Exclusion of the α₂ subunit of platelet-activating factor acetylhydrolase 1b (PAFAH1B2) as a prothrombotic gene in a protein C-deficient kindred and population-based case-control sample

Summary

Protein C deficiency increases the risk of venous thromboembolic disease among members of KindredVermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (107–119Mb, nominal P<0.0001), with weaker support on chromosomes 10p12 (11–25Mb, P<0.0003) and 18p11.2-q11 (12–24Mb, P<0.0007).The 11q23 region contains the α₂ subunit (gene name PAFAH1B2) of platelet-activating factor acetylhydrolase 1b, a candidate prothrombotic gene. Re-sequencing of the PAFAH1B2 regulatory region in 137 pedigree members, including 25 thrombosis cases, revealed 12 variants; eight were present in only 0–2 affected individuals; the other four assorted into three haplotypes and included three variants predicted to destroy transcription factor-binding sites. More extensive re-sequencing of the PAFAH1B2 gene in 11 affected and five unaffected pedigree members revealed an additional 13 variants that assorted into the same three haplotypes. We rejected as thrombosis risk factors each of the three presumed destructive variants as well as each of the three haplotypes. We also rejected (odds ratio=1.31 CI: 0.91–1.88) one of the three variants in 469 cases and 472 controls from the Leiden Thrombophilia Study (LETS). Therefore, PAFAH1B2 is not the gene responsible for the linkage evidence on chromosome 11q23.

