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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. / Folkersen, L.; Gustafsson, S.; Wang, Q.; Hansen, D.H.; Hedman, Å.K.; Schork, A.; Page, K.; Zhernakova, D.V.; Wu, Y.; Peters, J.; Eriksson, N.; Bergen, S.E.; Boutin, T.S.; Bretherick, A.D.; Enroth, S.; Kalnapenkis, A.; Gådin, J.R.; Suur, B.E.; Chen, Y.; Matic, L.; Gale, J.D.; Lee, J.; Zhang, W.; Quazi, A.; Ala-Korpela, M.; Choi, S.H.; Claringbould, A.; Danesh, J.; Davey Smith, G.; de Masi, F.; Elmståhl, S.; Engström, G.; Fauman, E.; Fernandez, C.; Franke, L.; Franks, P.W.; Giedraitis, V.; Haley, C.; Hamsten, A.; Ingason, A.; Johansson, Å.; Joshi, P.K.; Lind, L.; Lindgren, C.M.; Lubitz, S.; Palmer, T.; Macdonald-Dunlop, E.; Magnusson, M.; Melander, O.; Michaelsson, K.; Morris, A.P.; Mägi, R.; Nagle, M.W.; Nilsson, P.M.; Nilsson, J.; Orho-Melander, M.; Polasek, O.; Prins, B.; Pålsson, E.; Qi, T.; Sjögren, M.; Sundström, J.; Surendran, P.; Võsa, U.; Werge, T.; Wernersson, R.; Westra, H.-J.; Yang, J.; Zhernakova, A.; Ärnlöv, J.; Fu, J.; Smith, J.G.; Esko, T.; Hayward, C.; Gyllensten, U.; Landen, M.; Siegbahn, A.; Wilson, J.F.; Wallentin, L.; Butterworth, A.S.; Holmes, M.V.; Ingelsson, E.; Mälarstig, A.

In: Nature Metabolism, Vol. 2, No. 10, 16.10.2020, p. 1135-1148.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Folkersen, L, Gustafsson, S, Wang, Q, Hansen, DH, Hedman, ÅK, Schork, A, Page, K, Zhernakova, DV, Wu, Y, Peters, J, Eriksson, N, Bergen, SE, Boutin, TS, Bretherick, AD, Enroth, S, Kalnapenkis, A, Gådin, JR, Suur, BE, Chen, Y, Matic, L, Gale, JD, Lee, J, Zhang, W, Quazi, A, Ala-Korpela, M, Choi, SH, Claringbould, A, Danesh, J, Davey Smith, G, de Masi, F, Elmståhl, S, Engström, G, Fauman, E, Fernandez, C, Franke, L, Franks, PW, Giedraitis, V, Haley, C, Hamsten, A, Ingason, A, Johansson, Å, Joshi, PK, Lind, L, Lindgren, CM, Lubitz, S, Palmer, T, Macdonald-Dunlop, E, Magnusson, M, Melander, O, Michaelsson, K, Morris, AP, Mägi, R, Nagle, MW, Nilsson, PM, Nilsson, J, Orho-Melander, M, Polasek, O, Prins, B, Pålsson, E, Qi, T, Sjögren, M, Sundström, J, Surendran, P, Võsa, U, Werge, T, Wernersson, R, Westra, H-J, Yang, J, Zhernakova, A, Ärnlöv, J, Fu, J, Smith, JG, Esko, T, Hayward, C, Gyllensten, U, Landen, M, Siegbahn, A, Wilson, JF, Wallentin, L, Butterworth, AS, Holmes, MV, Ingelsson, E & Mälarstig, A 2020, 'Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals', Nature Metabolism, vol. 2, no. 10, pp. 1135-1148. https://doi.org/10.1038/s42255-020-00287-2

APA

Folkersen, L., Gustafsson, S., Wang, Q., Hansen, D. H., Hedman, Å. K., Schork, A., Page, K., Zhernakova, D. V., Wu, Y., Peters, J., Eriksson, N., Bergen, S. E., Boutin, T. S., Bretherick, A. D., Enroth, S., Kalnapenkis, A., Gådin, J. R., Suur, B. E., Chen, Y., ... Mälarstig, A. (2020). Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nature Metabolism, 2(10), 1135-1148. https://doi.org/10.1038/s42255-020-00287-2

Vancouver

Folkersen L, Gustafsson S, Wang Q, Hansen DH, Hedman ÅK, Schork A et al. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nature Metabolism. 2020 Oct 16;2(10):1135-1148. https://doi.org/10.1038/s42255-020-00287-2

