Elucidating mechanisms of genetic cross-disease associations: ­an integrative approach implicates protein C as a causal pathway in arterial and venous diseases

David Stacey, et al.

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Received Date: 30th March 20

David Stacey, Lingyan Chen, Joanna Howson, Amy M Mason, Stephen Burgess, Stephen MacDonald, Jonathan Langdown, Harriett McKinney, Kate Downes, Neda Farahi, James E Peters, Saonli Basu, James S Pankow, Nathan Pankratz, Weihong Tang, Maria Sabater-Lleal, Paul S de Vries, Nicholas L Smith, CHARGE Hemostasis Working Group, Amy D Gelinas, Daniel J Schneider, Nebojsa Janjic, Charlotte Summers, Edwin R Chilvers, John Danesh, Dirk S Paul

Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in the PROCR gene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. In a phenome scan of 12 cardiometabolic diseases and 24 molecular factors, we found that PROCR-219Gly associated with higher plasma levels of zymogenic and activated protein C as well as coagulation factor VII. Using statistical colocalization and Mendelian randomization analyses, we uncovered shared genetic etiology across activated protein C, factor VII, CAD and VTE, identifying p.S219G as the likely causal variant at the locus. In a recall-by-genotype study of 52 healthy volunteers stratified by p.S219G, we detected 2.5-fold higher soluble EPCR levels and 1.2-fold higher protein C levels in plasma per effect allele, suggesting the allele induces EPCR shedding from the membrane of endothelial cells. Finally, in cell adhesion assays, we found that increasing concentrations of activated protein C, but not soluble EPCR, reduced leukocyte–endothelial cell adhesion, a marker for vascular inflammation. These results support a role for protein C as a causal factor in arterial and venous diseases, suggesting that PROCR-219Gly protects against CAD through anti-inflammatory mechanisms while it promotes VTE risk through pro-thrombotic mechanisms. Overall, our study illustrates a multi-modal approach that can help reveal molecular underpinnings of cross-disease associations.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature