Identification of genetic variants influencing the human plasma proteome
Identification of genetic variants influencing the human plasma proteome
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DOI：
10.1073/pnas.1217238110
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发表时间：
2013-03-19
影响因子：
11.1
通讯作者：
Gyllensten, Ulf
中科院分区：
文献类型：
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作者：
Johansson, Asa;Enroth, Stefan;Gyllensten, Ulf
影响转录组的遗传变异已经被广泛研究。然而，遗传因素对人类蛋白质组的影响在很大程度上还没有被探索，主要是因为缺乏合适的高通量方法。在这里，我们提出了通过结合高通量和高分辨率质谱仪(MS)和全基因组SNP数据，对影响人类血浆蛋白谱的遗传变异进行独特和全面的鉴定。我们鉴定和量化了1,056个经胰酶消化的多肽的丰度，代表来自两个基于人群的队列的1,060个个体的血浆中的163个蛋白质。近五分之一(19%)的多肽的丰度水平被发现是可遗传的，遗传力在0.08到0.43之间。顺式作用的SNPs影响了25种蛋白质中60种多肽的水平，占所研究蛋白质的15%。我们发现并复制了影响5个蛋白质中11个多肽的顺式作用SNPs(结合P值范围从3.1×10(-52)到2.9×10(-12))。这些SNP既代表了调节性SNPs，也代表了定义疾病等位基因的非同义变化，如载脂蛋白E(APOE)的epsilon 4等位基因，它已被证明会增加阿尔茨海默病的风险。我们的结果表明，高通量质谱学是一种很有前途的大规模表征人类蛋白质组的方法，允许对单个蛋白质进行量化和测序。蛋白质的丰度和多肽组成在许多疾病的病因、诊断和治疗中起着重要作用。因此，更好地了解遗传对血浆蛋白质组的影响对于评估常见疾病的潜在生物标志物和治疗剂是重要的。
Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis-acting SNPs. We identified and replicated individual cis-acting SNPs (combined P value ranging from 3.1 x 10(-52) to 2.9 x 10(-12)) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the epsilon 4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.