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Quantitative variability of 342 plasma proteins in a human twin population.

Liu Y, Buil A, Collins BC, Gillet LC, Blum LC, Cheng LY, Vitek O, Mouritsen J, Lachance G, Spector TD, Dermitzakis ET, Aebersold R - Mol. Syst. Biol. (2015)

Bottom Line: Because the twin study design provides a natural opportunity to estimate the relative contribution of heritability and environment to different traits in human population, we applied here the highly accurate and reproducible SWATH mass spectrometry technique to quantify 1,904 peptides defining 342 unique plasma proteins in 232 plasma samples collected longitudinally from pairs of monozygotic and dizygotic twins at intervals of 2-7 years, and proportioned the observed total quantitative variability to its root causes, genes, and environmental and longitudinal factors.The data further strongly suggest that the plasma concentrations of clinical biomarkers need to be calibrated against genetic and temporal factors.These results therefore have immediate implications for the effective design of blood-based biomarker studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland liu@imsb.biol.ethz.ch aebersold@imsb.biol.ethz.ch.

No MeSH data available.


Related in: MedlinePlus

pQTL discovery in human plasmaA Manhattan plot of the best P-value per gene, highlighting the 13 statistically significant pQTL associations. The asterisks indicate that the corresponding eQTLs were found in human tissues. The cutoff of the P-value is 6.166e-3.B Examples of pQTLs: plasma protein levels among the cohort of four proteins associated with innate immune response distributed by distinct genotypes of the SNPs (see Supplementary Table S3 for all abbreviations of protein names).
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fig05: pQTL discovery in human plasmaA Manhattan plot of the best P-value per gene, highlighting the 13 statistically significant pQTL associations. The asterisks indicate that the corresponding eQTLs were found in human tissues. The cutoff of the P-value is 6.166e-3.B Examples of pQTLs: plasma protein levels among the cohort of four proteins associated with innate immune response distributed by distinct genotypes of the SNPs (see Supplementary Table S3 for all abbreviations of protein names).

Mentions: Finally, we carried out association analysis to identify cis-SNPs regulating the levels of 303 (of the 342 measured) proteins that we could uniquely map to known genes. We first selected a total of 113 out of 116 individuals which passed the genotyping data quality control step. Second, we used the twin proteomic data to map the protein quantitative trait loci, or pQTLs by determining the statistical significance of the association between SNPs 1 Kb up and down the transcription start site for each gene and protein expression values. The final number of tested SNPs was 758. We found 13 genes with at least a statistically significant pQTL (Fig5A). Among them, four plasma proteins (ficolin-2, coagulation factor XII, complement component C8 gamma chain and complement C5) were annotated with the “innate immune response” process. The close association between genotype alleles and protein levels is shown in Fig5B. Similar distributions were obtained for all identified pQTLs (Supplementary Fig S9). We observed that most of the discovered pQTLs lie in regulatory regions and only 2 of them are in the coding region, but synonymous (Supplementary Table S4). To explore the functional role of the pQTLs, we assessed whether they have an effect on gene expression. We checked the association of the pQTLs with gene expression in four tissues (fat, skin, blood and lymphocyte cell lines (LCL)) in a cohort of about 800 female twins of the same population that are part of the Twin UK cohort with an identical age range. We called gene expression QTLs (eQTLs) in the four tissues by using gene expression measured by RNA-seq and genotype information (Buil et al, 2015). We could measure the gene expression of 9 of the 13 proteins with pQTLs, and we found that 5 of the 9 pQTLs are associated with eQTLs in at least one of the four tissues (Fig5A and Supplementary Table S4).


Quantitative variability of 342 plasma proteins in a human twin population.

Liu Y, Buil A, Collins BC, Gillet LC, Blum LC, Cheng LY, Vitek O, Mouritsen J, Lachance G, Spector TD, Dermitzakis ET, Aebersold R - Mol. Syst. Biol. (2015)

pQTL discovery in human plasmaA Manhattan plot of the best P-value per gene, highlighting the 13 statistically significant pQTL associations. The asterisks indicate that the corresponding eQTLs were found in human tissues. The cutoff of the P-value is 6.166e-3.B Examples of pQTLs: plasma protein levels among the cohort of four proteins associated with innate immune response distributed by distinct genotypes of the SNPs (see Supplementary Table S3 for all abbreviations of protein names).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358658&req=5

fig05: pQTL discovery in human plasmaA Manhattan plot of the best P-value per gene, highlighting the 13 statistically significant pQTL associations. The asterisks indicate that the corresponding eQTLs were found in human tissues. The cutoff of the P-value is 6.166e-3.B Examples of pQTLs: plasma protein levels among the cohort of four proteins associated with innate immune response distributed by distinct genotypes of the SNPs (see Supplementary Table S3 for all abbreviations of protein names).
Mentions: Finally, we carried out association analysis to identify cis-SNPs regulating the levels of 303 (of the 342 measured) proteins that we could uniquely map to known genes. We first selected a total of 113 out of 116 individuals which passed the genotyping data quality control step. Second, we used the twin proteomic data to map the protein quantitative trait loci, or pQTLs by determining the statistical significance of the association between SNPs 1 Kb up and down the transcription start site for each gene and protein expression values. The final number of tested SNPs was 758. We found 13 genes with at least a statistically significant pQTL (Fig5A). Among them, four plasma proteins (ficolin-2, coagulation factor XII, complement component C8 gamma chain and complement C5) were annotated with the “innate immune response” process. The close association between genotype alleles and protein levels is shown in Fig5B. Similar distributions were obtained for all identified pQTLs (Supplementary Fig S9). We observed that most of the discovered pQTLs lie in regulatory regions and only 2 of them are in the coding region, but synonymous (Supplementary Table S4). To explore the functional role of the pQTLs, we assessed whether they have an effect on gene expression. We checked the association of the pQTLs with gene expression in four tissues (fat, skin, blood and lymphocyte cell lines (LCL)) in a cohort of about 800 female twins of the same population that are part of the Twin UK cohort with an identical age range. We called gene expression QTLs (eQTLs) in the four tissues by using gene expression measured by RNA-seq and genotype information (Buil et al, 2015). We could measure the gene expression of 9 of the 13 proteins with pQTLs, and we found that 5 of the 9 pQTLs are associated with eQTLs in at least one of the four tissues (Fig5A and Supplementary Table S4).

Bottom Line: Because the twin study design provides a natural opportunity to estimate the relative contribution of heritability and environment to different traits in human population, we applied here the highly accurate and reproducible SWATH mass spectrometry technique to quantify 1,904 peptides defining 342 unique plasma proteins in 232 plasma samples collected longitudinally from pairs of monozygotic and dizygotic twins at intervals of 2-7 years, and proportioned the observed total quantitative variability to its root causes, genes, and environmental and longitudinal factors.The data further strongly suggest that the plasma concentrations of clinical biomarkers need to be calibrated against genetic and temporal factors.These results therefore have immediate implications for the effective design of blood-based biomarker studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland liu@imsb.biol.ethz.ch aebersold@imsb.biol.ethz.ch.

No MeSH data available.


Related in: MedlinePlus