Plasma levels of the anti-coagulation protein C and the risk of ischaemic heart diseaseA Mendelian randomisation study
Received:08 July 2016
Accepted after major revision:19 October 2016
13 November 2017 (online)
Protein C is an environmentally modifiable anticoagulant, which protects against venous thrombosis, whether it also protects against ischaemic heart disease is unclear, based on observational studies and relatively small genetic studies. It was our study aim to clarify the role of protein C in ischaemic heart disease. The risk of coronary artery disease/myocardial infarction (CAD/MI) was assessed according to genetically predicted protein C in very large studies. Associations with lipids and diabetes were similarly assessed to rule out effects via traditional cardiovascular disease risk factors. Separate sample instrumental variable analysis with genetic instruments (Mendelian randomisation) was used to obtain an unconfounded estimate of the association of protein C (based on (rs867186 (PROCR), rs3746429 (EDEM2), rs7580658 (inter/PROC)) with CAD/MI in an extensively genotyped case (n=64374)-control (n=130681) study, CARDIoGRAMplusC4D. Associations with lipids and diabetes were similarly assessed using the Global Lipids Genetics Consortium Results (n=196,475) and the DIAbetes Genetics Replication And Meta-analysis case (n=34,380)-control (n=114,981) study. Genetically predicted protein C was negatively associated with CAD/MI, odds ratio (OR) 0.85 µg/ml, 95 % confidence interval 0.80 to 0.90, but had no such negative association with lipids or diabetes. Results were similar for the SNP rs867186 functionally relevant to protein C, and including additional potentially pleiotropic SNPs (rs1260326 (GCKR), rs17145713 (BAZ1B) and rs4321325 (CYP27C1)). In conclusion, protein C may protect against CAD/MI. Whether environmental or dietary items that raise protein C protect against ischaemic cardiovascular disease by that mechanism should be investigated.
Supplementary Material to this article is available online at www.thrombosis-online.com.
- 1 Murray CJ, Vos T, Lozano R. et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2197-2223.
- 2 Ezzati M, Obermeyer Z, Tzoulaki I. et al. Contributions of risk factors and medical care to cardiovascular mortality trends. Nat Rev Cardiol 2015; 12: 508-530.
- 3 Jackson N, Atar D, Borentain M. et al. Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology. Eur Heart J 2016; 37: 747-754.
- 4 Stone NJ, Robinson JG, Lichtenstein AH. et al. Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013**** American College of Cardiology/American Heart Association cholesterol guideline. Ann Intern Med 2014; 160: 339-343.
- 5 Lemaitre JF, Berger V, Bonenfant C. et al. Early-late life trade-offs and the evolution of ageing in the wild. Proc Biol Sci 2015; 282: 20150209.
- 6 Teumer A, Qi Q, Nethander M. et al. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell 2016; 15: 811-824.
- 7 Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M. et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 2011; 03: 70ra13.
- 8 Zhao JV, Schooling CM. Endogenous androgen exposures and ischaemic heart disease, a separate sample Mendelian randomisation study. Int J Cardiol 2016; 222: 940-945.
- 9 Prandoni P. Venous thromboembolism and atherosclerosis: is there a link?. J Thromb Haemost 2007; 05 (Suppl. 01) 270-275.
- 10 Espana F, Gilabert J, Estelles A. et al. Functionally active protein C inhibitor/plasminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma and complexes with prostate-specific antigen. Thromb Res 1991; 64: 309-320.
- 11 Laurell M, Christensson A, Abrahamsson PA. et al. Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive system. J Clin Invest 1992; 89: 1094-1101.
- 12 Elisen MG, van Kooij RJ, Nolte MA. et al. Protein C inhibitor may modulate human sperm-oocyte interactions. Biol Reprod 1998; 58: 670-677.
- 13 van Wersch JW, De Vries-Hanje JC, Ubachs JM. Coagulation and fibrinolysis markers in seminal plasma of patients under evaluation for involuntary childlessness. Eur J Clin Chem Clin Biochem 1992; 30: 467-471.
- 14 Carroll VA, Griffiths MR, Geiger M. et al. Plasma protein C inhibitor is elevated in survivors of myocardial infarction. Arterioscler Thromb Vasc Biol 1997; 17: 114-118.
- 15 Mosnier LO, Zlokovic BV, Griffin JH. Cytoprotective-selective activated protein C therapy for ischaemic stroke. Thromb Haemost 2014; 112: 883-892.
- 16 Folsom AR, Aleksic N, Wang L. et al. Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study. Arterioscler Thromb Vasc Biol 2002; 22: 1018-1022.
