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Sickle cell disease (SCD) is a genetic disorder that affects millions of people worldwide. According to the Centers for Disease Control and Prevention, over 100,000 Americans have SCD, and more than 2 million Americans have a sickle cell trait (SCT). People with SCD are more likely than others to suffer premature mortality. Genetic screening is an important step in improving quality of life and increasing longevity for those with SCD. Early detection may lead to effective management of the disease and reduction of complicating factors. The purpose of this quasi-experimental study was to determine whether health education about SCD would impact college students' knowledge, attitudes, perceived risk, and intention to seek genetic screening and counseling in relation to the disease. The theoretical foundation for this study was the health belief model (HBM). This study involved 80 college students selected from a North Texas college. These students completed pre and post versions of an SCD questionnaire. Independent samples t tests were used to determine if there were significant differences in pre- and posttest scores of participants in both groups, and a MANOVA was used to determine differences among the scores of participants in the experimental group when grouped by age, gender, race, religiosity, and socioeconomic status. The results of this study showed that SCD health education improved the knowledge of and attitudes towards participants. Future research could explore barriers to seeking SCD screening and genetic counseling. Results of this study may further social change by encouraging the development of college-based health education efforts to increase awareness about SCD.

Sickle cell disease (SCD) is a genetic disorder that affects millions of people worldwide. According to the Centers for Disease Control and Prevention, over 100,000 Americans have SCD, and more than 2 million Americans have a sickle cell trait (SCT). People with SCD are more likely than others to suffer premature mortality. Genetic screening is an important step in improving quality of life and increasing longevity for those with SCD. Early detection may lead to effective management of the disease and reduction of complicating factors. The purpose of this quasi-experimental study was to determine whether health education about SCD would impact college students' knowledge, attitudes, perceived risk, and intention to seek genetic screening and counseling in relation to the disease. The theoretical foundation for this study was the health belief model (HBM). This study involved 80 college students selected from a North Texas college. These students completed pre and post versions of an SCD questionnaire. Independent samples t tests were used to determine if there were significant differences in pre- and posttest scores of participants in both groups, and a MANOVA was used to determine differences among the scores of participants in the experimental group when grouped by age, gender, race, religiosity, and socioeconomic status. The results of this study showed that SCD health education improved the knowledge of and attitudes towards participants. Future research could explore barriers to seeking SCD screening and genetic counseling. Results of this study may further social change by encouraging the development of college-based health education efforts to increase awareness about SCD.

This dissertation should supplement the knowledge of the genetic coronary heart disease (CHD) architecture by analysing known common variation as well as finding novel associated loci and genes. Genotype and allele frequencies, also haplotype blocks were determined in the Lithuanian population according to the list of 60 SNPs associated with CHD. The number of risk alleles per person was determined. The intrapopulation comparison of allele frequencies and haplotype blocks was performed. Allele frequencies were compared with different populations of European ancestry. The association analyses for new loci and candidate gene identification were performed. It was revealed that the common and unique genetic disease architecture variants for different populations exist. Regarding the genetic structure and diversity of the risk SNPs of CHD, Lithuanian population as compared with