Ethnic diversity in the genetics of venous thromboembolism

Summary

Genetic susceptibility is considered as a crucial factor for the development of venous thromboembolism (VTE). Epidemiologic and genetic studies have revealed clear disparities in the incidence of VTE and the distribution of genetic factors for VTE in populations stratified by ethnicity worldwide. While gain-of-function polymorphisms in the procoagulant genes are common inherited factors in European-origin populations, the most prevalent molecular basis for venous thrombosis in Asians is confirmed to be dysfunctional variants in the anticoagulant genes. With the breakthrough of genomic technologies, a set of novel common alleles and rare mutations associated with VTE have also been identified, in different ethnic groups. Several putative pathways contributing to the pathogenesis of thrombophilia in populations of African-ancestry are largely unknown, as current knowledge of hereditary and acquired risk factors do not fully explain the highest risk of VTE in Black groups. In-depth studies across diverse ethnic populations are needed to unravel the whole genetics of VTE, which will help developing individual risk prediction models and strategies to minimise VTE in all populations.

Keywords

Ethnic - genetics - thrombosis - variant - venous thromboembolism

• References

• 1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167-1173.
• 2 Reitsma PH. et al. Mechanistic view of risk factors for venous thromboembolism. Arterioscl Thromb Vasc Biol 2012; 32: 563-568.
• 3 Souto JC. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Human Gen 2000; 67: 1452-1459.
• 4 Zoller B. et al. Familial transmission of venous thromboembolism: a cohort study of 80 214 Swedish adoptees linked to their biological and adoptive parents. Circulation Cardiovasc Gen 2014; 7: 296-303.
• 5 Zakai NA, McClure LA. Racial differences in venous thromboembolism. J Thromb Haemost 2011; 9: 1877-1882.
• 6 Montagnana M. et al. The role of ethnicity, age and gender in venous thromboembolism. J Thromb Thrombol 2010; 29: 489-496.
• 7 White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res 2009; 123 (Suppl 4) S11-17.
• 8 Roberts LN. et al. Venous thromboembolism and ethnicity. Br J Haematol 2009; 146: 369-383.
• 9 White RH. et al. Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb Hae 2005; 93: 298-305.
• 10 Zoller B. et al. Risk of venous thromboembolism in first- and second-generation immigrants in Sweden. Eur J Intern Med 2012; 23: 40-47.
• 11 Margaglione M, Grandone E. Population genetics of venous thromboembolism narrative review. Thromb Haemost 2011; 105: 221-231.
• 12 Liao S. et al. Incidence of venous thromboembolism in different ethnic groups: a regional direct comparison study. J Thromb Haemost 2014; 12: 214-219.
• 13 Peedicayil A. et al. Incidence and timing of venous thromboembolism after surgery for gynecological cancer. Gynecol Oncol 2011; 121: 64-69.
• 14 Itakura H. Racial disparities in risk factors for thrombosis. Curr Opin Hematol 2005; 12: 364-369.
• 15 Molina JA. et al. Venous thromboembolism at the National Healthcare Group, Singapore. Ann Acad Med Singapore 2009; 38: 470-478.
• 16 Blondon M. et al. Racial and ethnic differences in the risk of postpartum venous thromboembolism: a population-based, case-control study. J Thromb Haemost 2014; 12: 2002-2009.
• 17 Rodriguez AO. et al. Venous thromboembolism in uterine cancer. Intern J Gynecol Cancer 2011; 21: 870-876.
• 18 Ali M. et al. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Digest Dis Sci 2011; 56: 2152-2159.
• 19 Sandhu R. et al. The incidence of venous thromboembolism and its effect on survival among patients with primary bladder cancer. Cancer 2010; 116: 2596-2603.
• 20 Khorana AA. et al. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110: 2339-2346.
• 21 Keenan CR. et al. High risk for venous thromboembolism in diabetics with hyperosmolar state: comparison with other acute medical illnesses. J Thromb Haemost 2007; 5: 1185-1190.
• 22 James AH. et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194: 1311-1315.
• 23 Chew HK. et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166: 458-464.
• 24 White RH. et al. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003; 90: 446-455.
• 25 Bertina RM. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
• 26 Koster T. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506.
• 27 Dahlback B. et al. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008.
• 28 Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood 2008; 112: 19-27.
• 29 Zivelin A. et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997; 89: 397-402.
