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Identificació dels factors genètics que determinen la variabilitat dels nivells de FVII a la població espanyola. Resultats del Projecte GAIT
| Content Provider | Semantic Scholar |
|---|---|
| Author | Lleal, Maria Sabater |
| Copyright Year | 2006 |
| Abstract | La trombofilia es la tendencia genetica al tromboembolisme venos. Amb la finalitat daprofundir en les bases genetiques de la trombofilia hereditaria, lobjectiu principal daquesta tesi es la identificacio dels factors genetics que determinen la variabilitat dels nivells de FVII a la poblacio espanyola. En primer lloc, es va calcular lheretabilitat dels nivells de FVII en un 53%, i mitjancant una analisi global del genoma es va localitzar el gen responsable de la variabilitat dels nivells de FVII en la zona 13q, just on es localitza el gen estructural del FVII "(F7)". Aquest resultat indica que els factors genetics que determinen la variabilitat de FVII en plasma es troben en el gen estructural. A continuacio es va realitzar una analisi genetica exhaustiva i es van obtenir 49 posicions polimorfiques al llarg del gen "(F7)", la majoria canvis duna sola base (SNPs). A mes, mitjancant una analisi de lorganitzacio haplotipica de la variacio en la sequencia del "(F7)", es va observar que existeixen tres clars llinatges dhaplotips que shan mantingut parallelament en la poblacio espanyola per seleccio estabilitzadora, molt probablement per un avantatge dels individus heterozigots. Lanalisi dassociacio entre aquests llinatges i els nivells de FVII indica que un dells, caracteritzat pels allels [-670C, -630G, -402A] esta associat a nivells elevats en la poblacio, i un altre, caracteritzat pels allels [-2989A, -401T, -323ins10, -122C] esta associat a nivells reduits. Les analisis posteriors de transfeccio "in vitro" amb els diferents allels utilitzant un sistema "reporter" GFP "(Green Fluorescent Protein)" van permetre determinar que les variants 323ins10 i 122C tenen un efecte reductor sobre els nivells de proteina, i que la variant 402A provoca un augment significatiu dels nivells de FVII. Finalment, la nova variant 2989A incrementa tambe de forma molt significativa els nivells dexpressio. Aquests resultats es confirmen a mes en un estudi cas-control amb pacients amb trombosi venosa profunda, aixi com en dues families amb deficiencia de FVII. El disseny, lestrategia i la metodologia emprades son un bon exemple de com localitzar i identificar "loci" implicats en caracters complexes. "SUMMARY: There is a definite genetic predisposition to venous thromboembolism. The levels of FVII in plasma has been clearly implicated in thrombophilia. The aim of this thesis was to identify and characterize the genetic factors that determine the variability of FVII plasma levels in the Spanish population. First, the heritability of FVII levels was calculated as 53%indicating a substantial genetic component. A Genome Wide Scan allowed the localization of the responsible gene on the long arm of chromosome 13, exactly where the FVII (F7) structural gene has been located. This indicates that the genetic factors that determine FVII variability are localized in the structural gene. Second, from an exhaustive genetic analysis, we obtained 49 polymorphisms (variants) in the F7 gene. Further, by an analysis of sequence variations and haplotype organization, three main haplotype lineages were detected that have been maintained presumably by balanced selection, probably due to an advantage of heterozygous individuals. The association analysis among these lineages and the FVII levels indicates that one of these lineages, containing allelic variants [-670C, -630G, -402A] was associated with elevated FVII levels. Also, another lineage, containing allelic variants [-2989A, -401T, -323ins10, -122C] was associated with reduced levels of FVII. Posterior functional analyses of in vitro transfection of the different variants in a reporter system with GFP (Green Fluorescent Protein) showed that allelic variants 323ins10 i 122C significantly reduce expression levels while allelic variant 402A significantly increases them. The new allelic variant 2989A also increases expression levels significantly. Finally, these results have been confirmed in a case-control study with patients with deep venous thrombosis and in a study of two families with a FVII deficiency. The strategy and methodology of the present work are good examples of how to localize and identify genes implicated in complex human diseases. " |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/1/00.MSL_Titol.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/9/08.MSL_Bibliografia.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/5/04.MSL_Material_i_Metodes.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/6/05.MSL_Resum_resultats.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/3/02.MSL_Introduccio.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/4/03.MSL_Objectius.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/2/01.MSL_Glosari.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/7/06.MSL_Discussio.pdf |
| Alternate Webpage(s) | http://diposit.ub.edu/dspace/bitstream/2445/41891/8/07.MSL_Conclusions.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
