Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
Por:
Stacey, D, Chen, LY, Stanczyk, PJ, Howson, JMM, Mason, AM, Burgess, S, MacDonald, S, Langdown, J, McKinney, H, Downes, K, Farahi, N, Peters, JE, Bas, S, Pankowf, JS, Tang, WH, Pankratz, N, Sabater-Llear, M, de Vries, PS, Smith, NL, Gelinas, AD, Schneider, DJ, Janjic, N, Samani, NJ, Ye, S, Summers, C, Chilvers, ER, Danesh, J, Paul, DS, CHARGE Hemostasis Working Grp
Publicada:
9 mar 2022
Resumen:
Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.
Many individual genetic risk loci associate with multiple diseases, but the molecular basis of these loci often remains unclear. Here, the authors provide a framework to reveal the genetic cross-disease associations at the PROCR vascular disease locus.
Filiaciones:
Stacey, D:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Chen, LY:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Stanczyk, PJ:
Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England
Univ Leicester, Natl Inst Hlth Res Leicester Biomed Res Ctr, Leicester, Leics, England
Howson, JMM:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Novo Nordisk Res Ctr Oxford, Dept Genet, Innovat Bldg,Old Rd Campus,Roosevelt Dr, Oxford, England
Mason, AM:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Burgess, S:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Univ Cambridge, Med Res Council Biostat Unit, Cambridge, England
MacDonald, S:
Cambridge Univ Hosp NHS Fdn Trust, Specialist Haemostasis Unit, Cambridge, England
Langdown, J:
Cambridge Univ Hosp NHS Fdn Trust, Specialist Haemostasis Unit, Cambridge, England
McKinney, H:
Univ Cambridge, Dept Haematol, Cambridge, England
Natl Hlth Serv Blood & Transplant, Cambridge, England
Downes, K:
Univ Cambridge, Dept Haematol, Cambridge, England
Natl Hlth Serv Blood & Transplant, Cambridge, England
Univ Cambridge, Natl Inst Hlth Res BioResource, Cambridge, England
Farahi, N:
Univ Cambridge, Dept Med, Cambridge, England
Peters, JE:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Imperial Coll London, Dept Immunol & Inflammat, Ctr Inflammatory Dis, London, England
Hlth Data Res UK London, London, England
Bas, S:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
Pankowf, JS:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Tang, WH:
Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
Pankratz, N:
Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA
Sabater-Llear, M:
IIB St Pau, St Pau Biomed Res Inst, Genom Complex Dis Grp, Barcelona, Spain
Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med, Cardiovasc Med Unit,Dept Med, Stockholm, Sweden
de Vries, PS:
Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA
Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA
Smith, NL:
Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA
Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA
Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA
Gelinas, AD:
SomaLogic Inc, Boulder, CO USA
Schneider, DJ:
SomaLogic Inc, Boulder, CO USA
Janjic, N:
SomaLogic Inc, Boulder, CO USA
Samani, NJ:
Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England
Univ Leicester, Natl Inst Hlth Res Leicester Biomed Res Ctr, Leicester, Leics, England
Ye, S:
Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England
Univ Leicester, Natl Inst Hlth Res Leicester Biomed Res Ctr, Leicester, Leics, England
Summers, C:
Univ Cambridge, Dept Med, Cambridge, England
Chilvers, ER:
Imperial Coll London, Natl Heart & Lung Inst, London, England
Danesh, J:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England
Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Res Unit Do, Cambridge, England
Wellcome Genome Campus, Hlth Data Res UK Cambridge, Cambridge, England
Univ Cambridge, Cambridge, England
Wellcome Sanger Inst, Dept Human Genet, Hinxton, England
Paul, DS:
Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England
Univ Cambridge, British Heart Fdn Ctr Res Excellence, Cambridge, England
Wellcome Sanger Inst, Dept Human Genet, Hinxton, England
Green Published, gold, All Open Access, Gold, Green
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