中表达的基因。我们的结论是，在基因和全基因组关联研究的背景下，基因-环境相互作用的研究可能为复杂性状和疾病的基因发现工作提供重要的优势。

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引用次数: 6

The chaperone function: meanings and myths. 伴侣功能:意义和神话。

Novartis Foundation Symposium

Pub Date : 2008-01-01 DOI: 10.1002/9780470754030.ch3

Peter A Lund, R John Ellis

What are molecular chaperones and how should we think about them? We propose that it is better to think in terms of a chaperone function rather than in terms of chaperone molecules. We define the chaperone function as the prevention or reversal of incorrect interactions that may occur when reactive macromolecular surfaces are transiently exposed to the intracellular environment. We suggest that this function is a distinct and essential cellular function, mediated by many different proteins. Chaperones have evolved to reduce, by a variety of mechanisms, the aggregation of proteins into non-functional, and sometimes cytotoxic, structures. Chaperones may also have evolved to have additional roles. A cellular or extracellular event mediated by a chaperone protein is not necessarily a consequence of that protein's chaperone function. The aim of this article is to provide a brief summary of the origin and concepts used in the intracellular chaperone field, to provide a backdrop for discussion of their possible roles outside the cell.

什么是分子伴侣，我们应该如何看待它们?我们建议最好考虑伴侣的功能，而不是伴侣分子。我们将伴侣的功能定义为防止或逆转反应性大分子表面短暂暴露于细胞内环境时可能发生的不正确相互作用。我们认为这种功能是一种独特而必要的细胞功能，由许多不同的蛋白质介导。通过各种机制，伴侣蛋白已经进化到减少蛋白质聚集成无功能的，有时是细胞毒性的结构。伴侣也可能进化出了更多的角色。由伴侣蛋白介导的细胞或细胞外事件不一定是该蛋白伴侣蛋白功能的结果。本文的目的是简要概述细胞内伴侣领域中使用的起源和概念，为讨论它们在细胞外的可能作用提供背景。

引用次数: 4

Extracellular functions of thioredoxin. 硫氧还蛋白的细胞外功能。

Novartis Foundation Symposium

Pub Date : 2008-01-01 DOI: 10.1002/9780470754030.ch14

Hajime Nakamura

Thioredoxin (TRX) is a small multifunctional protein with a redox-active dithiol/disulfide in the conserved active site. Human TRX was originally identified as a cytokine-like factor in virus-transformed cells. The TRX family of proteins share the active site sequence: -Cys-Xxx-Xxx-Cys-. Intracellularly TRX scavenges reactive oxygen species and regulates various signal transduction pathways in cellular activation and apoptosis. TRX is induced and released from cells in response to oxidative stress. TRX levels in plasma or serum are good markers for oxidative stress. Extracellularly, TRX shows anti-inflammatory effects. Circulating TRX in plasma inhibits neutrophil extravasation into the inflammatory sites. More recently we found that TRX inhibits the expression and release of macrophage migration inhibitory factor (MIF), which is a classical proinflammatory cytokine and a member of TRX family. Administration of recombinant TRX protein may become a novel therapeutic strategy for acute inflammatory disorders.

硫氧还蛋白(TRX)是一种小的多功能蛋白，在保守的活性位点具有氧化还原活性的二硫醇/二硫。人类TRX最初被确定为病毒转化细胞中的细胞因子样因子。TRX家族蛋白共享活性位点序列:- cys - xxx - xxx - cys -。细胞内TRX清除活性氧并调节细胞活化和凋亡的各种信号转导途径。TRX在细胞氧化应激反应中被诱导和释放。血浆或血清中的TRX水平是氧化应激的良好标志。细胞外，TRX具有抗炎作用。血浆循环TRX可抑制中性粒细胞向炎症部位外渗。最近，我们发现TRX抑制巨噬细胞迁移抑制因子(macrophage migration inhibitory factor, MIF)的表达和释放，MIF是一种经典的促炎细胞因子，是TRX家族的成员。重组TRX蛋白可能成为急性炎症性疾病的一种新的治疗策略。

引用次数: 22

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