• 30 Hiltunen L. et al. An unfavorable combination of Factor V Leiden with age, weight, and blood group causes high risk of pregnancy-associated venous thrombosis: a population-based nested case-control study. Thromb Res 2007; 119: 423-432.
• 31 Juul K. et al. Factor V Leiden: The Copenhagen City Heart Study and 2 metaanalyses. Blood 2002; 100: 3-10.
• 32 Larsen TB. et al. The Arg506Gln mutation (FV Leiden) among a cohort of 4188 unselected Danish newborns. Thromb Res 1998; 89: 211-215.
• 33 Pasquier E. et al. Inherited thrombophilias and unexplained pregnancy loss: an incident case-control study. J Thromb Haemost 2009; 7: 306-311.
• 34 Sottilotta G. et al. High incidence of factor V Leiden and prothrombin G20210A in healthy southern Italians. Clinical and applied thrombosis/hemostasis : official journal of the International Acad Clin Appl Thromb Hemost 2009; 15: 356-359.
• 35 Ridker PM. et al. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. J Am Med Assoc 1997; 277: 1305-1307.
• 36 Hadhri S. et al. Factor V Leiden, prothrombin 20210G>A, MTHFR 677C>T and 1298A>C, and homocysteinemia in Tunisian blood donors. J Clin Lab Anal 2012; 26: 167-173.
• 37 Bourouba R. et al. The prevalence of methylenetetrahydrofolate reductase 677 C-T, factor V 1691 G-A, and prothrombin 20210 G-A mutations in healthy populations in Setif, Algeria. Clin Appl Thromb Hemost 2009; 15: 529-534.
• 38 Settin A. et al. Frequency of factor V Leiden mutation in Egyptian cases with myocardial infarction. Hematology 2008; 13: 170-174.
• 39 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-586.
• 40 de Paula Sabino A. et al. Increased Factor V Leiden frequency is associated with venous thrombotic events among young Brazilian patients. J Thromb Thrombol 2007; 24: 261-266.
• 41 Genoud V. et al. Prevalence of three prothrombotic polymorphisms. Factor V G1691A, factor II G20210A and methylenetetrahydrofolate reductase (MTHFR) C 677T in Argentina. On behalf of the Grupo Cooperativo Argentino de Hemostasia y Trombosis. Thromb Res 2000; 100: 127-131.
• 42 Majluf-Cruz A. et al. Activated protein C resistance and factor V Leiden in Mexico. Clin Appl Thromb Hemost 2008; 14: 428-437.
• 43 Rees DC. et al. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134.
• 44 Eroglu A. et al. The role of Factor V Leiden in adult patients with venous thromboembolism: a meta-analysis of published studies from Turkey. Clin Appl Thromb Hemost 2012; 18: 40-44.
• 45 Farajzadeh M. et al. Polymorphisms in thrombophilic genes are associated with deep venous thromboembolism in an Iranian population. Meta gene 2014; 2: 505-513.
• 46 Said JM. et al. The prevalence of inherited thrombophilic polymorphisms in an asymptomatic Australian antenatal population. Austral N Zeal J Obstet Gynaecol 2008; 48: 536-541.
• 47 Clark JS. et al. Allele frequency distribution of 1691G >A F5 (which confers Factor V Leiden) across Europe, including Slavic populations. J Appl Genet 2013; 54: 441-446.
• 48 Zoller B. et al. High prevalence of the FVR506Q mutation causing APC resistance in a region of southern Sweden with a high incidence of venous thrombosis. Thromb Res 1996; 83: 475-477.
• 49 Holm J. et al. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Intern Med 1996; 239: 221-226.
• 50 Poort SR. 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.
• 51 Danckwardt S. et al. 3' end processing of the prothrombin mRNA in thrombophilia. Acta Haematol 2006; 115: 192-197.
• 52 Jadaon MM. Epidemiology of Prothrombin G20210A Mutation in the Mediterranean Region. Mediterr J Hematol Infect Dis 2011; 3: e2011054.
• 53 Rosendaal FR. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-708.
• 54 Mazoyer E. et al. Prevalence of factor V Leiden and prothrombin G20210A mutation in a large French population selected for nonthrombotic history: geographical and age distribution. Blood Coag Fibrinol 2009; 20: 503-510.
• 55 Souto JC. et al. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80: 366-369.
• 56 Dowling NF. et al. The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study. J Thromb Haemost 2003; 1: 80-87.
• 57 Frere C. et al. Factor V Leiden G1691A and prothrombin G20210A mutations are common in Tunisia. J Thromb Haemost 2003; 1: 2451-2452.
• 58 Franco RF. et al. Prevalence of the G20210A polymorphism in the 3'-untranslated region of the prothrombin gene in different human populations. Acta Haematol 1998; 100: 9-12.
• 59 Stur E. et al. Polymorphism analysis of MTHFR, factor II, and factor V genes in the Pomeranian population of Espirito Santo, Brazil. Gen Test Mol Biomark 2012; 16: 219-222.
• 60 Almawi WY. et al. Varied prevalence of factor V G1691A (Leiden) and prothrombin G20210A single nucleotide polymorphisms among Arabs. J Thromb Thrombol 2005; 20: 163-168.
