The latest scientific publications arising from the Cardiovascular BioResource Studies.
Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
David Stacey, Lingyan Chen, Paulina J Stanczyk, Joanna M M Howson, Amy M Mason, Stephen Burgess, Stephen MacDonald, Jonathan Langdown, Harriett McKinney, Kate Downes, Neda Farahi, James E Peters, Saonli Basu, James S Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S de Vries, Nicholas L Smith, CHARGE Hemostasis Working Group, Amy D Gelinas, Daniel J Schneider, Nebojsa Janjic, Nilesh J Samani, Shu Ye, Charlotte Summers, Edwin R Chilvers, John Danesh & Dirk S Paul
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.
Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference
Laura J Corbin, Vanessa Y Tan, David A Hughes, Kaitlin H Wade, Dirk S Paul, Katherine E Tansey, Frances Butcher, Frank Dudbridge, Joanna M M Howson, Momodou W Jallow, Catherine John, Nathalie Kingston, Cecilia M Lindgren, Michael O’Donavan, Stephen O’Rahilly, Michael J Owen, Colin N A Palmer, Ewan R Pearson, Robert A Scott, David A van Heel, John Whittaker, Tim Frayling, Martin D Tobin, Louise V Wain, George Davey Smith, David M Evans, Fredrik Karpe, Mark I McCarthy, John Danesh, Paul W Franks & Nicholas J Timpson
Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
Joanna M M Howson, Wei Zhao, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Lindsay L Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B Wilk, Anne Tybjærg-Hansen, Katrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, CARDIoGRAMplusC4D, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, Wen-Jane Lee, Kent D Taylor, Ying-Hsiang Chen, I-Te Lee, Xiuqing Guo, Ren-Hua Chung, Yi-Jen Hung, Jerome I Rotter, Jyh-Ming J Juang, Thomas Quertermous, Tzung-Dau Wang, Asif Rasheed, Philippe Frossard, Dewan S Alam, Abdulla al Shafi Majumder, Emanuele Di Angelantonio, Rajiv Chowdhury, EPIC-CVD, Yii-Der Ida Chen, Børge G Nordestgaard, Themistocles L Assimes, John Danesh, Adam S Butterworth & Danish Saleheen
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.