Study of the ethnic origin of the prothrombin gene (F2) in the admixed Venezuelan population. / Origen étnico del gen de la protrombina (F2) en la población venezolana.
Resumen
Abstract.
The prothrombin (coagulation factor II), codified by the F2 gene, is the precursor of thrombin that cleaves fibrinogen, leading to a blood clot formation. The F2 mutation 20210 G>A (c.*97G>A) is associated with prothrombin thrombophilia, and carriers have a higher than average risk for developing deep venous thrombosis. The 20210A variant is almost absent in populations other than Caucasoid European, and was not found in a Venezuelan population sample of 160 healthy individuals. To assess the possible ethnic origin of the F2 gene in our admixed population, four intragenic SNPs (rs2070850, rs2070852, rs2282686 and rs1799963), with different allelic frequencies according to ethnic groups, were studied and compared with the main 1000 Genomes Project super-populations. The results showed intermediate allelic frequencies in all the SNPs, without differentiating a single specific population, confirming the joint ancestral genetic contribution of the parental populations in Latin America: Spaniards, Africans and Amerindians. Our allelic frequency distribution of the F2 polymorphisms was closer to the AMR (American admixed) subset population of the 1000 Genomes Project. According to this ethnic composition, there is a low probability of detecting carriers of the risk allele 20201A in the Venezuelan healthy general population.
Resumen.
La protrombina (factor de coagulación II), codificada por el gen F2, es un precursor de la trombina, la cual escinde al fibrinógeno, conducente a la formación de un coágulo de sangre. La mutación F2 20210 G>A (c. * 97G> A) se asocia con trombofilia y los portadores tienen un riesgo superior al promedio de desarrollar trombosis venosa profunda. La variante 20210A está casi ausente en poblaciones distintas a la europea caucasoidea, y no se encontró en una muestra de 160 individuos sanos de la población venezolana. Para evaluar el posible origen étnico del gen F2 en nuestra población mezclada, se estudiaron cuatro SNP intragénicos (rs2070850, rs2070852, rs2282686 y rs1799963) con diferentes frecuencias alélicas, según los grupos étnicos y se compararon con las principales superpoblaciones del Proyecto 1000 Genomas. Los resultados mostraron frecuencias alélicas intermedias en todos los SNP, sin diferenciar una única población específica, lo que confirma la contribución genética ancestral conjunta de las poblaciones parentales en América Latina: españoles, africanos y amerindios. Nuestra distribución de frecuencias alélicas de los polimorfismos de F2 fue más parecida al subconjunto AMR (American admixed population) del Proyecto 1000 Genomas. De acuerdo con esta composición étnica, existe una baja probabilidad de detectar portadores del alelo de riesgo 20201A en la población general sana venezolana.
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Soria JM, Almasy L, Souto JC, Tirado I, Borell M, Mateo J, Slifer S, Stone W, Blangero J, Fontcuberta J. Linkage analy- sis demonstrates that the prothrombin G20210A mutation jointly influences plas- ma prothrombin levels and risk of thrombo- sis. Blood 2000;95:2780-2785.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrom- bin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88:3698-3703.
Ceelie H, Bertina RM, van Hylckama Vlieg A, Rosendaal FR, Vos HL. Polymorphisms in the prothrombin gene and their asso- ciation with plasma prothrombin levels. Thromb Hemost 2001; 85:1066-1070.
Girolami A, Simioni P, Scarano L, Carra- ro G. Prothrombin and the prothrombin 20210 G to A polymorphism: their relation- ship with hypercoagulability and thrombo- sis. Blood Reviews 1999; 13:205-210.
Mannucci PM. Laboratory detection of in- herited thrombophilia: a historical perspec- tive. Semin Thromb Hemost 2005; 31:5-10.
Martinelli I, Battaglioli T, Tosetto A, Leg- nani C, Sottile L, Ghiotto R, Mannucci PM. Prothrombin A19911G polymorphism and the risk of venous thromboembolism. J Thromb Hemost 2006; 4:2582-2586.
Rosendaal F, Doggen C, Zivelin A, Arruda V, Aiach M, Siscovick D, Hillarp A, Watzke HH, Bernardi F, Cumming A, Preston F, Reitsma P. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79:706-708.
Aznar J, Vayá A, Estellés A, Mira Y, Seguí R, Villa P, Ferrando F, Falcó C, Corella D, España F. Risk of venous thrombosis in ca- rriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000; 85:1271-1276.
Burzotta F, Paciaroni K, De Stefano V, Chiusolo P, Manzoli A, Casorelli I, Leone AM, Rossi E, Leone G, Maseri A, Andreot- ti F. Increased prevalence of the G20210A prothrombin gene variant in acute coronary syndromes without metabolic or acquired risk factors or with limited extent of disea- se. Eur Heart J 2002; 23:26-30.
Reznikoff-Etiévan MF1, Cayol V, Carbonne B, Robert A, Coulet F, Milliez J. Factor V Leiden and G20210A prothrombin muta- tions are risk factors for very early recurrent miscarriage. BJOG 2001; 10812:1251-1254.
Tosetto A, Missiaglia E, Frezzato M, Ro- deghiero F. The VITA project: prothrombin G20210A mutation and venous throm- boembolism in the general population. Thromb Haemost 1999; 82:1395-1398.
Yapijakis C, Serefoglou Z, Nixon AM, Vy- lliotis A, Ragos V, Vairaktaris E. Preva- lence of thrombosis-related DNA polymor- phisms in a healthy Greek population. In Vivo 2012; 26:1095-1101.
Marchi R, Marcos L, Paradisi I. Compari- son by sex between thrombin generation and fibrin network characteristics in a healthy population. Clin Chim Acta 2015; 441:86-89.
Zivelin A, Mor-Cohen R, Kovalsky V, Kor- nbrot N, Conard J, Peyvandi F, Kyrle PA, Bertina R, Peyvandi F, Emmerich J, Se- ligsohn U. Prothrombin 20210 G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood 2006; 107: 4666-46689.
Gehring NH, Frede U, Neu-Yilik G, Hunds- doerfer P, Vetter B, Hentze MW, Kulozik AE. Increased efficiency of mRNA 3-prime end formation: a new genetic mechanism contributing to hereditary thrombophilia. Nature Genet 2001; 28: 389-392.
Franco RF, Trip MD, ten Cate H, van den Ende A, Prins MH, Kastelein JJ, Reitsma PH.The 20210 G>A mutation in the 3’-un- translated region of the prothrombin gene and the risk for arterial thrombotic disease. Br J Haematol 1999; 104:50-54.
Castro de Guerra D, Figuera Pérez C, Izaguirre MH, Arroyo Barahona E, Rodrí- guez-Larralde A, Vívenes de Lugo M. Gen- der differences in ancestral contribution and admixture in Venezuelan populations. Hum Biol 2011; 83:345-361.
