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Tilley, Louise. "Genetic risk factors in sporadic Alzheimer's disease." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311748.
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Salfati, Elias Levy Itshak. "Genetic determinants of cardiovascular disease : heritability and genetic risk score." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S014/document.
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Les maladies complexes telles que les maladies cardio-Vasculaires (MCV) sont influencées par des facteurs génétiques et environnementaux. L’estimation du risque cardio-Vasculaire chez un individu est généralement évaluée par la sommation des facteurs de risque reconnu des MCV (p. ex. l’âge, le sexe, le tabac, la pression artérielle et le cholestérol). Dernièrement, plusieurs bio-Marqueurs ont été examiné pour leur aptitude à améliorer la prédiction des maladies cardio-Vasculaires au-Delà des facteurs de risques traditionnels. L’intérêt de découvrir de nouveaux loci est incité notamment par les découvertes qui émergent des études d'association pangénomique (GWAS) qui permettent de tester l’association de variation génétique au risque de contracter une maladie commune. Les GWAS ont considérablement amélioré notre connaissance de l'architecture génétique des maladies cardio-Vasculaires, à ce jour plus de 50 variations génétiques sont formellement associées à des maladies cardio-Vasculaires, de même plus de 200 marqueurs génétiques seraient associés à des facteurs de risque cardiovasculaire traditionnels (p. ex. le taux sanguin des lipides, la pression artérielle, l’indice de masse corporelle et le diabète de type 2). Le succès remarquable de ces études d’association, qui a permis l’identification de nombreux bio-Marqueurs, a conduit à une réévaluation des données génétiques dans le but de définir des informations cliniquement utiles pour limiter et mieux prédire les risques de maladies, grâce à une application plus efficace des stratégies de prévention. Dans cette thèse, nous examinons tout d'abord une nouvelle approche pour étudier l'architecture génétique de l'hypertension artérielle (HTA; facteur de risque majeur des maladies cardiovasculaires prématurées), puis nous avons constitué plusieurs modèles pour prédire le risque de développer une maladie coronarienne (MC; type le plus commun de MCV), enfin nous avons déterminé une base génétique commune du principal prédicteur de complications cliniques des maladies coronariennes – l'athérosclérose subclinique - afin d'ajouter une valeur pronostique supplémentaire en plus des scores de risque traditionnels à différents âges. Nous avons estimé l'héritabilité de la première mesure de la pression artérielle systolique (PAS) à ~25%/~45% et à ~30%/~37% pour la pression artérielle diastolique (PAD) chez les sujets d’origine Européenne (N = 8901) et d’origine Africaine (N = 2860) faisant respectivement partie de la cohorte Atherosclerosis Risk in Communities (ARIC), en accord avec les études antérieures. Par ailleurs, nous avons développé un moyen de combiner un score de risque génétique (SRC) – somme des effets génétiques parmi un ensemble de marqueurs – avec une évaluation indépendante du risque clinique, en utilisant un système d'équations log-Linéaire. Nous avons employé cet outil à la prédiction de la maladie coronarienne (MC) dans la cohorte ARIC. L'ajout d'un score de risque génétique (SRG) à un score de risque clinique (SRC) améliore à la fois la discrimination et l'étalonnage des maladies coronariennes dans la cohorte ARIC, et révèle par la même comment cette information génétique influence l'évaluation des risques ainsi que l’approche clinique. Enfin, parmi 1561 cas et 5068 contrôles (de la présence ou non de calcifications coronaires), faisant partie de plusieurs ensembles de données cliniques et génétiques disponibles via la base de données NCBI de Génotypes et Phénotypes (dbGAP), nous avons constaté qu’une augmentation d'un écart-Type dans le score de risque génétique de 49 bio-Marqueurs de MC est associée à 28 % d’augmentation de risque de développer une athérosclérose coronarienne subclinique diagnostiquée à un stade avancé (p=1.43x10-16). Cette augmentation du risque est significative dans chaque catégorie d'âge (de 15 ans en 15 ans) (0,01 > p > 9.4x10-7) et a été remarquablement similaire dans toutes les catégories d'âge (test d'hétérogénéité p = 0.98). (...)<br>Complex diseases such as cardiovascular disease (CVD) are influenced by both genetic and environmental factors. Estimation of an individual’s cardiovascular risk usually involves measurement of risk factors correlated with risk of CVD (e.g. age, sex, smoking, blood pressure, and total cholesterol). Lately, several biomarkers have been evaluated for their ability to improve prediction of cardiovascular disease beyond traditional risk factors. The interest in novel loci is propelled notably by emerging discoveries from the advent of genome-Wide association studies (GWAS) of genetic variants associated with risk for common diseases. GWAS has greatly enhanced our knowledge of the genetic architecture of cardiovascular disease, yielding over 50 variants confirmed to be associated with CVD to date, as well as over 200 associated with traditional cardiovascular risk factors (e.g. lipids, blood pressure, body mass index, and type 2 diabetes mellitus). This recent and continuing success in discovering increasing numbers of robustly associated genetic markers has led to reassessment of whether genetic data can provide clinically useful information by refining risk prediction and moderating disease risk through a more efficient application of prevention strategies. In this thesis, we first address novel approach to survey the genetic architecture of hypertension (i.e. major risk factor for premature CVD), then construct risk prediction models for coronary artery disease (CAD; i.e. most common type of CVD) and finally establish a common genetic basis of the strongest predictor of clinical complications of CAD, subclinical atherosclerosis, to add incremental prognostic value above traditional risk scores across a range of ages. We show that, for first visit measurements, the heritability is ~25%/~45% and ~30%/~37% for systolic (SBP) and diastolic blood pressure (DBP) in European (N=8,901) and African (N=2,860) ancestry individuals from the Atherosclerosis Risk in Communities (ARIC) cohort, respectively, in accord with prior studies. Then we present a means to combine a polygenic risk score - genetic effects among an ensemble of markers - with an independent assessment of clinical risk using a log-Link function. We apply the method to the prediction of coronary heart disease (CHD) in the ARIC cohort. The addition of a genetic risk score (GRS) to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC and subsequently reveal how this genetic information influences risk assessment and thus potentially clinical management. Finally, Among 1561 cases and 5068 controls, from several clinical and genetic datasets available through the NCBI's database of Genotypes and Phenotypes (dbGAP), we found a one SD increase in the genetic risk score of 49 CAD SNPs was associated with a 28% increased risk of having advanced subclinical coronary atherosclerosis (p = 1.43 x 10-16). This increase in risk was significant in every 15-Year age stratum (.01 > p > 9.4 x 10-7) and was remarkably similar across all age strata (p test of heterogeneity = 0.98). We obtained near identical results and levels of significance when we restricted the genetic risk score to 32 SNPs not associated with traditional risk factors. Accordingly, common variation largely recapitulates the known heritability of blood pressure traits. The vast majority of this heritability varies by chromosome, depending on its length, and is largely concentrated in intronic and intergenic regions of the genome but widely distributed across the common allele frequency spectrum. Respectively, our proposed method to combine genetic information at established susceptibility loci with a nongenetic risk prediction tool facilitates the standardized incorporation of a GRS in risk assessment. (...)
