Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells.
Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells.
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自身免疫性疾病基因表达的调控和 CD4+ 效应记忆 T 细胞增殖的遗传基础。
DOI：
10.1371/journal.pgen.1004404
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
Raychaudhuri S
中科院分区：
文献类型：
--
作者：
Hu X;Kim H;Raj T;Brennan PJ;Trynka G;Teslovich N;Slowikowski K;Chen WM;Onengut S;Baecher-Allan C;De Jager PL;Rich SS;Stranger BE;Brenner MB;Raychaudhuri S
全基因组关联研究（GWAS）和随后的相关基因座的密集基因分型确定了100多个与类风湿性关节炎（RA）、1型糖尿病（T1 D）和乳糜泻（CeD）风险相关的单核苷酸多态性（SNP）变体。免疫学和遗传学研究表明，CD 4阳性效应记忆T（CD+ TEM）细胞在这些疾病的发病机制中的作用。为了阐明自身免疫性疾病等位基因的机制，我们研究了可能受这些变体影响的CD 4+效应记忆T细胞的分子表型。在一组基因分型的健康个体中，我们从外周血中分离出高纯度的CD 4 + TEM细胞，然后测定相对丰度，T细胞受体（TCR）刺激后的增殖，以及刺激前后疾病位点内215个基因的转录。我们确定了46个基因调控的顺式作用的表达数量性状位点（eQTL），其中大部分我们在刺激的细胞中检测到。46个eQTL基因中有11个在外周血单个核细胞中未检测到。在RA、T1 D和/或CeD的96个高风险等位基因中，有11个cis-eQTL重叠，其中5个等位基因完全解释了各自的信号。非编码变体rs389862 A增加了增殖反应（p = 4.75×10−8）。 此外，静息细胞中17个基因的基线表达可靠地预测了TCR刺激后的增殖反应。然而，引人注目的是，没有证据表明风险等位基因调节CD 4 + TEM丰度或增殖。我们的研究强调了检查相关细胞中的分子表型和条件对于了解疾病变异的致病机制的作用。全基因组关联研究已经确定了数百种与自身免疫性疾病相关的遗传变异。为了了解这些变异影响的机制和途径，需要对分子表型和功能进行后续研究。鉴于免疫系统内细胞类型的多样性和功能的专门化，这些研究重点关注特定和相关的细胞类型至关重要。在这里，我们研究了CD 4阳性效应记忆T（CD 4 + TEM）细胞的遗传和细胞特征，这在类风湿性关节炎，乳糜泻和1型糖尿病的发病中特别重要。在一组健康个体中，我们纯化了CD 4 + TEM细胞，测定了全基因组单核苷酸多态性（SNP），血液中CD 4 + TEM细胞的丰度，T细胞受体刺激后的增殖，以及静息和刺激状态下的215个基因转录本。我们发现46个基因的表达水平受附近SNP的调控，包括疾病相关SNP。这些表达数量性状基因座中的许多基因座以前没有在更异质的外周血细胞的研究中发现。我们证明了CD 4 + TEM细胞的相对丰度和增殖反应在人群中各不相同，但是疾病等位基因不太可能通过调节这种细胞类型中的这些特征来赋予风险。
Genome-wide association studies (GWAS) and subsequent dense-genotyping of associated loci identified over a hundred single-nucleotide polymorphism (SNP) variants associated with the risk of rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CeD). Immunological and genetic studies suggest a role for CD4-positive effector memory T (CD+ TEM) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4+ effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4+ TEM cells from peripheral blood, then assayed relative abundance, proliferation upon T cell receptor (TCR) stimulation, and the transcription of 215 genes within disease loci before and after stimulation. We identified 46 genes regulated by cis-acting expression quantitative trait loci (eQTL), the majority of which we detected in stimulated cells. Eleven of the 46 genes with eQTLs were previously undetected in peripheral blood mononuclear cells. Of 96 risk alleles of RA, T1D, and/or CeD in densely genotyped loci, eleven overlapped cis-eQTLs, of which five alleles completely explained the respective signals. A non-coding variant, rs389862A, increased proliferative response (p = 4.75×10−8). In addition, baseline expression of seventeen genes in resting cells reliably predicted proliferative response after TCR stimulation. Strikingly, however, there was no evidence that risk alleles modulated CD4+ TEM abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants. Genome-wide association studies have identified hundreds of genetic variants associated to autoimmune diseases. To understand the mechanisms and pathways affected by these variants, follow-up studies of molecular phenotypes and functions are required. Given the diversity of cell types and specialization of functions within the immune system, it is crucial that such studies focus on specific and relevant cell types. Here, we studied genetic and cellular traits of CD4-positive effector memory T (CD4+ TEM) cells, which are particularly important in the onset of rheumatoid arthritis, celiac disease, and type 1 diabetes. In a cohort of healthy individuals, we purified CD4+ TEM cells, assayed genome-wide single nucleotide polymorphisms (SNPs), abundance of CD4+ TEM cells in blood, proliferation upon T cell receptor stimulation, and 215 gene transcripts in resting and stimulated states. We found that expression levels of 46 genes were regulated by nearby SNPs, including disease-associated SNPs. Many of these expression quantitative trait loci were not previously seen in studies of more heterogeneous peripheral blood cells. We demonstrated that relative abundance and proliferative response of CD4+ TEM cells varied in the population, however disease alleles are unlikely to confer risk by modulating these traits in this cell type.
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影响因子：
4.5
作者：
Stranger BE;Montgomery SB;Dimas AS;Parts L;Stegle O;Ingle CE;Sekowska M;Smith GD;Evans D;Gutierrez-Arcelus M;Price A;Raj T;Nisbett J;Nica AC;Beazley C;Durbin R;Deloukas P;Dermitzakis ET
通讯作者：
Dermitzakis ET
影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
影响因子：
20.3
作者：
Sattler, Arne;Wagner, Ulf;Thiel, Andreas
通讯作者：
Thiel, Andreas
影响因子：
5.3
作者：
Saule, P;Trauet, J;Labalette, M
通讯作者：
Labalette, M
影响因子：
4.4
作者：
Sommers, Connie L.;Gurson, Jordan M.;Samelson, Lawrence E.
通讯作者：
Samelson, Lawrence E.