the European populations falls into the Northern-Southern gradient showing that the Lithuanian gene pool could have experienced the geographical climate and ecological influence during the evolution process. Considering the risk allele number per person of the investigated SNPs, the majority of Lithuanian population individuals have a relatively average risk of developing CHD. Association analyses showed eight new loci associated with CHD, four of which were confirmed and ITPR2 and FBXL17 were found to be the putative candidate genes that could participate in the pathogenesis of CHD and atherosclerosis. / Siekiant papildyti žinias apie genetinę koronarinės širdies ligos (KŠL) architektūrą, užsibrėžta atlikti žinomų genetinių sričių siejamų su KŠL analizę ir naujų genetinių sričių siejamų su šia liga paiešką Lietuvos populiacijoje. Pagal atrinktas žinomas 60 genetinių sričių, siejamų su rizika susirgti KŠL, tiriamiems asmenims nustatyti genotipų ir alelių dažniai, sukonstruoti haplotipų blokai, atliktas vidupopuliacinis alelių dažnių ir haplotipų blokų palyginimas, tarppopuliacinis alelių dažnių palyginimas, nustatytas rizikos alelių tenkančių asmeniui pasiskirstymas populiacijoje. Nustatyta, kad skirtingoms populiacijoms yra būdingi tiek bendri, tiek ir unikalūs genetinės architektūros vienetai, o bendros Lietuvos lietuvių populiacijos genetinę struktūrą ir įvairovę pagal tirtus žymenis galima orientuoti gradientiškai Europos Šiaurės-Pietų kryptimi, tai aiškinant geografinių platumų lemiama klimato ir ekologijos įtaka genofondui evoliucijos eigoje. Pagal tirtų rizikos alelių skaičių tenkantį asmeniui, daugiausia asmenų tirtoje Lietuvos lietuvių populiacijoje turi vidutinę riziką susirgti KŠL. Genetinės asociacijos analize nustatytos aštuonios potencialios naujos kandidatinės su KŠL asocijuotos genetinės sritys, iš jų patvirtintos – keturios, o ITPR2 ir FBXL17 genai yra galimi genai kandidatai dalyvaujantys KŠL ir aterosklerozės patogenezėje.

Siekiant papildyti žinias apie genetinę koronarinės širdies ligos (KŠL) architektūrą, užsibrėžta atlikti žinomų genetinių sričių siejamų su KŠL analizę ir naujų genetinių sričių siejamų su šia liga paiešką Lietuvos populiacijoje. Pagal atrinktas žinomas 60 genetinių sričių, siejamų su rizika susirgti KŠL, tiriamiems asmenims nustatyti genotipų ir alelių dažniai, sukonstruoti haplotipų blokai, atliktas vidupopuliacinis alelių dažnių ir haplotipų blokų palyginimas, tarppopuliacinis alelių dažnių palyginimas, nustatytas rizikos alelių tenkančių asmeniui pasiskirstymas populiacijoje. Nustatyta, kad skirtingoms populiacijoms yra būdingi tiek bendri, tiek ir unikalūs genetinės architektūros vienetai, o bendros Lietuvos lietuvių populiacijos genetinę struktūrą ir įvairovę pagal tirtus žymenis galima orientuoti gradientiškai Europos Šiaurės-Pietų kryptimi, tai aiškinant geografinių platumų lemiama klimato ir ekologijos įtaka genofondui evoliucijos eigoje. Pagal tirtų rizikos alelių skaičių tenkantį asmeniui, daugiausia asmenų tirtoje Lietuvos lietuvių populiacijoje turi vidutinę riziką susirgti KŠL. Genetinės asociacijos analize nustatytos aštuonios potencialios naujos kandidatinės su KŠL asocijuotos genetinės sritys, iš jų patvirtintos – keturios, o ITPR2 ir FBXL17 genai yra galimi genai kandidatai dalyvaujantys KŠL ir aterosklerozės patogenezėje. / This dissertation should supplement the knowledge of the genetic coronary heart disease (CHD) architecture by analysing known common variation as well as finding novel associated loci and genes. Genotype and allele frequencies, also haplotype blocks were determined in the Lithuanian population according to the list of 60 SNPs associated with CHD. The number of risk alleles per person was determined. The intrapopulation comparison of allele frequencies and haplotype blocks was performed. Allele frequencies were compared with different populations of European ancestry. The association analyses for new loci and candidate gene identification were performed. It was revealed that the common and unique genetic disease architecture variants for different populations exist. Regarding the genetic structure and diversity of the risk SNPs of CHD, Lithuanian population as compared with the European populations falls into the Northern-Southern gradient showing that the Lithuanian gene pool could have experienced the geographical climate and ecological influence during the evolution process. Considering the risk allele number per person of the investigated SNPs, the majority of Lithuanian population individuals have a relatively average risk of developing CHD. Association analyses showed eight new loci associated with CHD, four of which were confirmed and ITPR2 and FBXL17 were found to be the putative candidate genes that could participate in the pathogenesis of CHD and atherosclerosis.