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Hughes, Katherine Carlson. "Dietary and Genetic Risk Factors for Parkinson's Disease." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27201728.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease. Motor symptoms typically do not manifest until significant neuronal loss has already occurred, highlighting the need for early detection and prevention. In this dissertation, we sought to improve our understanding of PD epidemiology by studying associations between potential modifiable risk factors, including antioxidant vitamins, dairy products, and urate, and PD risk. We conducted prospective analyses within three large cohort studies: the Nurses’ Health Study, the Health Professionals Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. Across all analyses, PD cases were identified via biennial questionnaires and confirmed through medical record review by neurologists specializing in movement disorders.
In our first two aims, we used Cox proportional hazards models to calculate relative risks of PD according to cumulative average intakes of foods and nutrients of interest. In aim 1, we found no associations between intake of vitamin E, vitamin C, or carotenoids and risk of PD. In our second aim, we found that low fat dairy intake was associated with increased PD risk, and that this association appeared to be driven by an increased risk of PD associated with skim and low-fat milk intake. The results of a meta-analysis including previously conducted prospective investigations of milk intake and PD risk suggested a relative risk of PD comparing extreme milk intake levels of 1.80 (95% CI 1.44-2.25). In our third aim, although a large body of research suggests that higher urate levels could be protective against PD risk and progression, we found that genetic variants in the SLC2A9 gene that influence circulating urate levels were not associated with risk of PD.
Our analyses suggest that while antioxidant vitamins are unlikely to alter PD risk, dairy products may represent an important modifiable PD risk factor. Whether dairy products also alter rates of PD progression or conversion from premotor PD to clinical PD are important, answerable questions. Finally, the results of our third analysis suggest that genetic variants associated with plasma urate levels are not associated with PD risk; however, larger studies are needed to confirm these results.
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Duan, Qingling. "Pharmacogenomics and genetic risk factors of coronary artery disease." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115665.
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Coronary artery disease (CAD) is the most prevalent disorder and the leading cause of death worldwide. There are a number of CAD medications, which are effective and safe in most patients, but have been associated with adverse reactions such as angioedema induced by angiotensin I-converting enzyme inhibitors (AE-ACEi). In this study, we identified aminopeptidase P (APP) activity as an endophenotype for AE-ACEi, which is a heritable quantitative trait (heritability =0.336 +/- 0.251 SD) and is significantly reduced in a majority of our cases. Although initial mutation screening did not reveal any coding variants in XPNPEP2, which encodes membrane-bound APP, subsequent linkage analysis of APP activity in eight families provided a maximum LOD score (3.75) for this locus. Sequencing of additional cases identified a splice variant (314_431del) and a non-coding polymorphism (rs3788853) in this locus, which cosegregate with low plasma APP activity. The latter accounts for the linkage signal and is associated with AE-ACEi (P = 0.036). In addition, we identified other potential loci for APP activity and demonstrated that certain ACEi (Captopril and Enalapril) non-specifically inhibit APP activity. Furthermore, we detected polymorphisms associated with reduced APP and ACE activities among females with estrogen-dependent inherited angioedema.<br>We also conducted a genetic investigation of depression among CAD patients to identify common susceptibility loci which might explain the correlation between these diseases. Our candidate gene association study identified a polymorphism (rs216873) in the von Willebrand factor gene that was significantly associated (P = 7.4 x 10-5) with elevated depressive symptoms in our CAD cohort. These results suggest that risk factors for atherosclerosis also underlie susceptibility to depression among CAD patients.<br>This dissertation contributes to the field of genetics and pharmacogenomics of CAD. A better understanding of the toxic effects of CAD drugs will assist in the development of safer and more effective treatments. In addition, our results may facilitate clinical assays to identify individuals who are susceptible to angioedema prior to ACEi or estrogen therapy. Finally, our genetic investigation of depression in CAD patients reveals a novel drug target (VWF) for treatment of depression in cardiac cases.
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Ossei-Gerning, Nicholas. "Genetic polymorphisms and the risk of coronary artery disease." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391615.
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Hayashi, Satomi. "HYPERHOMOCYSTEINEMIA: GENETIC POLYMORPHISMS AND RISK OF CORONARY ARTERY DISEASE." Thesis, The University of Arizona, 2003. http://hdl.handle.net/10150/610473.
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This comprehensive literature review focuses on homocysteine, gene
polymorphisms related to homocysteine metabolism and their relationship to coronary
artery disease (CAD). Currently, CAD is known as a multifactorial genetic disease,
resulting from complex interactions between genetic factors and various environmental
influences. In recent years, tremendous knowledge about the hereditary aspect of CAD
has been gained, including an understanding of CAD as a multifactorial condition
resulting from complex interactions between genetic factors and various environmental
influences that trigger, accelerate, or exacerbate the disease process. Among the risk
factors for CAD, hyperhomocysteinemia has been recognized for its relation to
atherosclerotic alterations in the vessels. In addition, gene polymorphisms in methylene -
tetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR),
methionine synthase (MS), and cystathionine ß - synthase (CßS), which are involved in
homocysteine metabolism, have been identified as a result of advances in genetic
research related to cardiovascular pathophysiology. In particular, the results of recent
salient studies have provided evidence of significant association of these genetic
polymorphisms and CAD in Japanese and part of European populations but not in the
United States, Australian, and part of European populations. This disparity may explain
the variation of prevalence of CAD among different populations. Potential gene -
environment interactions may elevate homocysteine levels and increase the risk of CAD.
This discussion includes the pathogenesis of hyperhomocysteinemia, definitions of
normal and elevated homocysteine levels, the physiological background of
homocysteine metabolism, polymorphisms of genes involved in homocysteine
metabolism from the perspective of CAD risk, and implications for nursing practice
based on emerging information regarding hyperhomocysteinemia as a risk factor for
CAD. Findings from these recent studies are important for nurses, clinicians, and
researchers to be able to incorporate cardiovascular genetic information in their practice
and research and provide more adequate care to reduce the risk for CAD and improve
patient outcomes.
