A Gene-centric Analysis of Activated Partial Thromboplastin Time and Activated Protein C Resistance Using the HumanCVD Focused Genotyping Array

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2012 Nov 29

PMID 23188048

Citations 10

Authors

Tom R Gaunt

Gordon D O Lowe

Debbie A Lawlor

Juan-Pablo Casas

Ian N M Day

Affiliations

Soon will be listed here.

Abstract

Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.

Citing Articles

Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients.

Tavares V, Pinto R, Assis J, Coelho S, Brandao M, Alves S Pharmacogenomics J. 2020; 21(2):222-232.

PMID: 33161412 DOI: 10.1038/s41397-020-00201-9.

The Roles of GRKs in Hemostasis and Thrombosis.

Chen X, Zhao X, Cooper M, Ma P Int J Mol Sci. 2020; 21(15).

PMID: 32731360 PMC: 7432802. DOI: 10.3390/ijms21155345.

Assessing the causal association of glycine with risk of cardio-metabolic diseases.

Wittemans L, Lotta L, Oliver-Williams C, Stewart I, Surendran P, Karthikeyan S Nat Commun. 2019; 10(1):1060.

PMID: 30837465 PMC: 6400990. DOI: 10.1038/s41467-019-08936-1.

Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.

Sennblad B, Basu S, Mazur J, Suchon P, Martinez-Perez A, van Hylckama Vlieg A Hum Mol Genet. 2017; 26(3):637-649.

PMID: 28053049 PMC: 5703348. DOI: 10.1093/hmg/ddw401.

Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.

Olson N, Butenas S, Lange L, Lange E, Cushman M, Jenny N J Thromb Haemost. 2015; 13(10):1867-77.

PMID: 26286125 PMC: 4946166. DOI: 10.1111/jth.13111.

References

Reilly M, Li M, He J, Ferguson J, Stylianou I, Mehta N . Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet. 2011; 377(9763):383-92. PMC: 3297116. DOI: 10.1016/S0140-6736(10)61996-4. View

Teupser D, Baber R, Ceglarek U, Scholz M, Illig T, Gieger C . Genetic regulation of serum phytosterol levels and risk of coronary artery disease. Circ Cardiovasc Genet. 2010; 3(4):331-9. DOI: 10.1161/CIRCGENETICS.109.907873. View

Tripodi A, Chantarangkul V, Martinelli I, Bucciarelli P, Mannucci P . A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood. 2004; 104(12):3631-4. DOI: 10.1182/blood-2004-03-1042. View

. A haplotype map of the human genome. Nature. 2005; 437(7063):1299-320. PMC: 1880871. DOI: 10.1038/nature04226. View

Korte W, Clarke S, Lefkowitz J . Short activated partial thromboplastin times are related to increased thrombin generation and an increased risk for thromboembolism. Am J Clin Pathol. 2000; 113(1):123-7. DOI: 10.1309/g98j-ana9-rmnc-xlyu. View

Houlihan L, Davies G, Tenesa A, Harris S, Luciano M, Gow A . Common variants of large effect in F12, KNG1, and HRG are associated with activated partial thromboplastin time. Am J Hum Genet. 2010; 86(4):626-31. PMC: 2850435. DOI: 10.1016/j.ajhg.2010.02.016. View

Warren D, Soria J, Souto J, Comuzzie A, Fontcuberta J, Blangero J . Heritability of hemostasis phenotypes and their correlation with type 2 diabetes status in Mexican Americans. Hum Biol. 2005; 77(1):1-15. DOI: 10.1353/hub.2005.0034. View

Alving B, Baldwin P, Richards R, Jackson B . The dilute phospholipid APTT: a sensitive assay for verification of lupus anticoagulants. Thromb Haemost. 1985; 54(3):709-12. View

Lowe G, Rumley A, Woodward M, Reid E, Rumley J . Activated protein C resistance and the FV:R506Q mutation in a random population sample--associations with cardiovascular risk factors and coagulation variables. Thromb Haemost. 1999; 81(6):918-24. View

10.

Tsuchida-Straeten N, Ensslen S, Schafer C, Woltje M, Denecke B, Moser M . Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG). J Thromb Haemost. 2005; 3(5):865-72. DOI: 10.1111/j.1538-7836.2005.01238.x. View

11.

Lowe G, Haverkate F, Thompson S, Turner R, Bertina R, Turpie A . Prediction of deep vein thrombosis after elective hip replacement surgery by preoperative clinical and haemostatic variables: the ECAT DVT Study. European Concerted Action on Thrombosis. Thromb Haemost. 1999; 81(6):879-86. View

12.

Poon I, Patel K, Davis D, Parish C, Hulett M . Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma. Blood. 2010; 117(7):2093-101. DOI: 10.1182/blood-2010-09-303842. View

13.

Keating B, Tischfield S, Murray S, Bhangale T, Price T, Glessner J . Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS One. 2008; 3(10):e3583. PMC: 2571995. DOI: 10.1371/journal.pone.0003583. View

14.

Bertina R, Koeleman B, Koster T, Rosendaal F, Dirven R, de Ronde H . Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994; 369(6475):64-7. DOI: 10.1038/369064a0. View

15.

Miller S, Dykes D, Polesky H . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16(3):1215. PMC: 334765. DOI: 10.1093/nar/16.3.1215. View

16.

Dahlback B, Hildebrand B . Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A. 1994; 91(4):1396-400. PMC: 43165. DOI: 10.1073/pnas.91.4.1396. View

17.

Morange P, Oudot-Mellakh T, Cohen W, Germain M, Saut N, Antoni G . KNG1 Ile581Thr and susceptibility to venous thrombosis. Blood. 2011; 117(13):3692-4. DOI: 10.1182/blood-2010-11-319053. View

18.

Gill J, Bauer P, Marks Jr W, Montgomery R . The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood. 1987; 69(6):1691-5. View

19.

Klarmann D, Eggert C, Geisen C, Becker S, Seifried E, Klingebiel T . Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents. Transfusion. 2010; 50(7):1571-80. DOI: 10.1111/j.1537-2995.2010.02604.x. View

20.

De Stefano V, Leone G . Resistance to activated protein C due to mutated factor V as a novel cause of inherited thrombophilia. Haematologica. 1995; 80(4):344-56. View