Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
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年龄，性别和遗传学在塑造人类免疫反应对微生物挑战的转录变化中的独特作用。
DOI：
10.1073/pnas.1714765115
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发表时间：
2018-01-16
影响因子：
11.1
通讯作者：
Milieu Intérieur Consortium
中科院分区：
文献类型：
--
作者：
Piasecka B;Duffy D;Urrutia A;Quach H;Patin E;Posseme C;Bergstedt J;Charbit B;Rouilly V;MacPherson CR;Hasan M;Albaud B;Gentien D;Fellay J;Albert ML;Quintana-Murci L;Milieu Intérieur Consortium
确定人类免疫系统个体间多样性的驱动因素对于了解其对免疫介导疾病的影响至关重要。通过检查1000个个体对各种微生物挑战的转录反应，我们发现年龄和性别影响许多免疫相关基因的表达，但它们的影响总体上是温和的，而遗传因素影响较小的基因集，但具有更强的影响。我们确定了许多影响感染转录变异的遗传变异，其中许多与自身免疫性或炎症性疾病有关。这些结果使我们能够进一步探索调节变异在免疫相关疾病发病机制中的作用，并提高我们对年龄、性别和遗传对免疫反应变异的各自影响的理解。宿主遗传和非遗传因素对人类免疫差异的影响在很大程度上仍未明确。在这里，我们在1000名年龄和性别平衡的健康个体中生成了细菌、真菌和病毒诱导的免疫转录谱，并寻找免疫反应变异的决定因素。我们发现年龄和性别影响大多数免疫相关基因的转录反应，与性别影响相比，年龄影响更具刺激特异性，这在很大程度上是在不同条件下共享的。虽然特定的细胞群介导年龄和性别对基因表达的影响，包括年龄的CD8+ T细胞和性别的CD4+ T细胞和单核细胞，但我们发现这些内在因素对大多数免疫基因有直接影响。表达数量性状位点（eqtl）图谱显示，遗传因素对免疫基因调控的影响强于年龄和性别，但影响的基因数量较少。重要的是，我们发现了许多只在免疫刺激上表现出调节作用的遗传变异，包括在CR1位点上的白色念珠菌特异性主调节剂。这些应答等效qtl在疾病相关变异中富集，特别是在自身免疫和炎症性疾病中，这表明疾病风险的差异可能是由于调节变异仅在免疫应激存在时发挥其作用。总之，本研究量化了年龄、性别、遗传和细胞异质性对免疫反应个体间变异性的各自影响，并为进一步探索不同感染风险或疾病结果的背景下提供了宝贵的资源。
Identifying the drivers of the interindividual diversity of the human immune system is crucial to understand their consequences on immune-mediated diseases. By examining the transcriptional responses of 1,000 individuals to various microbial challenges, we show that age and sex influence the expression of many immune-related genes, but their effects are overall moderate, whereas genetic factors affect a smaller gene set but with a stronger effect. We identify numerous genetic variants that affect transcriptional variation on infection, many of which are associated with autoimmune or inflammatory disorders. These results enable additional exploration of the role of regulatory variants in the pathogenesis of immune-related diseases and improve our understanding of the respective effects of age, sex, and genetics on immune response variation. The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
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影响因子：
64.5
作者：
Brodin P;Jojic V;Gao T;Bhattacharya S;Angel CJ;Furman D;Shen-Orr S;Dekker CL;Swan GE;Butte AJ;Maecker HT;Davis MM
通讯作者：
Davis MM
影响因子：
12.3
作者：
Gibson G;Powell JE;Marigorta UM
通讯作者：
Marigorta UM
DOI：
10.1073/pnas.1115761109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Barreiro, Luis B.;Tailleux, Ludovic;Gilad, Yoav
通讯作者：
Gilad, Yoav
影响因子：
30.5
作者：
Davis MM;Tato CM;Furman D
通讯作者：
Furman D
影响因子：
30.8
作者：
Bentham J;Morris DL;Graham DSC;Pinder CL;Tombleson P;Behrens TW;Martín J;Fairfax BP;Knight JC;Chen L;Replogle J;Syvänen AC;Rönnblom L;Graham RR;Wither JE;Rioux JD;Alarcón-Riquelme ME;Vyse TJ
通讯作者：
Vyse TJ