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Romagnoli, Martina <1987>. "Genetic, immune and environmental risk factors in Alzheimer's disease." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amsdottorato.unibo.it/7930/1/Romagnoli_Martina_tesi.pdf.
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Alzheimer's disease (AD) is a complex multi-factorial disease in which several pathogenetic, clinical, environmental and stochastic factors are involved. It is on record that persistent virus infections, the progressive decline of immune competence with ageing and chronic psychological stress exposures might play a pivotal role in AD.
This study shows that in patients with clinical and neurological AD diagnosis, antiviral immune response is defective in the majority of AD brain samples. Moreover, gene variants of APOE and IRF7 strongly affect antiviral gene expression profiles in hippocampus. These findings suggest that brains from AD patients have defective antimicrobial immune defences and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, further decreases brain immune efficiency.
Chronic stress at different stages of life, including intrauterine life, has a negative impact on AD pathology and prenatal stress (PNS) is an important programming factor in brain development and function. The second part of this thesis shows that experimental animal research has the advantage of enabling strict control of environmental factors, such as PNS exposure, that might have a role in AD-related behaviour and neuropathology. Long-term cognitive consequences of PNS in AD mice and the PNS-early neurobiological effects in wild type animals were investigated. As these, mouse represented a useful model to suggest that PNS affects the onset of AD cognitive deficit in a sex-dependent manner and that the impairment of fetal neurodevelopment might influence adult mental health and brain ageing.
In conclusion, the presented study gives new perspectives for prevention and treatment of the ageing-associated cognitive decline and AD. Protecting women from chronic stress during pregnancy, on the one side, and maintenance of efficient immune responses during ageing, on the other one, might slowdown neurodegenerative mechanisms associated with senile dementia and positively influence both prevalence and incidence of AD.
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Ylönen, S. (Susanna). "Genetic risk factors for movement disorders in Finland." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223988.
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Abstract Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movement disorders that typically manifest in adulthood. In this study, genetic risk factors contributing to these two movement disorders were investigated in Finnish patients. Patients with early-onset or late-onset Parkinson’s disease as well as population controls were examined. The p.L444P mutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compound heterozygous mutations were detected in two patients with Parkinson’s disease and rare length variants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 or CHCHD10, previously detected in other populations, were not detected, suggesting that they are rare or even absent in the Finnish population. Patients with Huntington’s disease were investigated for HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongated CAG repeat. Haplogroup A was less common in Finns than in other European populations, whereas it was significantly more common in patients with Huntington’s disease than in the general population. Certain HTT haplotypes as well as the parental gender were found to affect the repeat instability. We found that compound heterozygous mutations in POLG1 were causative of Parkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease and GBA p.L444P was significantly more frequent in patients than in the controls, which suggests that these mutations are associated with the development of Parkinson’s disease. The low prevalence of Huntington’s disease in Finland correlates with the low frequency of the disease-associated HTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeat expansion. Movement disorders in Finland were found to share some of the same genetic risk factors found in other European populations, but some other recognized genetic variants could not be detected<br>Tiivistelmä Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauksia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liikehäiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla oli varhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja. GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonin tautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin varianttien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin. Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistosta lainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Huntingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutusta Huntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A oli suomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavasti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikuttivat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt toistojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia ja harvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suomessa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrolleilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioituvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Paternaalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä. Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muualla Euroopassa, mutta kaikkia tutkittuja variantteja emme havainneet
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Chen, Lu-hua, and 陈璐华. "Genetic risk factors for late-onset Alzheimer's disease in Chinese." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B49617588.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with genetic factors playing critical roles in its pathogenesis. Mutations in APP, PSEN1 and PSEN2 genes are confirmed to be causative risk factors for early-onset Alzheimer’s disease (EOAD). For late-onset Alzheimer’s disease (LOAD), growing evidence suggests it is caused by multiple genetic risk factors in corporation with the environmental exposures. Although, so far, APOE is the most well recognized common genetic risk factor for LOAD, other susceptible candidate genes, such as CR1, CLU and PICALM, have recently been identified in Caucasians using genome-wide association approach. In order to have a better understanding on the genetic components of LOAD in Chinese as well as identify other potential genetic risk factors for Chinese ethnic population, we conducted a case-control study using candidate gene association approach.
In view of increasing evidence on the neural protective effects of sex steroid hormones both in vivo and in vitro, we hypothesized variations on sex steroid metabolic pathway genes were associated with LOAD. Four candidate genes (ESR1, ESR2, CYP19A1, CYP11A1) were evaluated based on 462 cases and 350 non-demented controls. Apart from consistent result for APOE, polymorphisms in ESR2 and CYP11A1 were found to be significantly associated with the disease. When stratification according to gender, marginally significant associations were detected for ESR1 and ESR2 variants in men while CYP11A1 variants relevant to LOAD risk were detected exclusively in women. Additionally, genotypic and phenotypic correlation analysis revealed CYP19A1 was significantly relevant to serum 17-estradiol (E2) levels in 689 subgroup participants, especially in 400 LOAD patients of subgroup. Further gene-level analyses based on whole sample confirmed above disease association for ESR2 and CYP11A1 and pathway-level analyses highlighted the impact of sex steroid metabolic pathway on disease predisposition.
The independent follow-up study for CR1, CLU and PICALM previously reported by genome-wide association study (GWAS) in Caucasians was conducted in the same Chinese cohort. Similar to the Caucasian cohort, polymorphisms in CR1 and CLU were found to be significantly different between cases and non-demented controls. However, significant disease association for PICAML was detected only in the APOE ε4 (-) subgroup of our Chinese cohort.
In conclusions, genetic abnormalities were founded in Chinese LOAD patients. In addition to confirmation disease susceptibility for APOE, CR1, CLU and PICALM, we were first to report the associations between several sex steroid metabolic pathway genes and LOAD. This valuable genetic information obtained from Chinese patients may lead to the development of novel diagnostic strategies and therapeutic interventions in LOAD.<br>published_or_final_version<br>Biochemistry<br>Doctoral<br>Doctor of Philosophy
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Sarwar, Nadeem. "Emerging molecular and genetic risk factors for coronary heart disease." Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611549.
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Baumgaertel, Johanna, Robert Haußmann, Antonia Gruschwitz, et al. "Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-214315.
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Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients.
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Stojanova, Jana. "Environmental and genetic risk factors for post-transplant lymphoproliferative disease." Limoges, 2013. http://aurore.unilim.fr/theses/nxfile/default/6c517c4c-5de7-490e-a6f5-5fc542155ba9/blobholder:0/2013LIMO310E.pdf.
