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Profiles of circulating histidine-rich glycoprotein associate with chronological age and risk of all-cause mortality

View ORCID ProfileMun-Gwan Hong, View ORCID ProfileTea Dodig-Crnković, View ORCID ProfileXu Chen, Kimi Drobin, View ORCID ProfileWoojoo Lee, Yunzhang Wang, Fredrik Edfors, View ORCID ProfileDavid Kotol, Cecilia Engel Thomas, View ORCID ProfileRonald Sjöberg, View ORCID ProfileJacob Odeberg, Anders Hamsten, View ORCID ProfileAngela Silveira, View ORCID ProfilePer Hall, View ORCID ProfilePeter Nilsson, View ORCID ProfileYudi Pawitan, View ORCID ProfileSara Hägg, View ORCID ProfileMathias Uhlén, View ORCID ProfileNancy L. Pedersen, View ORCID ProfilePatrik K. E. Magnusson, View ORCID ProfileJochen M. Schwenk
doi: https://doi.org/10.1101/464909
Mun-Gwan Hong
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Tea Dodig-Crnković
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Xu Chen
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
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Kimi Drobin
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Woojoo Lee
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
3Department of Public Health Science, Graduate School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea
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Yunzhang Wang
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
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Fredrik Edfors
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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David Kotol
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Cecilia Engel Thomas
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Ronald Sjöberg
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Jacob Odeberg
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
4Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Solna, Sweden
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Anders Hamsten
5Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Akademiska Stråket 1, SE-171 64 Solna, Sweden
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Angela Silveira
5Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Akademiska Stråket 1, SE-171 64 Solna, Sweden
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Per Hall
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
6Department of Oncology, Södersjukhuset, Sjukhusbacken 10, SE-118 83 Stockholm, Sweden
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Peter Nilsson
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Yudi Pawitan
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
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Sara Hägg
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
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Mathias Uhlén
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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Nancy L. Pedersen
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
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Patrik K. E. Magnusson
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, SE-171 77 Stockholm, Sweden
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Jochen M. Schwenk
1Science for Life Laboratory, Department of Protein Science, KTH - Royal Institute of Technology, Tomtebodavägen 23, SE-171 21 Solna, Sweden
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  • For correspondence: jochen.schwenk@scilifelab.se
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1. SUMMARY

Despite recognizing aging as risk factor of human diseases, little is still known about the molecular traits of biological age and mortality risk. To identify age-associated proteins circulating human blood, we screened 156 subjects aged 50-92 years using an exploratory and multiplexed affinity proteomics approach. We corroborated the top age-associated protein profile (adjusted P < 0.001) in eight additional study sets (N = 4,044 individuals), and confirmed a consistent age-associated increase (P = 6.61 × 10-6) by meta-analysis. Applying antibody validation determined circulating histidine-rich glycoprotein (HRG) as the target, and we observed that sequence variants influenced the antibodies ability to bind to the protein. Profiles of circulating HRG were associated to several clinical traits and predicted the risk of mortality during a follow-up period of 8.5 years (IQR = 7.7-9.3 years) after blood sampling (HR = 1.25 per SD; 95% CI = 1.12-1.39; P = 7.41 × 10-5). In conclusion, our affinity proteomics analysis found associations between the molecular traits of circulating HRG with age and all-cause mortality. This suggests that the profiles of multi-purpose protein HRG could serve as an accessible indicator of physiological processes related to aging.

Footnotes

  • The manuscript was revised to improve clarification of what we measured. More possible explanations were added why the profiles affected by 204th amino-acid of histidine-rich glycoprotein (HRG) could predict all-cause mortality. The investigation of HRG profiles on clinical traits and molecular analysis using mass spectrometry were included.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 02, 2020.
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Profiles of circulating histidine-rich glycoprotein associate with chronological age and risk of all-cause mortality
Mun-Gwan Hong, Tea Dodig-Crnković, Xu Chen, Kimi Drobin, Woojoo Lee, Yunzhang Wang, Fredrik Edfors, David Kotol, Cecilia Engel Thomas, Ronald Sjöberg, Jacob Odeberg, Anders Hamsten, Angela Silveira, Per Hall, Peter Nilsson, Yudi Pawitan, Sara Hägg, Mathias Uhlén, Nancy L. Pedersen, Patrik K. E. Magnusson, Jochen M. Schwenk
bioRxiv 464909; doi: https://doi.org/10.1101/464909
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Profiles of circulating histidine-rich glycoprotein associate with chronological age and risk of all-cause mortality
Mun-Gwan Hong, Tea Dodig-Crnković, Xu Chen, Kimi Drobin, Woojoo Lee, Yunzhang Wang, Fredrik Edfors, David Kotol, Cecilia Engel Thomas, Ronald Sjöberg, Jacob Odeberg, Anders Hamsten, Angela Silveira, Per Hall, Peter Nilsson, Yudi Pawitan, Sara Hägg, Mathias Uhlén, Nancy L. Pedersen, Patrik K. E. Magnusson, Jochen M. Schwenk
bioRxiv 464909; doi: https://doi.org/10.1101/464909

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