• 61 Ameen G. et al. An Arab selective gradient in the distribution of factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T. J Thromb Haemost 2005; 3: 2126-2127.
• 62 Lu Y. et al. Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population. Thromb Res 2002; 106: 7-12.
• 63 Zivelin A. et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood 2006; 107: 4666-4668.
• 64 Tait RC. et al Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-112.
• 65 Corral J. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109: 4258-4263.
• 66 Tregouet DA. 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. Blood 2009; 113: 5298-5303.
• 67 Bezemer ID. et al. Gene variants associated with deep vein thrombosis. J Am Ned Assoc 2008; 299: 1306-1314.
• 68 Hamasaki N. Unmasking Asian thrombophilia: is APC dysfunction the real culprit?. J Thromb Haemost 2012; 10: 2016-2018.
• 69 Tang L. et al. Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. PloS one 2012; 7: e35773.
• 70 Tang L. et al. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost 2012; 10: 2019-2026.
• 71 Ding Q. et al. Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. Thromb Haemost 2013; 109: 614-624.
• 72 Tang L. et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Human Gen 2013; 92: 177-187.
• 73 Kunz G. et al. Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function. Blood 2002; 99: 3646-3653.
• 74 Heit JA. et al. Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case-control study. J Thromb Haemost 2005; 3: 710-717.
• 75 Kim HJ. et al. Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population. Haematologica 2014; 99: 561-569.
• 76 Kimura R. et al. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood 2006; 107: 1737-1738.
• 77 Liu W. et al. Protein S K196E mutation, a genetic risk factor for venous thromboembolism, is limited to Japanese. Thromb Res 2013; 132: 314-315.
• 78 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
• 79 Miletich J. et al. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-996.
• 80 Dykes AC. 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.
• 81 Zhu T. et al. Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group. Haematologica 2011; 96: 1033-1040.
• 82 Angchaisuksiri P. et al. Risk factors of venous thromboembolism in thai patients. Intern J Hematol 2007; 86: 397-402.
• 83 Liu HW. et al. High incidence of thrombophilia detected in Chinese patients with venous thrombosis. Thromb Haemost 1994; 71: 416-419.
• 84 Heit JA. et al. Comparison of characteristics from White- and Black-Americans with venous thromboembolism: a cross-sectional study. Am J Hematol 2010; 85: 467-471.
• 85 Patel RK. et al. Risk factors for venous thrombosis in the black population. Thromb Haemost 2003; 90: 835-838.
• 86 de Visser MC. et al. Genome-wide linkage scan in affected sibling pairs identifies novel susceptibility region for venous thromboembolism: Genetics In Familial Thrombosis study. J Thromb Haemost 2013; 11: 1474-1484.
• 87 Heit JA. et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J Thromb Haemost 2012; 10: 1521-1531.
• 88 Morange PE. et al. KNG1 Ile581Thr and susceptibility to venous thrombosis. Blood 2011; 117: 3692-3694.
• 89 Morange PE. et al. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1. Am J Human Gen 2010; 86: 592-595.
• 90 Buil A. et al. C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies. Blood 2010; 115: 4644-4650.
• 91 Antoni G. et al. A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism. J Thromb Haemost 2010; 8: 2671-2679.
• 92 Austin H. et al. New gene variants associated with venous thrombosis: a replication study in White and Black Americans. J Thromb Haemost 2011; 9: 489-495.
• 93 Bean CJ. et al. Increased risk of venous thromboembolism is associated with genetic variation in heme oxygenase-1 in Blacks. Thromb Res 2012; 130: 942-947.
• 94 Simioni P. et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361: 1671-1675.
• 95 Saposnik B. et al. Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma. Blood 2008; 111: 3442-3451.
• 96 Lotta LA. et al. Next-generation sequencing study finds an excess of rare, coding single-nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. J Thromb Haemost 2013; 11: 1228-1239.
• 97 Nogami K. et al. Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden. Blood 2014; 123: 2420-2428.
• 98 Miyawaki Y. et al. Thrombosis from a prothrombin mutation conveying anti-thrombin resistance. N Engl J Med 2012; 366: 2390-2396.
• 99 Vlieg A. et al. Genetic variations associated with recurrent venous thrombosis. Circulation Cardiovasc Gen 2014; 7: 806-813.
• 100 de Haan HG. et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120: 656-663.