Author

Folkersen, L. ; Gustafsson, S. ; Wang, Q. ; Hansen, D.H. ; Hedman, Å.K. ; Schork, A. ; Page, K. ; Zhernakova, D.V. ; Wu, Y. ; Peters, J. ; Eriksson, N. ; Bergen, S.E. ; Boutin, T.S. ; Bretherick, A.D. ; Enroth, S. ; Kalnapenkis, A. ; Gådin, J.R. ; Suur, B.E. ; Chen, Y. ; Matic, L. ; Gale, J.D. ; Lee, J. ; Zhang, W. ; Quazi, A. ; Ala-Korpela, M. ; Choi, S.H. ; Claringbould, A. ; Danesh, J. ; Davey Smith, G. ; de Masi, F. ; Elmståhl, S. ; Engström, G. ; Fauman, E. ; Fernandez, C. ; Franke, L. ; Franks, P.W. ; Giedraitis, V. ; Haley, C. ; Hamsten, A. ; Ingason, A. ; Johansson, Å. ; Joshi, P.K. ; Lind, L. ; Lindgren, C.M. ; Lubitz, S. ; Palmer, T. ; Macdonald-Dunlop, E. ; Magnusson, M. ; Melander, O. ; Michaelsson, K. ; Morris, A.P. ; Mägi, R. ; Nagle, M.W. ; Nilsson, P.M. ; Nilsson, J. ; Orho-Melander, M. ; Polasek, O. ; Prins, B. ; Pålsson, E. ; Qi, T. ; Sjögren, M. ; Sundström, J. ; Surendran, P. ; Võsa, U. ; Werge, T. ; Wernersson, R. ; Westra, H.-J. ; Yang, J. ; Zhernakova, A. ; Ärnlöv, J. ; Fu, J. ; Smith, J.G. ; Esko, T. ; Hayward, C. ; Gyllensten, U. ; Landen, M. ; Siegbahn, A. ; Wilson, J.F. ; Wallentin, L. ; Butterworth, A.S. ; Holmes, M.V. ; Ingelsson, E. ; Mälarstig, A. / Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. In: Nature Metabolism. 2020 ; Vol. 2, No. 10. pp. 1135-1148.

Bibtex

@article{35abdb95069140ba82676d67313ec17d,
title = "Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals",
abstract = "Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health. ",
keywords = "ABC transporter A1, ADAM protein, biological marker, caspase 8, chemokine receptor CCR2, chemokine receptor CCR5, chitinase 3 like protein 1, creatinine, CXCL16 chemokine, epidermal growth factor, galanin, growth differentiation factor 15, high density lipoprotein cholesterol, interleukin 16, macrophage elastase, macrophage inflammatory protein 1alpha, myoglobin, pregnancy associated plasma protein A, programmed death 1 ligand 1, protein kinase, RANTES, somatomedin binding protein, spondin 1, triacylglycerol, tribbles homolog 1, tumor necrosis factor, unclassified drug, Article, atherosclerosis, atopy, bioinformatics, body mass, bone density, cardiovascular disease, cardiovascular risk, clinical article, clinical outcome, cohort analysis, enzyme linked immunosorbent assay, estimated glomerular filtration rate, gene expression, genetic analysis, genetic regulation, genetic susceptibility, genome-wide association study, genotype, haplotype, human, human tissue, IC50, lipid metabolism, machine learning, Mendelian randomization analysis, meta analysis, metabolite, observational study, personalized medicine, phenotype, pleiotropy, priority journal, quantitative trait locus, risk factor, single nucleotide polymorphism",
author = "L. Folkersen and S. Gustafsson and Q. Wang and D.H. Hansen and {\AA}.K. Hedman and A. Schork and K. Page and D.V. Zhernakova and Y. Wu and J. Peters and N. Eriksson and S.E. Bergen and T.S. Boutin and A.D. Bretherick and S. Enroth and A. Kalnapenkis and J.R. G{\aa}din and B.E. Suur and Y. Chen and L. Matic and J.D. Gale and J. Lee and W. Zhang and A. Quazi and M. Ala-Korpela and S.H. Choi and A. Claringbould and J. Danesh and {Davey Smith}, G. and {de Masi}, F. and S. Elmst{\aa}hl and G. Engstr{\"o}m and E. Fauman and C. Fernandez and L. Franke and P.W. Franks and V. Giedraitis and C. Haley and A. Hamsten and A. Ingason and {\AA}. Johansson and P.K. Joshi and L. Lind and C.M. Lindgren and S. Lubitz and T. Palmer and E. Macdonald-Dunlop and M. Magnusson and O. Melander and K. Michaelsson and A.P. Morris and R. M{\"a}gi and M.W. Nagle and P.M. Nilsson and J. Nilsson and M. Orho-Melander and O. Polasek and B. Prins and E. P{\aa}lsson and T. Qi and M. Sj{\"o}gren and J. Sundstr{\"o}m and P. Surendran and U. V{\~o}sa and T. Werge and R. Wernersson and H.-J. Westra and J. Yang and A. Zhernakova and J. {\"A}rnl{\"o}v and J. Fu and J.G. Smith and T. Esko and C. Hayward and U. Gyllensten and M. Landen and A. Siegbahn and J.F. Wilson and L. Wallentin and A.S. Butterworth and M.V. Holmes and E. Ingelsson and A. M{\"a}larstig",
year = "2020",
month = oct,
day = "16",
doi = "10.1038/s42255-020-00287-2",
language = "English",
volume = "2",
pages = "1135--1148",
journal = "Nature Metabolism",
number = "10",

}

RIS

TY - JOUR

T1 - Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

AU - Folkersen, L.