- 17 Folsom AR, Ohira T, Yamagishi K. et al. Low protein C and incidence of ischaemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. J Thromb Haemost 2009; 07: 1774-1778.
- 18 van der Bom JG, Bots ML, Haverkate F. et al. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996; 125: 265-269.
- 19 Soare AM, Popa C. Deficiencies of proteins C, S and antithrombin and activated protein C resistance--their involvement in the occurrence of Arterial thromboses. J Med Life 2010; 03: 412-415.
- 20 Tang W, Basu S, Kong X. et al. Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study. Blood 2010; 116: 5032-5036.
- 21 Dennis J, Johnson CY, Adediran AS. et al. The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. Blood 2012; 119: 2392-2400.
- 22 Tang W, Schwienbacher C, Lopez LM. et al. Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease. Am J Hum Genet 2012; 91: 152-162.
- 23 Schunkert H, Konig IR, Kathiresan S. et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011; 43: 333-338.
- 24 Deloukas P, Kanoni S, Willenborg C. et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013; 45: 25-33.
- 25 Nikpay M, Goel A, Won HH. et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47: 1121-1130.
- 26 Willer CJ, Schmidt EM, Sengupta S. et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013; 45: 1274-1283.
- 27 Morris AP, Voight BF, Teslovich TM. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012; 44: 981-990.
- 28 Locke AE, Kahali B, Berndt SI. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197-206.
- 29 Shungin D, Winkler TW, Croteau-Chonka DC. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 2015; 518: 187-196.
- 30 Rietveld CA, Esko T, Davies G. et al. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. Proc Natl Acad Sci USA 2014; 111: 13790-13794.
- 31 Ripke S, Wray NR, Lewis CM. et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013; 18: 497-511.
- 32 Wald A. The Fitting of Straight Lines if Both Variables Are Subject to Error. Ann Math Stat 1940; 11: 284-300.
- 33 Bowden J, Davey Smith G, Haycock PC. et al. Consistent Estimation in Mendelian Randomisation with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol 2016; 40: 304-314.
- 34 Athanasiadis G, Buil A, Souto JC. et al. A genome-wide association study of the Protein C anticoagulant pathway. PLoS One 2011; 06: e29168.
- 35 Oudot-Mellakh T, Cohen W, Germain M. et al. Genome wide association study for plasma levels of natural anticoagulant inhibitors and protein C anticoagulant pathway: the MARTHA project. Br J Haematol 2012; 157: 230-239.
- 36 Munir MS, Weng LC, Tang W. et al. Genetic markers associated with plasma protein C level in African Americans: the atherosclerosis risk in communities (ARIC) study. Genet Epidemiol 2014; 38: 709-713.
- 37 Manco-Johnson MJ, Bomgaars L, Palascak J. et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost 2016; 116: 58-68.
- 38 Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008; 14: 1214-1221.
- 39 Germain M, Chasman DI, de Haan H. et al. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet 2015; 96: 532-542.
- 40 van Mens TE, Levi M, Middeldorp S. Evolution of Factor V Leiden. Thromb Haemost 2013; 110: 23-30.
- 41 Bentley P, Peck G, Smeeth L. et al. Causal relationship of susceptibility genes to ischaemic stroke: comparison to ischaemic heart disease and biochemical determinants. PLoS One 2010; 05: e9136.
- 42 Gill JC, Castaman G, Windyga J. et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126: 2038-2046.
- 43 Smith NL, Chen MH, Dehghan A. et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121: 1382-1392.
- 44 Christiaans SC, Wagener BM, Esmon CT. et al. Protein C and acute inflammation: a clinical and biological perspective. Am J Physiol Lung Cell Mol Physiol 2013; 305: L455-466.
- 45 Anderson RA, Ludlam CA, Wu FC. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost 1995; 74: 693-697.
- 46 FDA. Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. 2015.
- 47 Canada H. Information Update - Possible cardiovascular problems associated with testosterone products. 2014..
- 48 Glueck CJ, Prince M, Patel N. et al. Thrombophilia in 67 Patients With Thrombotic Events After Starting Testosterone Therapy. Clin Appl Thromb Hemost 2016; 22: 548-553.
- 49 Chan KC, Yin MC, Chao WJ. Effect of diallyl trisulfide-rich garlic oil on blood coagulation and plasma activity of anticoagulation factors in rats. Food Chem Toxicol 2007; 45: 502-507.
- 50 Ku SK, Han MS, Bae JS. Sulforaphane inhibits endothelial protein C receptor shedding in vitro and in vivo. Vascul Pharmacol 2014; 63: 13-18.