scholarly journals Consequences of natural perturbations in the human plasma proteome

2017 ◽  
Author(s):  
Benjamin B. Sun ◽  
Joseph C. Maranville ◽  
James E. Peters ◽  
David Stacey ◽  
James R. Staley ◽  
...  
Keyword(s):  
Human Plasma ◽  
Drug Targets ◽  
Fold Increase ◽  
Plasma Proteome ◽  
Genetic Associations ◽  
Protein Biomarkers ◽  
Protein Levels ◽  
Drug Databases ◽  
Potential Safety ◽  
Human Plasma Proteome

AbstractProteins are the primary functional units of biology and the direct targets of most drugs, yet there is limited knowledge of the genetic factors determining inter-individual variation in protein levels. Here we reveal the genetic architecture of the human plasma proteome, testing 10.6 million DNA variants against levels of 2,994 proteins in 3,301 individuals. We identify 1,927 genetic associations with 1,478 proteins, a 4-fold increase on existing knowledge, including trans associations for 1,104 proteins. To understand consequences of perturbations in plasma protein levels, we introduce an approach that links naturally occurring genetic variation with biological, disease, and drug databases. We provide insights into pathogenesis by uncovering the molecular effects of disease-associated variants. We identify causal roles for protein biomarkers in disease through Mendelian randomization analysis. Our results reveal new drug targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

scholarly journals Statistical Analysis of Variation in the Human Plasma Proteome

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Todd H. Corzett ◽  
Imola K. Fodor ◽  
Megan W. Choi ◽  
Vicki L. Walsworth ◽  
Kenneth W. Turteltaub ◽  
...  
Keyword(s):  
Human Plasma ◽  
Individual Variation ◽  
Fixed Effects ◽  
Biomarker Discovery ◽  
Plasma Proteome ◽  
Protein Levels ◽  
Mixed Effects Modeling ◽  
Experimental Variation ◽  
Analysis Of Variation ◽  
Human Plasma Proteome

Quantifying the variation in the human plasma proteome is an essential prerequisite for disease-specific biomarker detection. We report here on the longitudinal and individual variation in human plasma characterized by two-dimensional difference gel electrophoresis (2-D DIGE) using plasma samples from eleven healthy subjects collected three times over a two week period. Fixed-effects modeling was used to remove dye and gel variability. Mixed-effects modeling was then used to quantitate the sources of proteomic variation. The subject-to-subject variation represented the largest variance component, while the time-within-subject variation was comparable to the experimental variation found in a previous technical variability study where one human plasma sample was processed eight times in parallel and each was then analyzed by 2-D DIGE in triplicate. Here, 21 protein spots had larger than 50% CV, suggesting that these proteins may not be appropriate as biomarkers and should be carefully scrutinized in future studies. Seventy-eight protein spots showing differential protein levels between different individuals or individual collections were identified by mass spectrometry and further characterized using hierarchical clustering. The results present a first step toward understanding the complexity of longitudinal and individual variation in the human plasma proteome, and provide a baseline for improved biomarker discovery.

Detectability of Plasma Proteins in SRM Measurements

2018 ◽  
Vol 16 (1) ◽  
pp. 74-81 ◽  
Author(s):  
Olga I. Kiseleva ◽  
Elena A. Ponomarenko ◽  
Yulia A. Romashova ◽  
Ekaterina V. Poverennaya ◽  
Andrey V. Lisitsa
Keyword(s):  
Blood Plasma ◽  
Human Plasma ◽  
Limit Of Detection ◽  
Human Blood Plasma ◽  
Analytical Sensitivity ◽  
Plasma Proteome ◽  
Protein Targets ◽  
Blood Plasma Sample ◽  
Specificity And Sensitivity ◽  
Human Plasma Proteome

Background: Liquid chromatography coupled with targeted mass spectrometry underwent rapid technical evolution during last years and has become widely used technology in clinical laboratories. It offers confident specificity and sensitivity superior to those of traditional immunoassays. However, due to controversial reports on reproducibility of SRM measurements, the prospects of clinical appliance of the method are worth discussing. </P><P> Objective: The study was aimed at assessment of capabilities of SRM to achieve a thorough assembly of the human plasma proteome. </P><P> Method: We examined set of 19 human blood plasma samples to measure 100 proteins, including FDA-approved biomarkers, via SRM-assay. </P><P> Results: Out of 100 target proteins 43 proteins were confidently detected in at least two blood plasma sample runs, 36 and 21 proteins were either not detected in any run or inconsistently detected, respectively. Empiric dependences on protein detectability were derived to predict the number of biological samples required to detect with certainty a diagnostically relevant quantum of the human plasma proteome. </P><P> Conclusion: The number of samples exponentially increases with an increase in the number of protein targets, while proportionally decreasing to the logarithm of the limit of detection. Analytical sensitivity and enormous proteome heterogeneity are major bottlenecks of the human proteome exploration.

Study of the human plasma proteome of rheumatoid arthritis

2009 ◽  
Vol 1216 (16) ◽  
pp. 3538-3545 ◽  
Author(s):  
Xiaoyang Zheng ◽  
Shiaw-lin Wu ◽  
Marina Hincapie ◽  
William S. Hancock
Keyword(s):  
Rheumatoid Arthritis ◽  
Human Plasma ◽  
Plasma Proteome ◽  
Human Plasma Proteome

scholarly journals Site specific modification of the human plasma proteome by methylglyoxal

2015 ◽  
Vol 289 (2) ◽  
pp. 155-162 ◽  
Author(s):  
Michael J. Kimzey ◽  
Owen R. Kinsky ◽  
Hussein N. Yassine ◽  
George Tsaprailis ◽  
Craig S. Stump ◽  
...  
Keyword(s):  
Human Plasma ◽  
Plasma Proteome ◽  
Site Specific ◽  
Specific Modification ◽  
Human Plasma Proteome
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