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Post-transplant lymphoproliferative disorders (PTLDs) represent a serious complication in solid organ transplantation and are the first cause of cancer related mortality in this population. Furtehrmore, lymphomatous PTLD in this setting is frequently extranodal, can behave more aggressively and tends to have a worse prognosis. Previous work addressing risk factors for PTLD have been based on data from large registries, lacking the detail required to address the role of individual maintenance immunosuppressant drugs, taken over time. Studies looking at genetic risk factors for PTLD have focused on cytokine gene polymorphisms, but have been limited by small size, heterogeneous case/control populations, or both. Given a viral aetiology and a key role of the immune system, we hypothesise that a susceptibility to immunosuppression might favour lymphomagenesis. Moreover, we raise the question whether individual IS drugs have a role on lymphomagenesis additional to imuunosuppression. The effect of the calcineurin inhibitors on the transformation of peripheral blood mononuclear cells (PBMCs) was explored using two panels of 10 markers and flow cytometry: one panel to characterise the emerging lymphoblasts and the other to characterise the T cell response. Chronic administration was explored in a model of spontaneously occurring lymphoma model in transgenic mice expressing CD40/LMP1. We show that in the early steps of lymphomagenesis, chronic exposure to the CNIs does not appear to have a role outside of inhibiting the T response. In the CD40/LMP1 mouse model, there is evidence that chronic cyclosporine treatment enhances lymphomagenesis. A T response in this model cannot be ruled out, however the profile of T lymphocyte splenic infiltrates does not appear to be explained solely T cell inhibition by cyclosporine. Finally, we performed a case control study with the aim to study the pharmacogenetics of drug response and showed polymorphisms in IL10 and IL2 associate with PTLD, as well as azathioprine, whose use as an immunosuppressant in transplantation has fortunately largely been replaced by newer antimetabolite<br>Les lymphomes post-transplantation (PTLD) sont les complications malignes les plus fréquentes de l’immunosuppression (IS) après les cancers cutanés, et présentent la première cause de mortalité et de perte du greffon due aux cancers chez les transplantés. De plus, les lymphomes posttransplantation peuvent se comporter de manière plus agressive avec un plus mauvais pronostic. L’EBV joue un rôle clef dans la physiopathologie de la majorité des PTLDs. Chez l’hôte immunocompétent, les lymphocytes T cytotoxiques (LTC) spécifiques de l’EBV empêchent la croissance des lymphocytes B porteurs de l’EBV, mais cette immunovigilance est abaissée lors d’une immunosuppression, qu’elle soit thérapeutique ou pathologique. Les études s’intéressant aux facteurs de risque des PTLD ont été effectuées sur des données issues de larges registres de transplantation et qui sont par nature insuffisamment détaillées pour étudier l’influence du maintien d’un traitement IS au cours de temps sur le risque de PTLD. Les études s’intéressant aux risques génétiques des PTLDs ont été focalisées sur les polymorphismes des gènes des cytokines, mais elles étaient limitées par l’effectif réduit et/ou l’hétérogénéité des populations cas et témoins. Etant donnée l’étiologie virale des PTLDs et le rôle important du système immunologique, nous avons émis l’hypothèse qu’une hypoactivité spontanée des protéines cibles et des éléments de leurs voies de signalisation, ou une hypersensibilité de ces protéines en réponse à l’effet des IS seraient à l’origine d’une immunosuppression trop intense et par conséquent favoriseraient la lymphomagénèse. De plus, ce travail tente de répondre à la question suivante: est-ce que certains IS ont une influence particulière sur la survenue des PTLD, indépendamment de leur effet sur le système immunitaire? L'effet des inhibiteurs de la calcineurine (ICN) sur la transformation des cellules sanguines mononuclées (PBMC) par l’EBV a été exploré avec deux panels de 10 marquages par cytométrie en flux : l’un pour caractériser les lymphoblastes émergents et l’autre pour caractériser la réponse T. L’effet de l’administration chronique de la ciclosporine a été exploré sur un modèle de lymphome spontanée chez la souris, exprimant le transgène CD40/LMP1. Nous montrons que les ICN ne semblent pas avoir de rôle autre que l’inhibition des LTC. Chez les souris CD40/LMP1, la ciclosporine produit une augmentation des lymphocytes B activés dans la rate. Le profil des infiltrations des lymphocytes T dans la rate ne semble pas être expliqué seulement par une inhibition de LTC par la ciclosporine. Finalement, une étude pharmacogénétique clinique de type cas-témoins a été effectuée, et montre que des polymorphismes des gènes IL10 et IL2 sont associés à la pathologie, ainsi que l’administration d’azathioprine, un médicament immunosuppresseur heureusement aujourd’hui largement abandonné en transplantation
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Baumgaertel, Johanna, Robert Haußmann, Antonia Gruschwitz, et al. "Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease." Aging and Disease, 2016. https://tud.qucosa.de/id/qucosa%3A29982.
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Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients.
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Abelson, Anna-Karin. "Genetic Risk Factors for Systemic Lupus Erythematosus : From Candidate Genes to Functional Variants." Doctoral thesis, Uppsala : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9367.
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Wanby, Pär W. "On certain genetic and metabolic risk factors for carotid stenosis and stroke." Doctoral thesis, Linköpings universitet, Institutionen för medicin och hälsa, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-7467.
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The present study evaluated genetic and metabolic factors influencing the risk of acute cerebrovascular disease (CVD) and internal carotid artery stenosis (ICA stenosis) in a Swedish community. The threonine (T) containing protein of the FABP2 A54T gene polymorphism has a greater affinity for long chain fatty acids (FFAs) than the alanine (A) containing protein. This altered affinity for FFAs has been shown to affect the intestinal absorption of fatty acids and consequently the fatty acid composition of serum lipids, in particularly postprandially. Endothelium derived NO is a potent vasodilator and antiatherogenic agent. Asymmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS). ADMA has been shown to be involved in the pathogenesis of atherosclerotic disease, and ADMA inhibits eNOS by displacement of L-arginine from the enzyme, which in turn is believed to affect the amount of NO available within the endothelium. The FABP2 A54T gene polymorphism was analyzed in 407 patients with acute CVD and also in a subset of these patients whose carotids had been evaluated with ultrasound. Both the FABP2 polymorphism and a common polymorphism of the eNOS gene, Glu298Asp, were analyzed in a different population consisting of 54 matched pairs of patients with ICA stenosis and controls. ADMA levels were measured in both study populations. We found that the T54 allele was more frequent in patients with transient ischaemic attacks (TIA), and that the TT genotype was more prevalent in young, non-smoking patients with CVD than in controls. Increased concentrations of ADMA were observed in cardio-embolic infarction and TIA, but not significantly in non-cardio-embolic infarction nor in haemorrhagic stroke. In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group. A decreased arginine/ADMA ratio, a measure of NO availability was associated with CVD in the entire study population. Patients with severe carotid stenosis had significantly higher ADMA levels than the controls. Allele and genotype frequencies of the FABP2 and eNOS polymorphisms did not differ between patients with ICA stenosis and controls. Our results indicate that ADMA is a strong marker for TIA and severe ICA stenosis, and that relative defiency of arginine, measured as L-arginine/ADMA, is present in acute CVD. We also conclude that a common polymorphism of the FABP2 gene increases susceptibility to ischaemic stroke and TIA.<br>Figure 4 on page 17 is publshed with kind permisson from The Journal of Physiology (http://jp.physoc.org/).