AU - Gustafsson, S.

AU - Wang, Q.

AU - Hansen, D.H.

AU - Hedman, Å.K.

AU - Schork, A.

AU - Page, K.

AU - Zhernakova, D.V.

AU - Wu, Y.

AU - Peters, J.

AU - Eriksson, N.

AU - Bergen, S.E.

AU - Boutin, T.S.

AU - Bretherick, A.D.

AU - Enroth, S.

AU - Kalnapenkis, A.

AU - Gådin, J.R.

AU - Suur, B.E.

AU - Chen, Y.

AU - Matic, L.

AU - Gale, J.D.

AU - Lee, J.

AU - Zhang, W.

AU - Quazi, A.

AU - Ala-Korpela, M.

AU - Choi, S.H.

AU - Claringbould, A.

AU - Danesh, J.

AU - Davey Smith, G.

AU - de Masi, F.

AU - Elmståhl, S.

AU - Engström, G.

AU - Fauman, E.

AU - Fernandez, C.

AU - Franke, L.

AU - Franks, P.W.

AU - Giedraitis, V.

AU - Haley, C.

AU - Hamsten, A.

AU - Ingason, A.

AU - Johansson, Å.

AU - Joshi, P.K.

AU - Lind, L.

AU - Lindgren, C.M.

AU - Lubitz, S.

AU - Palmer, T.

AU - Macdonald-Dunlop, E.

AU - Magnusson, M.

AU - Melander, O.

AU - Michaelsson, K.

AU - Morris, A.P.

AU - Mägi, R.

AU - Nagle, M.W.

AU - Nilsson, P.M.

AU - Nilsson, J.

AU - Orho-Melander, M.

AU - Polasek, O.

AU - Prins, B.

AU - Pålsson, E.

AU - Qi, T.

AU - Sjögren, M.

AU - Sundström, J.

AU - Surendran, P.

AU - Võsa, U.

AU - Werge, T.

AU - Wernersson, R.

AU - Westra, H.-J.

AU - Yang, J.

AU - Zhernakova, A.

AU - Ärnlöv, J.

AU - Fu, J.

AU - Smith, J.G.

AU - Esko, T.

AU - Hayward, C.

AU - Gyllensten, U.

AU - Landen, M.

AU - Siegbahn, A.

AU - Wilson, J.F.

AU - Wallentin, L.

AU - Butterworth, A.S.

AU - Holmes, M.V.

AU - Ingelsson, E.

AU - Mälarstig, A.

PY - 2020/10/16

Y1 - 2020/10/16

N2 - Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.

AB - Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.

KW - ABC transporter A1

KW - ADAM protein

KW - biological marker

KW - caspase 8

KW - chemokine receptor CCR2

KW - chemokine receptor CCR5

KW - chitinase 3 like protein 1

KW - creatinine

KW - CXCL16 chemokine

KW - epidermal growth factor

KW - galanin

KW - growth differentiation factor 15

KW - high density lipoprotein cholesterol

KW - interleukin 16

KW - macrophage elastase

KW - macrophage inflammatory protein 1alpha

KW - myoglobin

KW - pregnancy associated plasma protein A

KW - programmed death 1 ligand 1

KW - protein kinase

KW - RANTES

KW - somatomedin binding protein

KW - spondin 1

KW - triacylglycerol

KW - tribbles homolog 1

KW - tumor necrosis factor

KW - unclassified drug

KW - Article

KW - atherosclerosis

KW - atopy

KW - bioinformatics

KW - body mass

KW - bone density

KW - cardiovascular disease

KW - cardiovascular risk

KW - clinical article

KW - clinical outcome

KW - cohort analysis

KW - enzyme linked immunosorbent assay

KW - estimated glomerular filtration rate

KW - gene expression

KW - genetic analysis

KW - genetic regulation

KW - genetic susceptibility

KW - genome-wide association study

KW - genotype

KW - haplotype

KW - human

KW - human tissue

KW - IC50

KW - lipid metabolism

KW - machine learning

KW - Mendelian randomization analysis

KW - meta analysis

KW - metabolite

KW - observational study

KW - personalized medicine

KW - phenotype

KW - pleiotropy

KW - priority journal

KW - quantitative trait locus

KW - risk factor

KW - single nucleotide polymorphism

U2 - 10.1038/s42255-020-00287-2

DO - 10.1038/s42255-020-00287-2

M3 - Journal article

VL - 2

SP - 1135

EP - 1148

JO - Nature Metabolism

JF - Nature Metabolism

IS - 10

ER -