Keywords

Genetics - linkage - likelihood

• References

• 1 Bovill EG, Hasstedt SJ, Leppert MF. et al. Hereditary thrombophilia as a model for multigenic disease. Thromb Haemost 1999; 82: 662-666.
• 2 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
• 3 Zöller B, Garcia de Frutos P, Hillarp A. et al. Thrombophilia as a multigenic disease. Haematologica 1999; 84: 59-70.
• 4 Vossen CY, Conard J, Fontcuberta J. et al. Risk of a first thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3: 459-464.
• 5 Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med 2003; 138: 128-134.
• 6 Wu O, Robertson L, Langhorne P. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94: 17-25.
• 7 Hoppe B, Tolou F, Dorner T. et al. Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population. Thromb Haemost 2006; 96: 465-470.
• 8 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
• 9 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703.
• 10 Bertina RM. Factor V Leiden and other coagulation factor mutations affecting thrombotic risk. Clin Chem 1997; 43: 1678-1683.
• 11 Tait RC, Walker ID, Islam SI. et al. Influence of demographic factors on antithrombin III activity in a healthy population. Br J Haematol 1993; 84: 476-480.
• 12 Miletich J, Sherman L, Broze Jr. G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-996.
• 13 Dykes AC, Walker ID, McMahon AD. et al. A study of protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001; 113: 636-641.
• 14 Reitsma PH. Protein C deficiency: summary of the 1995 database update. Nucleic Acids Res 1996; 24: 157-159.
• 15 Miletich JP, Prescott SM, White R. et al. Inherited predisposition to thrombosis. Cell 1993; 72: 477-480.
• 16 Tomczak JA, Ando RA, Sobel HG. et al. Genetic analysis of a large kindred exhibiting type I protein C deficiency and associated thrombosis. Thromb Res 1994; 74: 243-254.
• 17 Bovill EG, Bauer KA, Dickerman JD. et al. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-717.
• 18 Hasstedt SJ, Bovill EG, Callas PW. et al. An unknown genetic defect increases venous thrombosis risk, through interaction with protein C deficiency. Am J Hum Genet 1998; 63: 569-576.
• 19 Hasstedt SJ, Scott BT, Callas PW. et al. Genome scan of venous thrombosis in a pedigree with protein C deficiency. J Thromb Haemost 2004; 2: 868-873.
• 20 Moro F, Arrigo G, Fogli A. et al. The β and γ subunits of the human platelet-activating factor acetyl hydrolase isoform Ib (PAFAH1B2 and PAFAH1B3) map to chromosome 11q23 and 19q13.1, respectively. Genomics 1998; 51: 157-159.
• 21 Ho YS, Swenson L, Derewenda U. et al. Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. Nature 1997; 385: 89-93.
• 22 Adachi H, Tsujimoto M, Hattori M. et al. Differential tissue distribution of the β- and γ-subunits of human cytosolic platelet-activating factor acetylhydrolase (isoform I). Biochem Biophys Res Commun 1997; 233: 10-13.
• 23 Prescott SM, McIntyre TM, Zimmerman GA. et al. Sol Sherry lecture in thrombosis: molecular events in acute inflammation. Arterioscler Thromb Vasc Biol 2002; 22: 727-733.
• 24 Schlondorff D, Neuwirth R. Platelet-activating factor and the kidney. Am J Physiol 1986; 251: F1-11.
• 25 Zimmerman GA, McIntyre TM, Prescott SM. et al. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 2002; 30: S334-301.
• 26 Reitsma PH, Rosendaal FR. Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study. J Thromb Haemost 2004; 2: 619-622.
• 27 Chirinos JA, Heresi G, Velasquez H. et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45: 1467-1471.
• 28 Downing LJ, Strieter RM, Kadell AM. et al. IL-10 regulates thrombus-induced vein wall inflammation and thrombosis. J Immunol 1998; 161: 1471-1476.
• 29 Myers D, Wrobleski S, Londy F. et al. New and effective treatment of experimentally induced venous thrombosis with anti-inflammatory rPSGL-Ig. Thromb Haemost 2002; 87: 374-382.
• 30 Eppihimer MJ, Schaub RG. P-Selectin-dependent inhibition of thrombosis during venous stasis. Arterioscler Thromb Vasc Biol 2000; 20: 2483-2488.
• 31 Tunc SE, Aksu K, Keser G. et al. Platelet-activating factor and P-selectin activities in thrombotic and nonthrombotic Behcet’s patients. Rheumatol Int 2005; 25: 326-331.
• 32 Seth P, Kumari R, Dikshit M. et al. Effect of platelet activating factor antagonists in different models of thrombosis. Thromb Res 1994; 76: 503-512.
• 33 Bernat A, Herbert JM. Effect of various drugs on adriamycin-enhanced venous thrombosis in the rat: importance of PAF. Thromb Res 1994; 75: 91-97.
• 34 Herbert JM, Corseaux D, Lale A. et al. Hypoxia primes endotoxin-induced tissue factor expression in human monocytes and endothelial cells by a PAF-dependent mechanism. J Cell Physiol 1996; 169: 330-339.
• 35 van de Wouwer M, Collen D, Conway EM. Thrombomodulin- protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24: 1374-1383.
• 36 Heinemeyer T, Wingender E, Reuter I. et al. Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 1998; 26: 362-367.
• 37 Sobel E, Lange K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics. Am J Hum Genet 1996; 58: 1323-1337.
• 38 Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE. Mega2, a data-handling program for facilitating genetic linkage and association analyses. Am J Hum Genet 1999; 65: A436.
• 39 Hasstedt SJ. jPAP: Document-driven software for genetic analysis. Genet Epidemiol 2005; 29: 255.
• 40 Self SG, Liang K-Y. Asymptotic properties of maximum likelihood estimators and likelihood ratio tests under nonstandard conditions. J Am Stat Assoc 1987; 82: 605-610.
• 41 Elston RC, George VT. Age of onset, age at examination, and other covariates in the analysis of family data. Genet Epidemiol 1989; 6: 217-220.
• 42 Schaid DJ, McDonnell SK, Blute ML. et al. Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 1998; 62: 1425-1438.
• 43 Cui JS, Spurdle AB, Southey MC. et al. Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes, with application to a CYP17 polymorphism and breast cancer. Genet Epidemiol 2003; 24: 161-172.
• 44 Koster T, Rosendaal FR, de Ronde H. et al. Venous thrombosis due to a poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
• 45 van der Meer FJ, Koster T, Vandenbroucke JP, Briët E, Rosendaal FR. The Leiden Thrombophilia Study (LETS). Thromb Haemost 1997; 78: 631-635.
• 46 Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955; 19: 251-253.
• 47 Ness SA. Myb binding proteins: regulators and cohorts in transformation. Oncogene 1999; 13: 3039-3046.
• 48 Kurokawa M, Hirai H. Role of AML1/Runx1 in the pathogenesis of hematological malignancies. Cancer Sci 2003; 94: 841-846.
• 49 Souto JC, Blanco-Vaca F, Soria JM. et al. A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project. Am J Hum Genet 2005; 76: 925-933.
• 50 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165-176.