Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.
Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.
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DOI：
10.1016/j.celrep.2018.09.048
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发表时间：
2018-10-16
期刊：
影响因子：
8.8
通讯作者：
Goris A
中科院分区：
文献类型：
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作者：
Lagou V;Garcia-Perez JE;Smets I;Van Horebeek L;Vandebergh M;Chen L;Mallants K;Prezzemolo T;Hilven K;Humblet-Baron S;Moisse M;Van Damme P;Boeckxstaens G;Bowness P;Dubois B;Dooley J;Liston A;Goris A
免疫系统是高度多样化的，但其遗传结构的表征已经落后于新兴疾病的全基因组关联研究（GWAS）所取得的巨大进展。我们对489名健康个体中54种适应性免疫系统功能相关表型的GWAS确定了8种全基因组显著相关性，解释了6%-20%的方差。PTPRC和COMMD 10中的编码和剪接变体参与记忆T细胞分化。控制疾病相关辅助性T细胞亚群的遗传变异包括分别与Th 2和Th 17相关的RICTOR和STON 2，以及控制调节性T细胞增殖的干扰素-λ基因座。早期和记忆B细胞分化阶段与LARP 1 B和SP 4的变化相关。最后，latrophilin家族成员ADGRL 2与基线促炎性白细胞介素-6水平相关。暗示性关联揭示了自身免疫性疾病关联的机制，特别是与促炎细胞因子产生相关的机制。精确定位这些关键的人类免疫调节剂提供了有吸引力的治疗前景。GWAS提供了对形成适应性免疫系统的遗传因素的理解。常见和不太常见的变异解释了细胞变量10%的变异。相关性确定了B和T细胞分化的关键调节因子。相关性为控制促炎特征提供了治疗靶点。确定遗传因素解释个体间的适应性免疫系统组成的变化。因子精确定位控制B和T细胞分化以及疾病相关T辅助细胞和调节细胞水平的关键人类免疫调节因子。这些发现阐明了自身免疫性疾病的机制，并提供了治疗前景。
The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%–20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives. GWAS provides understanding of genetic factors shaping adaptive immune system Common and less common variants explain 10% of variance in cellular variables Associations pinpoint key regulators of B and T cell differentiation Associations offer therapeutic targets for controlling pro-inflammatory traits Lagou et al. identify genetic factors explaining interindividual variation in composition of the adaptive immune system. Factors pinpoint key human immune regulators controlling B and T cell differentiation and levels of disease-relevant T helper and regulatory cells. These findings shed light on mechanisms of autoimmune disease and offer therapeutic perspectives.
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影响因子：
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作者：
Freudenberg, Jan;Lee, Hye-Soon;Bae, Sang-Cheol
通讯作者：
Bae, Sang-Cheol
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Jia X;Zha T;Wu B;Zhang Y;Chen W;Wang X;Yu H;He G
通讯作者：
He G
DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M