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Daavittila, I. (Iita). "Genetic risk factors for lumbar intervertebral disc disease characterized by sciatica." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514283666.
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Abstract
Genetic factors have been shown to have an important role in intervertebral disc disease. The associations of known genetic risk factors and whole-body vibration, a proposed environmental risk factor, for intervertebral disc disease (IDD) were evaluated. Eleven variations in eight genes (COL9A2, COL9A3, COL11A2, IL1A, IL1B, IL6, MMP-3 and VDR) were genotyped in 150 male train engineers with an average of 21-year exposure to whole-body vibration and 61 male paper mill workers with no occupational exposure to vibration. The number of individuals belonging to the IDD group was significantly higher among train engineers (42% of train engineers vs. 17.5% of sedentary workers; p = 0.005). In addition, the IL1A-889T allele represented a risk factor for the IDD-phenotype.
In order to clarify the role of genetic variations in the genes coding for several proinflammatory mediators, hundred fifty-five Finnish individuals with IDD were analyzed for mutations in the genes coding for inflammatory mediators IL-1α, IL-1β, IL-6 and TNF-α. In addition, sixteen single nucleotide polymorphisms (SNPs) in inflammatory mediator genes were genotyped. An association was identified between IDD and IL6 polymorphism +15T>A in exon 5 (p = 0.007). In addition, IL6 haplotype GGGA of -597G>A, -572G>C, -174G>C and +15T>A in exon 5 associated with IDD (p = 0.0033).
A functional SNP in the CILP gene has been suggested to cause IDD in the Japanese population. This functional variation was analyzed in 243 Finnish IDD patients and 259 controls, and in 348 Chinese individuals with degenerative MRI findings and 343 Chinese individuals with normal MRI. No association was found in the Finnish and Chinese study populations.
In order to reveal chromosomal susceptibility loci and new candidate gene(s) for IDD a genome-wide scan was performed on 14 Finnish families with 186 individuals. Genome-wide and fine mapping analysis provided maximum two-point LOD scores of 2.71, 2.36 and 2.04 for chromosomes 21, 4, and 6, respectively. Second fine mapping confirmed the susceptibility of chromosome 21. Two candidate genes, ADAMTS-1 and ADAMTS-5, were analyzed in the region suggesting linkage, leading to the identification of thirteen sequence variations. However, none of the variations were disease causing.
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Caglayan, Safak [Verfasser]. "SORLA/SORL1 as genetic risk factor in Alzheimer disease / Safak Caglayan." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1043480935/34.
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Shah, S. H. "Discovery and application of genetic determinants of cardiovascular disease risk factors." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1417181/.
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The focus of my PhD has been two-‐fold: First, to improve the understanding of the biology behind a well-‐known cardiovascular disease (CVD) risk factor -‐ left ventricular mass, by identifying novel genetic loci associated with this risk factor. A large-‐scale association meta-‐analysis in over 10,000 individuals identified four novel loci associated with electrocardiographically-‐determined left ventricular mass. Second, to explore the application of known genetic determinants of the main blood lipid fractions, the latter being well-‐known CVD risk factors and therapeutic targets. I assess the use of genetic variants associated with total cholesterol, low-‐ density lipoprotein-‐cholesterol (LDL-‐C), high-‐density lipoprotein-‐cholesterol (HDL-‐C) and triglycerides for discriminating healthy individuals from those that have a high absolute risk of CVD, those that require lipid-‐lowering medication, and those that have a coronary event. The lipid genetic variants showed poor discriminatory ability for all three outcomes and provided no improvement over the widely-‐used, non-‐ genetic Framingham 10 year CVD risk score. Lipid-‐associated genetic variants were also used to generate genetic risk score instruments for LDL-‐C, HDL-‐C and triglycerides, which were applied in a Mendelian randomisation analysis to determine their causal relationship with carotid-‐intima media thickness (CIMT). CIMT has been a widely used surrogate outcome measure in clinical trials of CVD drugs. LDL-‐C-‐lowering drugs have shown to reduce CIMT progression and CHD risk in clinical trials. However, the extent of any causal association between HDL-‐C or triglycerides and CIMT is unclear. The results from this MR analysis support a casual relationship with LDL-‐C, but not with HDL-‐C and triglycerides, which may indicate that CIMT is a less useful surrogate end point in clinical trials of primarily HDL-‐C or triglyceride modifying therapies.
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McVey, David Graham. "Investigating genetic risk factors of coronary artery disease using genome editing." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/36614.
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Genome-wide association studies (GWAS) have identified the genetic loci associated with many complex diseases including coronary artery disease (CAD). The challenge now is to elucidate the biological and cellular pathways affected by disease-associated loci. In order to fully understand the functional mechanisms, the causal genetic variants need to be identified. The majority of GWAS loci lack candidate genes, and may instead be located in regulatory regions, making the functional effects of specific variants difficult to appreciate. Recently, genome editing techniques have become available that allow targeted alteration of the genome, producing isogenic cell lines that differ only at the site of interest. In this study, recombinant adeno-associated virus (rAAV) genome editing was established and used to investigate potentially functional disease-associated variants in the 1p13 and 9p21 CAD loci. Evidence from previous work suggests that 1p13 (rs12740374) and 9p21 (rs10811656 and rs10757278) single nucleotide polymorphisms (SNPs) affect transcription factor binding, leading to dysregulation of local genes. Specific alteration of these SNPs using this technique enabled the examination of these hypotheses directly. The 1p13 study has provided evidence to support the hypothesis that rs12740374 is the causal SNP at this locus. We observed genotype-dependent effects upon C/EBPα binding and the expression of four 1p13 genes (SORT1, CELSR2, PSRC1 and MYBPHL). Our examination of the 9p21 SNPs showed that these variants are capable of influencing STAT1 binding, but local gene expression was not affected. This suggests that variation of just rs10811656 and rs10757278 is insufficient to affect gene expression, and that other pathways may be involved. The first study to utilise the rAAV technique to examine non-coding, regulatory SNPs, this work demonstrates that isogenic cell lines produced by rAAV genome editing allow for the quantification of subtle, genotype-specific effects. This work suggests that this adaptable technology may be beneficial for other studies examining the genetics of complex diseases.
