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DOI 10.1038/s42255-020-00287-2

Медицинская библиотека · Nature metabolism · 2020

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

Folkersen Lasse, Gustafsson Stefan, Wang Qin, Hansen Daniel Hvidberg, Hedman Åsa K, Schork Andrew, Page Karen, Zhernakova Daria V, Wu Yang, Peters James, Eriksson Niclas, Bergen Sarah E, Boutin Thibaud S, Bretherick Andrew D, Enroth Stefan, Kalnapenkis Anette, Gådin Jesper R, Suur Bianca E, Chen Yan, Matic Ljubica, Gale Jeremy D, Lee Julie, Zhang Weidong, Quazi Amira, Ala-Korpela Mika, Choi Seung Hoan, Claringbould Annique, Danesh John, Davey Smith George, de Masi Federico, Elmståhl Sölve, Engström Gunnar, Fauman Eric, Fernandez Celine, Franke Lude, Franks Paul W, Giedraitis Vilmantas, Haley Chris, Hamsten Anders, Ingason Andres, Johansson Åsa, Joshi Peter K, Lind Lars, Lindgren Cecilia M, Lubitz Steven, Palmer Tom, Macdonald-Dunlop Erin, Magnusson Martin, Melander Olle, Michaelsson Karl, Morris Andrew P, Mägi Reedik, Nagle Michael W, Nilsson Peter M, Nilsson Jan, Orho-Melander Marju, Polasek Ozren, Prins Bram, Pålsson Erik, Qi Ting, Sjögren Marketa, Sundström Johan, Surendran Praveen, Võsa Urmo, Werge Thomas, Wernersson Rasmus, Westra Harm-Jan, Yang Jian, Zhernakova Alexandra, Ärnlöv Johan, Fu Jingyuan, Smith J Gustav, Esko Tõnu, Hayward Caroline, Gyllensten Ulf, Landen Mikael, Siegbahn Agneta, Wilson James F, Wallentin Lars, Butterworth Adam S, Holmes Michael V, Ingelsson Erik, Mälarstig Anders

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод пока не подготовлен

Аннотация

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.

Для цитирования: Folkersen Lasse, Gustafsson Stefan, Wang Qin, Hansen Daniel Hvidberg, Hedman Åsa K, Schork Andrew, Page Karen, Zhernakova Daria V, Wu Yang, Peters James, Eriksson Niclas, Bergen Sarah E, Boutin Thibaud S, Bretherick Andrew D, Enroth Stefan, Kalnapenkis Anette, Gådin Jesper R, Suur Bianca E, Chen Yan, Matic Ljubica, Gale Jeremy D, Lee Julie, Zhang Weidong, Quazi Amira, Ala-Korpela Mika, Choi Seung Hoan, Claringbould Annique, Danesh John, Davey Smith George, de Masi Federico, Elmståhl Sölve, Engström Gunnar, Fauman Eric, Fernandez Celine, Franke Lude, Franks Paul W, Giedraitis Vilmantas, Haley Chris, Hamsten Anders, Ingason Andres, Johansson Åsa, Joshi Peter K, Lind Lars, Lindgren Cecilia M, Lubitz Steven, Palmer Tom, Macdonald-Dunlop Erin, Magnusson Martin, Melander Olle, Michaelsson Karl, Morris Andrew P, Mägi Reedik, Nagle Michael W, Nilsson Peter M, Nilsson Jan, Orho-Melander Marju, Polasek Ozren, Prins Bram, Pålsson Erik, Qi Ting, Sjögren Marketa, Sundström Johan, Surendran Praveen, Võsa Urmo, Werge Thomas, Wernersson Rasmus, Westra Harm-Jan, Yang Jian, Zhernakova Alexandra, Ärnlöv Johan, Fu Jingyuan, Smith J Gustav, Esko Tõnu, Hayward Caroline, Gyllensten Ulf, Landen Mikael, Siegbahn Agneta, Wilson James F, Wallentin Lars, Butterworth Adam S, Holmes Michael V, Ingelsson Erik, Mälarstig Anders. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.. Nature metabolism. 2020. DOI: 10.1038/s42255-020-00287-2.

Предметные рубрики MeSH

ATP Binding Cassette Transporter 1AsthmaCardiovascular SystemChromosome MappingDrug Delivery SystemsGene Knockdown TechniquesGenome-Wide Association StudyGenomicsHumansInflammatory Bowel DiseasesInterleukin-1 Receptor-Like 1 ProteinIntracellular Signaling Peptides and ProteinsLinkage DisequilibriumMendelian Randomization AnalysisProtein Serine-Threonine KinasesProteomeQuantitative Trait LociReceptors, CCR2Receptors, CCR5
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