Quantitative variability of 342 plasma proteins in a human twin population

Liu, Yansheng; Buil, Alfonso; Collins, Ben C.; Gillet, Ludovic; Blum, Lorenz C.; Chen, Lin; Vitek, Olga; Mouritsen, Jeppe; Lachance, Geneviève; Spector, Tim D.; Dermitzakis, Emmanouil T.; Aebersold, Ruedi

doi:10.15252/msb.20145728

Cited by 315 publications

(352 citation statements)

References 80 publications

(135 reference statements)

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“…Mass spectrometry, a technology for peptide detection based on mass-to-charge ratio, has been used to quantify protein levels from plasma, detecting 1,904 peptides pertaining to 342 unique proteins 185 . Accurate quantification is challenging in mass spectrometry, but groups have solved this using relative quantification through labelling peptides with a different isotope per sample (the stable isotope labelling with amino acids in cell culture (SILAC) technique) and by developing methods for direct quantification that involve computational algorithms and machine calibration 197,198 .…”

Section: Figurementioning

confidence: 99%

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

2016

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Genome-wide strategies have driven the discovery of more than 300 susceptibility loci for autoimmune diseases. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in non-coding regions of the genome. A critical next step will be to identify the in vivo and ex vivo immunophenotypes that are affected by risk variants. To do this, key cell types and cell states that are implicated in autoimmune diseases will need to be defined. Functional genomic annotations from these cell types and states can then be used to resolve candidate genes and causal variants. Together with longitudinal studies, this approach may yield pivotal insights into how autoimmunity is triggered.

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Section: Figurementioning

confidence: 99%

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

2016

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“…A common approach to establishing a reference assay library involves numerous IDA experiments, usually using fractionated samples to create library depth. It is acknowledged that library building is time consuming, and for some samples, such as plasma which have a large dynamic range of protein abundances, IDA fails to have the penetrance to detect less abundant proteins in the sample (14,18). To underscore this point, it should be clearly recognized that a peptide must be present within an assay library for it to be detected and quantitated using the SWATH workflow with reference libraries.…”

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confidence: 99%

SWATH Mass Spectrometry Performance Using Extended Peptide MS/MS Assay Libraries

Song

Pascovici

et al. 2016

Molecular & Cellular Proteomics

101

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The use of data-independent acquisition methods such as SWATH for mass spectrometry based proteomics is usually performed with peptide MS/MS assay libraries which enable identification and quantitation of peptide peak areas. Reference assay libraries can be generated locally through information dependent acquisition, or obtained from community data repositories for commonly studied organisms. However, there have been no studies performed to systematically evaluate how locally generated or repository-based assay libraries affect SWATH performance for proteomic studies. To undertake this analysis, we developed a software workflow, SwathXtend, which generates extended peptide assay libraries by integration with a local seed library and delivers statistical analysis of SWATH-quantitative comparisons. We designed test samples using peptides from a yeast extract spiked into peptides from human K562 cell lysates at three different ratios to simulate protein abundance change comparisons. SWATH-MS performance was assessed using local and external assay libraries of varying complexities and proteome compositions. These experiments demonstrated that local seed libraries integrated with external assay libraries achieve better performance than local assay libraries alone, in terms of the number of identified peptides and proteins and the specificity to detect differentially abundant proteins. Our findings show that the performance of extended assay libraries is influenced by the MS/MS feature similarity of the seed and external libraries, while statistical analysis using multiple testing corrections increases the statistical rigor needed when searching against large extended assay libraries. Data Independent Acquisition (DIA) 1 mass spectrometry workflows are gaining increasing use for proteomic analysis of model systems (1-8). The first integrated DIA and quantitative analysis protocol, termed SWATH (2) was shown to offer accurate, reproducible, and robust proteomic quantification (9 -14). DIA offers advantages over conventional IDA methods (15) by overcoming the stochastic, intensity-based selection of peptide precursors-a problem which typically leads to inconsistent peptide detection and quantitation between replicate runs. By overcoming this problem, DIA is highly suited for large-scale comparative analyses as gaps in data points between samples are mostly eliminated. These digital, extensive proteome maps can be repeatedly mined for quantitative data by extracting ion chromatograms of defined peptides postacquisition, and yields fewer quantitative missing (NA) values than IDA. An important concept in DIA analysis is use of a LC-retention time referenced spectral ion assay library to enable peptide identification from DIA generated multiplexed MS/MS spectra (10,13,16). The depth and quality of this spectral reference library directly correlates with experimental outcome, therefore we consider it is essential to explore and understand this variable in detail.The reference assay library should contain all the prior knowle...

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“…Instead of coupling a quadrupole with an orbitrap mass analyzer, SWATH‐MS (sequential window acquisition of all theoretical masses) was implemented on a mass spectrometer which selects the precursors with a quadrupole and all fragment ions are analyzed by TOF 139. First clinical studies using SWATH‐MS demonstrated the usefulness of the method: Liu and colleagues concluded from the analysis of serum proteins of a longitudinal twin study that clinical serum biomarkers should be calibrated against genetic background and age adjusted 140.…”

Section: Resultsmentioning

confidence: 99%

Applications of targeted proteomics in systems biology and translational medicine

et al. 2015

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Biological systems are composed of numerous components of which proteins are of particularly high functional significance. Network models are useful abstractions for studying these components in context. Network representations display molecules as nodes and their interactions as edges. Because they are difficult to directly measure, functional edges are frequently inferred from suitably structured datasets consisting of the accurate and consistent quantification of network nodes under a multitude of perturbed conditions. For the precise quantification of a finite list of proteins across a wide range of samples, targeted proteomics exemplified by selected/multiple reaction monitoring (SRM, MRM) mass spectrometry has proven useful and has been applied to a variety of questions in systems biology and clinical studies. Here, we survey the literature of studies using SRM‐MS in systems biology and clinical proteomics. Systems biology studies frequently examine fundamental questions in network biology, whereas clinical studies frequently focus on biomarker discovery and validation in a variety of diseases including cardiovascular disease and cancer. Targeted proteomics promises to advance our understanding of biological networks and the phenotypic significance of specific network states and to advance biomarkers into clinical use.

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Quantitative variability of 342 plasma proteins in a human twin population

Cited by 315 publications

References 80 publications

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

SWATH Mass Spectrometry Performance Using Extended Peptide MS/MS Assay Libraries

Applications of targeted proteomics in systems biology and translational medicine

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