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Rodrigo, Undugodage Linduni Madushika. "Identifying novel, conditional and joint genetic effects on Parkinson's disease risk." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/212754/1/Undugodage_Rodrigo_Thesis.pdf.
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This study is an analysis of existing ExomeChip-based genome-wide association data to demonstrate the utility of genotype imputation with whole genome sequence-based haplotype reference panels, and recently developed statistical and machine learning approaches to identify novel common and rare genetic variants and their interactions associated with Parkinson’s disease risk.
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Almontashiri, Naif Ahmad. "The Genetic and Proteomic Detereminants of the Risk of Coronary Artery Disease." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32382.
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Coronary artery disease (CAD) remains the number one cause of morbidity and mortality in the world. CAD or atherosclerosis of the coronary arteries, results from the interaction of environmental and genetic risks factors and it is postulated that 50% of the susceptibility to CAD is genetic. With knowledge of specific genetic predispositions, people at risk could be screened earlier before the disease onset. I used information from genome wide association studies (GWASs) approach to characterize some of the genetic polymorphisms that increase the risk of CAD in large case-control studies. From the first top hit of the GWASs of CAD, I found that the CAD risk polymorphisms at the 9p21.3 risk locus are associated with increased human aortic smooth muscle cells (HAoSMCs) proliferation and down regulation of the expression of genes in the vicinity of the 9p21.3 risk locus, CDKN2A (p16) and CDKN2B (p15). Extensive bioinformatics scanning of the 58 kb long 9p21.3 risk locus identified two polymorphisms that disrupt the binding of TEA-domain (TEAD) transcription factors that play a role in controlling cell cycle. Over-expression of TEAD3 or TEAD4 in HAoSMCs homozygous for the non-risk allele led to increased expression of p16, while cells homozygous for the risk allele failed to respond. TEAD factors interact with SMAD3 to mediate TGFβ induction of p16 expression. HAoSMCs homozygous for the risk allele failed to induce p16 in response to TGFβ treatment. The disrupted binding of TEAD factors to its sites at the 9p21.3 risk locus is responsible for the impaired TEAD/ TGFβ induction of p16 at the 9p21.3 risk locus.
From another hit of GWASs, I characterized a gain-of-function polymorphism (rs12960) in a mitochondrial protease called spastic paraplegia 7 (SPG7). This variant escaped a novel phosphorylation regulated processing which rendered SPG7 constitutively active. HAoSMCs carrying the risk alleles showed increased protease activity and mitochondrial reactive oxygen species production (mROS). Increased mROS production led to increased cellular proliferation and mitochondrial fusion. Cellular proliferation and mROS production are potential risk factors for CAD.
GWASs discovered variants at PCSK9 that are linked to the risk of CAD. The mechanism on how PCSK9 has a major effect on the incidence of CAD-associated events relative to his effect on LDL-C is not clear. To address this, I measured plasma PCSK9 levels in two large angiographic case-control studies using ELISA. I found that plasma PCSK9 was significantly higher in patients with acute myocardial infarction (AMI) compared to those with CAD only or CAD with a previous (non-acute) MI. The association between plasma PCSK9 levels and AMI was independent of LDL-C. My work suggests that plasma PCSK9 levels could affect AMI by mechanisms independent of LDL-C.
My PhD work points to the importance of backing up the GWASs and genetics data with functional studies to understand the mechanism of how these variants and genes increases the risk of CAD.
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Perdigão, Catarina. "The impact of the genetic risk factor BIN1 to Alzheimer’s disease development." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Quimica e Biológica António Xavier, 2021. http://hdl.handle.net/10362/132008.
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" Alzheimer’s disease (AD) was identified more than a century ago. Yet, there is still no cure and the mechanisms behind the most common form of AD (late-onset, LOAD) are still an open question. BIN1 was the second gene most frequently associated with LOAD. Bin1 depletion has been linked with AD earliest pathomechanisms: increased beta-amyloid (Aβ) accumulation, endosomal abnormalities, and synaptic defects. Sequencing of BIN1 genomic locus identified regulatory and coding variants of BIN1, indicating that Bin1 correct levels and function are essential for a healthy brain. Two coding variants associated with LOAD (rs754834233, Bin1-PL, and rs138047593, Bin1-KR) lead to missense mutations in Bin1 protein. This work aimed to understand whether LOAD mutations in BIN1 result in Bin1 loss of function and contribute to LOAD early mechanisms. "<br>N/A
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Petersen, Desiree C. "Genetic aspects of HIV-1 risk in an African setting." Thesis, Link to the online version, 2006. http://hdl.handle.net/10019.1/1294.
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Eckart, Kerstin. "Identification and Functional Characterization of Genetic Risk Factors in Alzheimer´s Disease." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-102595.
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Clark, Graeme Richard. "The role of genetic risk factors on the phenotype of Parkinson's Disease." Thesis, University of Newcastle upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489728.