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Le Syndrome d’Ehlers-Danlos vasculaire (SEDv) est une pathologie génétique rare à transmission autosomique dominante. Les patients sont prédisposés à la survenue de ruptures vasculaires, digestives et utérines induisant une létalité précoce. Cette pathologie est due à des mutations du gène COL3A1 (codant le collagène de type III), majoritairement de type faux-sens, agissant via un mécanisme dominant négatif. Plus rarement, de larges délétions ou des mutations non-sens induisent une haplo-insuffisance. In fine, les conséquences de ces mutations portent essentiellement sur la synthèse du collagène de type III, aboutissant à une fragilité artérielle importante. A ce jour, aucun traitement curatif n’est disponible. L’inactivation du gène Col3a1 chez la souris entraine une mortalité in utero et néonatale quasi-systématique en cas d’homozygotie, mais les souris Col3a1+/- sont exemptes de phénotype vasculaire évident. Afin d’obtenir un modèle de dissection artérielle liée à un défaut de collagène de type III, une perfusion chronique d’Angiotensine II (Ang II) à dose pressive a été utilisée. Nos résultats montrent que l’haplo-insuffisance en collagène de type III confère une sensibilité artérielle majeure à l’Ang II. Cette fragilité est caractérisée par le développement de dissections/ruptures de l’aorte ascendante et induit des décès prématurés de ces animaux. Ce phénotype est lié non seulement à l’élévation de pression artérielle mais aussi à l’activation des voies de signalisation de l’Ang II. Enfin, nous montrons qu’un traitement associant un bêtabloquant (propranolol) et un vasodilatateur artériel (hydralazine) permet de réduire la mortalité induite par l’Ang II. Ces résultats suggèrent l’intérêt de l’ajout d’un traitement préventif par inhibiteur de l’Ang II au traitement bêtabloquant (Celiprolol) recommandé dans la pathologie humaine.Parallèlement, nous avons généré un modèle murin knock-in génétiquement plus proche des patients SEDv, par l’introduction d’une mutation ponctuelle faux-sens (Gly183Ser) observée chez un patient. L’analyse préliminaire de ce modèle montre que les souris Col3a1+/G183S décèdent spontanément, dès 4 semaines, de ruptures/dissections de l’aorte ascendante. Cependant, ces souris ne présentent de modification ni de leurs paramètres hémodynamiques, ni de leurs diamètres aortiques. En revanche, environ 20 % des souris Col3a1+/G183S présentent des plaies au niveau du dos et des pattes. Ce nouveau modèle de souris est actuellement le seul à récapituler aussi fidèlement le phénotype des patients SEDv. Il devrait donc permettre de tester différentes approches thérapeutiques. / Vascular Ehlers-Danlos (vEDS) syndrome is a rare, inherited, autosomal dominant disease that results from mutations in the COL3A1 gene, encoding type III collagen. Patients are mostly affected by missense mutations probably acting through a dominant negative mechanism. A few patients present large deletions or nonsense mutations leading to a haploinsufficient mechanism. These mutations are supposed to lead to a defect in the synthesis and secretion of collagen type III, resulting in arterial wall fragility. Consequently, vEDS is mostly characterized by ruptures/dissections in arteries at a young age, which ultimately lead to premature death. While there is currently no surgical or therapeutic treatments available, a recent study reported the beneficial effect of the beta-blocker celiprolol, which prevents vascular complications in patients.To investigate the vascular phenotype of vEDS, a mouse model of this disease has been generated by the complete and ubiquitous inactivation of the COL3A1 gene. Col3a1-/- mice exhibit severe perinatal mortality and die prematurely from spontaneous vascular rupture. However, Col3a1+/- mice are viable and exhibit no obvious vascular