A Genome-Wide Association Study of the Protein C Anticoagulant Pathway

The Protein C anticoagulant pathway regulates blood coagulation by preventing the inadequate formation of thrombi. It has two main plasma components: protein C and protein S. Individuals with protein C or protein S deficiency present a dramatically increased incidence of thromboembolic disorders. Here, we present the results of a genome-wide association study (GWAS) for protein C and protein S plasma levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. A total number of 397 individuals from 21 families were typed for 307,984 SNPs using the Infinium® 317 k Beadchip (Illumina). Protein C and protein S (free, functional and total) plasma levels were determined with biochemical assays for all participants. Association with phenotypes was investigated through variance component analysis. After correcting for multiple testing, two SNPs for protein C plasma levels (rs867186 and rs8119351) and another two for free protein S plasma levels (rs1413885 and rs1570868) remained significant on a genome-wide level, located in and around the PROCR and the DNAJC6 genomic regions respectively. No SNPs were significantly associated with functional or total protein S plasma levels, although rs1413885 from DNAJC6 showed suggestive association with the functional protein S phenotype, possibly indicating that this locus plays an important role in protein S metabolism. Our results provide evidence that PROCR and DNAJC6 might play a role in protein C and free protein S plasma levels in the population studied, warranting further investigation on the role of these loci in the etiology of venous thromboembolism and other thrombotic diseases.

[1]  P. Reitsma,et al.  High levels of protein C are determined by PROCR haplotype 3 , 2011, Journal of thrombosis and haemostasis : JTH.

[2]  P. Reitsma,et al.  Quantitative trait locus for protein C in a family with thrombophilia , 2010, Thrombosis and Haemostasis.

[3]  J. Reny,et al.  Paternal endothelial protein C receptor 219Gly variant as a mild and limited risk factor for deep vein thrombosis during pregnancy , 2010, Journal of thrombosis and haemostasis : JTH.

[4]  R. Camire,et al.  The molecular basis of factor V and VIII procofactor activation , 2009, Journal of thrombosis and haemostasis : JTH.

[5]  S. Heath,et al.  Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. , 2009, Blood.

[6]  P. Reitsma,et al.  Assessment of coagulation and fibrinolysis in families with unexplained thrombophilia , 2009, Thrombosis and Haemostasis.

[7]  C. Carty,et al.  PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study , 2008, Journal of thrombosis and haemostasis : JTH.

[8]  R. Bertina,et al.  Haplotypes of the EPCR gene, prothrombin levels, and the risk of venous thrombosis in carriers of the prothrombin G20210A mutation , 2008, Haematologica.

[9]  B. Dahlbäck,et al.  Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation. , 2008, Blood.

[10]  B. Dahlbäck.  The tale of protein S and C4b-binding protein, a story of affection , 2007, Thrombosis and Haemostasis.

[11]  J. Rosing,et al.  Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Bertina,et al.  Influence of the 4600A/G and 4678G/C polymorphisms in the endothelial protein C receptor (EPCR) gene on the risk of venous thromboembolism in carriers of factor V Leiden , 2005, Thrombosis and Haemostasis.

[13]  F R Rosendaal,et al.  Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis , 2004, Journal of thrombosis and haemostasis : JTH.

[14]  D. Collen,et al.  Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[15]  L. Almasy,et al.  Protein C Levels Are Regulated by a Quantitative Trait Locus on Chromosome 16: Results from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[16]  L. Almasy,et al.  Novel family‐based approaches to genetic risk in thrombosis , 2003, Journal of thrombosis and haemostasis : JTH.

[17]  L. Almasy,et al.  A Quantitative Trait Locus Influencing Free Plasma Protein S Levels on Human Chromosome 1q: Results From the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project , 2003, Arteriosclerosis, Thrombosis and Vascular Biology.

[18]  L. Almasy,et al.  Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. , 2000, American journal of human genetics.

[19]  P. Reitsma,et al.  Genetic risk factors for venous thrombosis. , 2000, Molecular genetics and metabolism.

[20]  L. Almasy,et al.  Genetic determinants of hemostasis phenotypes in Spanish families. , 2000, Circulation.

[21]  L. Almasy,et al.  Quantitative trait locus mapping using human pedigrees. , 2000, Human biology.

[22]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[23]  C. Esmon,et al.  Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. , 1997, Circulation.

[24]  P. Reitsma,et al.  Familial thrombophilia: a complex genetic disorder. , 1997, Seminars in hematology.

[25]  P. Mannucci,et al.  Inherited Thrombophilia: Part 1 , 1996, Thrombosis and Haemostasis.

[26]  C. Esmon,et al.  The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Reitsma,et al.  Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[28]  P. Reitsma,et al.  Protein C Deficiency: A Database of Mutations , 1993, Thrombosis and Haemostasis.

[29]  E. Boerwinkle,et al.  The use of measured genotype information in the analysis of quantitative phenotypes in man. , 1987, Annals of human genetics.

[30]  F. Walker.  Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. , 1981, The Journal of biological chemistry.

[31]  P. Simioni,et al.  Soluble endothelial protein C receptor (sEPCR) levels and venous thromboembolism in carriers of two dysfunctional protein C variants. , 2006, Thrombosis research.

[32]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[33]  L. Almasy,et al.  Variance component methods for detecting complex trait loci. , 2001, Advances in genetics.

[34]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[35]  B. Jude,et al.  Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. , 1995, Blood.

[36]  P. Fay,et al.  INACTIVATION OF FACTOR VIII BY ACTIVATED PROTEIN C AND PROTEIN S , 1987, Thrombosis and Haemostasis.

[37]  Eric Boerwinkle,et al.  Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study , 2022 .