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Parkinson's disease (PD) is the second most comInon neurodegenerative disease after Alzheimer's disease (AD), and effects approximately 1% of the over 50 population. PD can be clinically characterised by the so called 'cardinal features', which include resting tremor rigidity, bradykinesia and postural instability. Many PD patients later develop non-motor symptoms, including depression, psychosis, anxiety, insomnia and dementia. Previous studies have focussed on dementia in PD, with co-prevalence rates of between 10-80% being reported, the most consistent estimates being 25-30%. Also, PD patients have been shown to be around five times more likely to develop dementia than control subjects. It is also widely believed that PD and AD may share a common detrimental pathway. In recent years, studies have shown and association between a variety of genes and genetic risk factors, with the progression of cognitive decline in PD patients. Therefore this study will further investigate genetic risk factors which may modulate the dementia phenotype of PD. The main focus of this thesis is the effect of potential susceptibility genes on the phenotype ofPD patients. Initially, work was undertaken in order to assess the role of dementia susceptibility genes, and their interaction. This incorporated genotyping for the Microtubule associated protein tau (l'v1APT) risk haplotypes, the a-synuclein (SNCA) risk SNP (rs356219), the glycogen synthase kinase 3/3 (GSK3B) risk SNPs, and finally genotyping for Apolipoprotein E (ApoE). These genes were targeted for either their known role in PD (for example SNCA - a major component of Lewy bodies), for their known involvement in dementia in other neurodegenerative diseases (for example MAPT - in progressive supraneuclear palsy and corticobasal degeneration, ApoE e4 in Alzheimer's disease), or for their known interaction with dementia causing genes (for example GSK3B - involvement in MAPT phospohorylation). Our results suggest involvement of these genes, or their risk haplotypes, with the presence of dementia, but show variable interactions between them. Two further susceptibility genes were screened in order to determine their involvement in PD. Firstly, the SCAl7 gene (Tata-box binding protein -TBP) was shown to have a significant association with PD, through the presence of increased CAA/CAG repeats in PD patients. It should be noted that the range of repeats found in the PD group were of the upper limits of the normal repeat range. It was hypothesised that the TBP protein may accumulate in the LBs of individuals possessing larger CAG/CAA repeats, however immunohistochemical work showed no TBP protein localisation in the LBs. The initial association of TBP repeats could not be replicated in a larger Cambridge cohort. The final susceptibility gene screened in PD was the gene responsible for the lysosomal storage enzyme glucocerebrosidase (GBA). GBA gene mutations are responsible for Gaucher's Disease, whereby the protein structure is altered and results in abnormal lysosomal storage. A variety of clinical features are associated with GD, with particular interest shown in the development of Parkinsonism. Studies have shown the presence of GBA mutations in between 4-21% of PD with dementia and dementia with Lewy body's disease. In this thesis the entire sequencing region of the GBA gene was screened fur known and novel mutations in PDD and DLB cases. We found mutations to be present in approximately 6.6% of our patient group, with no mutations found in controls. These results suggest an association of GBA gene mutations and dementia in PD and DLB. The final element of this thesis was to evaluate the involvement of the LRRK2 6055G>A (G2019S) mutation in both idiopathic and familial PD. The LRPJ<2 (PARK8) gene is the most recent, and probably most exciting, monogenic cause identified for PD. It has been shown to be causative for 1-2% of idiopathic PD cases, and 6-7% offamilial PD of European origin. In this study, the aim was to replicate the findings of others, which showed a prevalence of the mutation in approximately 1% of idiopathic and 12% of familial PD cases. It has also been suggested that the G20l9S mutation in European subjects arose as the result of two separate founder events. We sought to elucidate these previous findings, and confirmed from the idiopathic and familial cases, that the mutation arose from at least two founder events. The data presented in this thesis highlights the heterogeneity of PD, and further demonstrates that it is a truly multifactorial range of disorders as opposed to a single disease entity.
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Chan, Daniel Kam Yin School of Physiology & Pharmacology UNSW. "Genetic and environmental risk factors for Parkinson's disease in Chinese and Australians." Awarded by:University of New South Wales. School of Physiology & Pharmacology, 2000. http://handle.unsw.edu.au/1959.4/17795.
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The aim of this work was to study the environmental and genetic factors for Parkinson???s disease (PD) in Chinese and Australian. Using a case-control method, environmental factors for PD were studied in a Chinese population (n=528) in Hong Kong. Current smoking (OR=0.437; p=0.013) and infrequent tea drinking (OR=1.51; p=0.02) were found to be protective factors, whereas family history and pesticide exposure during farming in females were found to be risk factors in the univariate analysis. In the multivariate analysis, current smoking reached borderline significance at the 5% level and the variables, years exposed to pesticides and family history were significant at the 10% level. Similarly, a case-control study involving 534 subjects was conducted in Australia. A positive family history was the strongest risk factor (OR=3.4; p<0.001). In addition, rural residency was found to be another risk factor (OR=1.8; p<0.001). Hypertension, stroke and well water ingestion were inversely correlated with PD (OR=0.2; p<0.001, OR=0.2; p<0.001 and OR=0.7; p<0.03 respectively). When genetic factors were examined in the Chinese population, no association to PD were found for the polymorphisms of the following candidate genes: CYP-2D6 debrisoquine hydroxyalse gene, dopamine transporter gene and monamine oxidase B (MAOB) gene. Furthermore, the Ala53Thr and Ala30Pro mutations of the alpha-synuclein gene were not found amongst this large Chinese population, indicating that variations of this gene are probably rare in Chinese. When candidate genes were studied amongst Caucasian Australians, the poor metaboliser genotype of CYP-2D6 was found to be weaky associated with PD (OR=1.36) in a meta-analysis. The length of the GT repeat alleles of MAOB gene were found to be significantly associated with PD (>188 base pair and 186 base pair) while angiotensin converting enzyme gene polymorphism was not found to be associated with PD. A pilot study was then conducted in Randwick, New South Wales to find out the latest prevalence of PD as well as putative risk factors in a random population. A validation study was carried out for a screening tool (questionnaire) for PD, which was then used for the main study. A total of 730 subjects were involved (527 in the community and 203 in institutions). The survey found that PD prevalence was between 3.6% and 4.9% (higher in aged care facilities). The putative risk factors positively identified were ???family history???(p<0.01) and ???exposure to chemicals at work or in surrounding environment??? (p<0.05). The age adjusted prevalence rate of PD revealed at least 42.5 % increase in the disease compared to 1966. We conclude that there may be an increase in the disease in Australia due to aging and other risk factors.
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Heslop, Claire Louise. "Emerging environmental, molecular, and genetic risk factors in stable coronary artery disease." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/11244.
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Both environmental and inherited risk factors make significant contributions to coronary artery disease, however susceptibility and age of disease onset for individuals with similar risk profiles varies widely. Novel biomarkers may yet be found which could improve detection of high-risk individuals, and highlight new areas of research for treatment discovery.
This thesis explores risk factors for coronary artery disease and cardiovascular mortality. The first study investigates one specific environmental variable—neighbourhood socioeconomic status—in a cohort of patients who underwent selective coronary angiography. In patients with coronary artery disease, neighbourhood-level disparities contributed to risk of non-cardiovascular mortality, particularly to deaths from cancer, but did not influence cardiovascular mortality risk. Although disparities in health and access to care may persist, these findings suggest other risk factors should be explored to improve cardiovascular patient risk assessment.