phenotype. To determine the susceptibility of Col3a1+/- mice to develop vascular rupture/dissection, an experimental model of aneurysm induction was used, through the chronic infusion of Angiotensin II (Ang II). Our results showed that Ang II infusion led to severe premature mortality in Col3a1+/- compared to wild type. This fragility was characterized by the development of rupture/dissection in the ascending aorta. These lesions could be caused by the elevation of blood pressure and/or the activation of Ang II signaling pathways. We showed that treatment with a beta-blocker (propranolol) and an arterial vasodilator (hydralazine) reduced the mortality induced by Ang II in Col3a1+/- mice. These results suggest the beneficial effect of adding a preventive treatment inhibitor of Ang II to the beta-blocker treatment recommended in human pathology.Meanwhile, given that a majority of human vEDS cases is caused by missense mutations in the COL3A1 gene, we established a knock-in mouse model bearing a point mutation (Gly183Ser) found in vEDS patients. The preliminary characterization of this model showed that Col3a1+/G183S mice die spontaneously as early as 4 weeks of age from a dissection or rupture of the ascending aorta. However, these mice do not showed any changes of their hemodynamic parameters or aortic diameter. Furthermore, about 20 % of mouse Col3a1+/G183S display wounds in the back and legs. This new mouse model is currently the only that mimic more closely the human disease and could therefore be used to test different therapeutic strategies.

La diffusion du séquençage haut débit (ou NGS pour Next Generation Sequencing) représente un tel changement d’échelle par rapport aux méthodes classiques de séquençage que les indications et l’organisation du diagnostic moléculaire s’en trouvent profondément modifiées. Le NGS permet à la fois de raccourcir le temps d’analyse et de rendu de résultat et d'élargir considérablement le nombre de gènes testés. Il promet donc d’augmenter la proportion de diagnostics posés et de faciliter l'identification de nouveaux variants et de nouveaux gènes impliqués en pathologie. Cependant dans tous les cas, il génère une quantité de données importante, données qui doivent être analysées et interprétées à l’aide d’outils bioinformatiques spécifiques.Dans la première partie de ce travail, les stratégies existantes ainsi que les difficultés et les enjeux du séquençage haut débit pour le diagnostic moléculaire des maladies génétiques sont discutés. Dans la deuxième partie, la mise en place et la validation technique de cette approche diagnostique sont décrites au sein du laboratoire de Génétique Moléculaire de la Timone à Marseille et illustrées par trois exemples concrets de diagnostics moléculaires posés grâce à la technique de séquençage à haut débit. Dans le domaine spécifique des maladies rares, ces nouvelles technologies sont porteuses d’un réel espoir pour les patients atteints de maladie génétique, permettant d'améliorer globalement leur prise en charge et d'accélérer les progrès dans le domaine de la recherche. / The diffusion of Next Generation Sequencing (NGS) technologies induces an important change that modifies molecular diagnostics indications and prompts laboratories to re-think their diagnostic strategies, up-to-now based on Sanger sequencing routine. Several high throughput approaches are available from the sequencing of a gene panel, to a whole exome, or even a whole genome. In all cases, a tremendous amount of data are generated, that have to be filtered, interpreted and analyzed by the use of powerful bioinformatics tools.In part 1, existing strategies and the difficulties and challenges of high-throughput sequencing for molecular diagnosis in genetic diseases are discussed. In part 2, the set up and the technical validation of this diagnostic approach in the Molecular Genetics’ Laboratory of the Timone Hospital in Marseille is presented and illustrated by 3 examples of complex diagnostics solved thanks to NGS. NGS promises to shorten significantly the time of analysis and results reporting, and to expand the number of tested genes. It also promises to increase the proportion of positive diagnoses. Finally, the NGS can identify new variants and new genes involved in human pathology, thus will globally improve patient clinical care.