Summary and Discussion
Summary and Discussion
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DOI：
10.1142/9789814460088_0016
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
S. Krauss;R. Hood
中科院分区：
文献类型：
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作者：
S. Krauss;R. Hood
本论文所描述的研究主要有两个主题：第一个主题是关于个体之间炎症生物标志物和代谢综合征特征的差异在多大程度上是由人与人之间的遗传和环境差异的影响引起的。本论文的第二个重点超越了DNA序列的影响，并研究了表观遗传变异。我谈到了遗传和非遗传变异来源对DNA甲基化的个体差异有多重要。DNA甲基化是一种越来越受到关注的表观遗传机制，因为它可能为人类疾病提供新的见解，并代表了导致人与人之间差异的额外层面。在本章中，我总结了最重要的结果，并在复杂性状遗传学研究的现状和未来方向的更广泛的背景下讨论了这些发现。在本论文的第一部分（第2章和第3章）中，我研究了遗传和环境影响对炎症生物标志物个体差异的重要性，包括促炎细胞因子（IL-6和TNF-α），可溶性细胞因子受体（sIL-6R）和急性期蛋白纤维蛋白原和CRP。扩展的双胞胎家族模型显示，所有这些炎症生物标志物的变异在很大程度上可以通过遗传变异来解释（图1）。IL-6 （h2 =21%）、TNF-α (h2 =39%)、CRP （h2 =45%）和纤维蛋白原（h2 =46%）的浓度具有中等遗传力。血中可溶性IL-6受体水平具有高度遗传性（h2 =72%）。遗传率反映了群体中某一性状的总体变异比例，可归因于遗传变异，但这一统计数据的价值并不能说明涉及的基因数量，也不能说明导致性状遗传的分子途径。如果遗传力的经典估计与测量的dna序列变异的分析相结合，就可以检查特定遗传变异对性状遗传力的贡献。在第3章中，我将这两种方法结合应用于血液中sIL-6R的浓度测定。sIL-6R的变异在很大程度上可以通过影响sIL-6R产生的IL6R基因中的一个SNP来解释（rs2228145，总变异解释=51%，占总遗传力的71%）。通过连锁分析，我们发现剩余遗传力主要是…
The research described in this thesis was characterized by two major themes: the first was related to the question to which extent variation between individuals in inflammation biomarkers and metabolic syndrome traits are caused by the impact of genetic and environmental differences between people. The second important focus of this thesis went beyond the influence of the DNA sequence and examined epigenetic variation. I addressed the question how important genetic and non-genetic sources of variation are for individual differences in DNA methylation. DNA methylation is an epigenetic mechanism that receives increasing attention as it may provide novel insights into human disease and represents an extra layer causing differences between people. In this chapter, I summarize the most important results and discuss these findings in the broader context of the current state and future directions of research on complex trait genetics. Part 1: Characterizing the genetic architecture of inflammation biomarkers In the first part of this thesis (chapters 2 and 3), I examined the importance of genetic and environmental influences for individual differences in inflammation biomarkers, including pro-inflammatory cytokines (IL-6 and TNF-α), a soluble cytokine receptor (sIL-6R) and acute-phase proteins fibrinogen and CRP. Extended twin-family models showed that variation in all of these biomarkers of inflammation is to an important extent explained by genetic variation (figure 1). Moderate heritabilities were found for the concentrations of IL-6 (H 2 =21%), TNF-α (H 2 =39%), CRP (H 2 =45%), and fibrinogen (H 2 =46%). The levels of soluble IL-6 receptor levels in blood were highly heritable (H 2 =72%). The heritability reflects the overall proportion of variation of a trait in the population that can be attributed to genetic variation, but the value of this statistic does not give insight in the number of genes involved, or in the molecular pathways that give rise to the inheritance of traits. The importance of currently identified genetic variants The contribution of particular genetic variants to the heritability of a trait can be examined if classical estimation of heritability is combined with the analysis of measured DNA-sequence variants. In chapter 3, I applied this combination of methods to the concentration of sIL-6R in blood. The variance of sIL-6R was largely explained by a single SNP in the IL6R gene that influences the production of sIL-6R (rs2228145, total variance explained=51%; 71% of the total heritability). Through linkage analysis, we found evidence that the remaining heritability is mostly …