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

Autori
Folkersen, Lasse ; ... ; Polašek, Ozren ; ... ; Mälarstig, Anders

Izvornik
Nature Metabolism (2522-5812) 2 (2020), 10; 1135-1148

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Asthma ; ATP Binding Cassette Transporter 1 ; Cardiovascular System ; Chromosome Mapping ; Drug Delivery Systems ; Gene Knockdown Techniques ; Genome-Wide Association Study ; Genomics ; Humans ; Inflammatory Bowel Diseases ; Interleukin-1 Receptor-Like 1 Protein ; Intracellular Signaling Peptides and Proteins ; Linkage Disequilibrium ; Mendelian Randomization Analysis ; Protein-Serine-Threonine Kinases ; Proteome ; Quantitative Trait Loci ; Receptors, CCR2 ; Receptors, CCR5

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA