High-Throughput Characterization of Blood Serum Proteomics of IBD Patients with Respect to Aging and Genetic Factors.
High-Throughput Characterization of Blood Serum Proteomics of IBD Patients with Respect to Aging and Genetic Factors.
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IBD 患者血清蛋白质组学与衰老和遗传因素的高通量表征
DOI：
10.1371/journal.pgen.1006565
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发表时间：
2017-01
期刊：
影响因子：
4.5
通讯作者：
Hao K
中科院分区：
文献类型：
--
作者：
Di Narzo AF;Telesco SE;Brodmerkel C;Argmann C;Peters LA;Li K;Kidd B;Dudley J;Cho J;Schadt EE;Kasarskis A;Dobrin R;Hao K
迄今为止，尚未对炎症性肠病（IBD）患者的血清蛋白质组进行大规模、系统的描述。通过使用微阵列技术，更完整地描述IBD患者的血液蛋白质组是可行的。这可能有助于更好地了解这种疾病。我们分析了欧洲血统IBD患者（84例克罗恩病（CD）患者和88例溃疡性结肠炎（UC）患者）以及15例健康对照者的1128种蛋白质的血清谱，并将蛋白质变异性与患者年龄（所有队列）和遗传成分（来自CD患者的基因型数据）联系起来。我们发现了新的，以前未报道的与衰老相关的蛋白质组学特征（如血清白蛋白水平），证实了以前报道的来自不同组织的结果（即APOE随着衰老而上调），并发现CD患者中MMP7的调节缺失。在对CD患者进行全基因组基因型-蛋白质关联研究（蛋白质组定量性状位点，pQTL）时，我们确定了41个受顺式pQTL影响的不同蛋白质组性状（潜在snp被称为psnp）。观察到同一基因对应的pqtl和cis eqtl之间存在显著的重叠，在某些情况下，QTL与炎症性疾病易感性相关。重要的是，我们发现MST1（巨噬细胞刺激1）的血清蛋白水平受SNP rs3197999的调控（p = 5.96E-10， FDR<5%），这是一个公认的IBD的GWAS位点。填补GWAS命中与疾病易感性之间分子机制的知识空白，需要系统地剖析基因座在细胞、mRNA表达和蛋白质水平上的影响。现在可用于大规模分子研究的技术和分析工具可以阐明由遗传多态性驱动的蛋白质组改变如何引起或提供预防疾病的保护。在此，我们通过将蛋白质组学和pqtl与现有的GWAS、mRNA表达和eQTL数据集整合，直接证明了这一点，从而深入了解IBD的生物学过程，并查明因果遗传变异及其下游分子后果。GWAS导致了100多个炎症性肠病（克罗恩病和溃疡性结肠炎）的易感位点。然而，这些疾病的分子病因尚不完全清楚。在这项研究中，我们分析了IBD和对照受试者的血清蛋白水平，并证明了一些蛋白质水平与克罗恩病（CD）和衰老之间的关联。我们首次报道了CD患者的蛋白质组学qtl (pQTLs)，鉴定了41个不同基因对应的蛋白质组学性状，这些基因在顺式中受到SNP基因型的显著影响。特别是，我们发现3号染色体上一个众所周知的IBD风险位点与巨噬细胞刺激1 （MST1）蛋白水平的显著变化有关。由于这一结果与肝脏和脂肪组织（但不是全血）中的MST1 eqtl一致，我们认为这种遗传多态性的一种可能的作用机制是改变MST1在某些组织（如肝脏和脂肪）中的表达和翻译，从而导致血清中MST1蛋白水平的改变，最终导致IBD风险增加。
To date, no large scale, systematic description of the blood serum proteome has been performed in inflammatory bowel disease (IBD) patients. By using microarray technology, a more complete description of the blood proteome of IBD patients is feasible. It may help to achieve a better understanding of the disease. We analyzed blood serum profiles of 1128 proteins in IBD patients of European descent (84 Crohn’s Disease (CD) subjects and 88 Ulcerative Colitis (UC) subjects) as well as 15 healthy control subjects, and linked protein variability to patient age (all cohorts) and genetic components (genotype data generated from CD patients). We discovered new, previously unreported aging-associated proteomic traits (such as serum Albumin level), confirmed previously reported results from different tissues (i.e., upregulation of APOE with aging), and found loss of regulation of MMP7 in CD patients. In carrying out a genome wide genotype-protein association study (proteomic Quantitative Trait Loci, pQTL) within the CD patients, we identified 41 distinct proteomic traits influenced by cis pQTLs (underlying SNPs are referred to as pSNPs). Significant overlaps between pQTLs and cis eQTLs corresponding to the same gene were observed and in some cases the QTL were related to inflammatory disease susceptibility. Importantly, we discovered that serum protein levels of MST1 (Macrophage Stimulating 1) were regulated by SNP rs3197999 (p = 5.96E-10, FDR<5%), an accepted GWAS locus for IBD. Filling the knowledge gap of molecular mechanisms between GWAS hits and disease susceptibility requires systematically dissecting the impact of the locus at the cell, mRNA expression, and protein levels. The technology and analysis tools that are now available for large-scale molecular studies can elucidate how alterations in the proteome driven by genetic polymorphisms cause or provide protection against disease. Herein, we demonstrated this directly by integrating proteomic and pQTLs with existing GWAS, mRNA expression, and eQTL datasets to provide insights into the biological processes underlying IBD and pinpoint causal genetic variants along with their downstream molecular consequences. GWAS have resulted in greater than one hundred susceptibility loci for inflammatory bowel disease (Crohn’s Disease and Ulcerative Colitis). However, the molecular etiology of these diseases is not completely understood. In this study we profiled serum protein levels in IBD and control subjects and demonstrated an association of the levels of some proteins to Crohn’s Disease (CD) as well as aging. For the first time, we report proteomic QTLs (pQTLs) among CD patients, identifying proteomic traits corresponding to 41 distinct genes that were significantly influenced by SNP genotypes in cis. Particularly, we found that a well-known IBD risk locus on chromosome 3 is associated with significant changes of Macrophage Stimulating 1 (MST1) protein levels. As this result is consistent with MST1 eQTLs in liver and adipose tissues (but not whole blood), we believe that one possible mechanism of action of this genetic polymorphism alters expression and translation of MST1 in certain tissues (e.g. liver and adipose), which in turn results in changes of serum levels of the MST1 protein, and ultimately leading to increased risk of IBD.