Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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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 -