Inflammation and oxidative stress contribute to all stages of atherosclerosis, and subsequent chapters focus on contributions of these pathways to cardiovascular risk. Interleukin-6 and C-reactive protein haplotypes were compared to plasma concentrations for prediction of coronary artery disease and cardiovascular mortality. Significant relationships observed between haplotypes, plasma concentrations, angiographic disease, and cardiovascular mortality did not demonstrate causality, which underscores the challenge of distinguishing causal from confounding pathways.
Plasma oxidative stress biomarkers were measured to evaluate their utility for risk prediction, compared to conventional cardiovascular risk factors. Elevated plasma myeloperoxidase predicted coronary artery disease and cardiovascular mortality risk, independent of conventional risk factors and disease severity. Polymorphisms in candidate oxidative stress genes were also explored for associations with coronary artery disease, and effects on plasma biomarkers. A compound genotype of five polymorphisms predicted angiographic coronary artery disease and elevations in plasma myeloperoxidase. Following validation, these polymorphisms may be useful markers of lifetime oxidative stress burden and cardiovascular disease risk.
Novel cardiovascular risk markers are explored in this thesis, and tested for association with angiographic coronary artery disease, conventional risk factors, and risk of mortality. New questions are raised regarding how disease susceptibility is influenced by environmental and inherited factors, and ideas for future research are discussed.
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Wang, Lisa Yuan [Verfasser], and Manu [Akademischer Betreuer] Sharma. "Genetic Risk Factors of Parkinson's disease / Lisa Yuan Wang ; Betreuer: Manu Sharma." Tübingen : Universitätsbibliothek Tübingen, 2018. http://d-nb.info/1168634261/34.
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Liolitsa, Danae. "Genetic risk factors in Alzheiner's disease : a hypothesis-based candidate gene approach." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252104.
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Patel, Bipen Dahyabhai. "Environmental and genetic risk factors for the development of obstructive airways disease." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613675.
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Erqou, Sebhat. "Lipoprotein(a) and the risk of vascular disease." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/225182.
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Background: Lipoprotein(a) [Lp(a)] is composed of a low density-lipoprotein (LDL) particle and a glycoprotein molecule known as apolipoprotein(a) [apo(a)]. Apo(a) exists in several differently-sized isoforms and is responsible for the unique properties of Lp(a). Although Lp(a) has been known for the past 40 years its relationship with coronary heart disease (CHD) has not been characterized in sufficient detail. Whether Lp(a) causes CHD is not clear. Furthermore, the role of apo(a) isoform variation and other sources of Lp(a) heterogeneity (e.g., level of oxidized phospholipids) in Lp(a)-disease association has not been determined. Objectives: To characterize in detail the association of circulating Lp(a) levels with the risk CHD To assess the nature of Lp(a)-CHD association using an integrative genetic study To explore the role of Lp(a) heterogeneity in its association with CHD Data sources: 1. The Emerging Risk Factors Collaboration (ERFC) database (36 studies, 127,000 participants) 2. The European Prospective Investigation of Cancer – Norfolk (EPIC-Norfolk) study (2200CHD cases, 2200 controls) 3. The Pakistani Risk of Myocardial Infarction Study (PROMIS) (1800 MI cases and 1800 controls) 4. Systematic quantitative reviews of published epidemiological studies Results: ERFC data - Analyses of cross-sectional data on up to 127,000 participants (predominantly of European descent) demonstrated that Lp(a) is generally not strongly correlated with known CHD risk factors. Weakly positive correlations were observed with LDL-cholesterol, apolipoprotein B100 and fibrinogen. Levels were over 2-fold higher in Blacks compared to Whites. Analyses of available data on repeat measurements in 6600 participants demonstrated that Lp(a) values have very high long-term within-person consistency (regression dilution ratio ~ 0.9). Outcome data involved 9300 incident CHD events, 1900 ischaemic strokes and 8100 nonvascular deaths. The risk ratio for CHD per 1SD higher Lp(a) concentration, adjusted for age, sex, lipids and other conventional vascular risk factors, was 1.13 (95% CI, 1.09-1.18). The corresponding risk ratios for ischaemic stroke and nonvascular death were 1.10 (1.02 – 1.18) and 1.01 (0.98-1.05), respectively. Data were too limited to assess association in nonwhites. PROMIS data – the adjusted odds ratio for MI in South Asians was comparable to that of Europeans. EPIC-Norfolk genetic data - The odds ratio for CHD per 1-SD higher Lp(a) concentration, after adjustment for cardiovascular risk factors, was 1.37 (1.20-1.56). Tagging SNPs rs10455872 and rs11751605 (minor allele frequency: 8% and 18%, respectively) were associated with 207% (95% CI, 188 - 227%) and 38% (31 - 46%) higher Lp(a) concentrations per copy of minor allele, respectively. These SNPs accounted for 35% and 5% of the variation in circulating Lp(a) levels, respectively, and were associated with an odds ratio for CHD of 1.34 (1.14-1.58) and 1.17 (1.04-1.33), respectively. The observed SNP-CHD associations were consistent with expected odds ratios corresponding to the Lp(a) effect of the SNPs. Systematic reviews – meta-analysis of published data from 40 studies (11,300 cases, 47,000 controls) demonstrated that people with smaller apo(a) isoforms have about a 2-fold higher risk of CHD or ischemic stroke than those with larger isoforms. Meta-analysis of published data from 10 studies (1500 cases, 10,200 controls) showed that people in the top third of baseline distribution of oxidized LDL levels have a 1.8-fold higher risk of CHD than those in bottom third. EPIC-Norfolk biomarker data – Levels of oxidized phospholipids were strongly correlated with Lp(a) concentration (r = 0.7, p-value < 0.0001). One SD higher concentration of oxidized phospholipids was associated with an adjusted odds ratio for CHD of 1.31 (1.15-1.49). The risk ratio was no longer significant after adjustment for Lp(a) concentration (1.08; 95% CI, 0.91-1.29). Conclusion: Lp(a) concentration is specifically, continuously and independently associated with the risk of ischaemic vascular outcomes. Available evidence supports the causal role of the particle in CHD. Lp(a) appears to induce vascular damage through causal mechanisms that involve apo(a) isoforms and oxidized phospholipids. A comprehensive study of markers of Lp(a) heterogeneity should help to understand the full impact of Lp(a) on cardiovascular diseases. In addition, further study is needed in nonwhites to assess the relevance of the factor to vascular disease risk in these populations.
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Naguib, M. "Late paraphrenia : phenomenology, classification and risk factors implicated in its causation." Thesis, King's College London (University of London), 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325085.
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Kennedy, Amy. "Genetic Markers, Birth Characteristics, and Childhood Leukemia Risk." FIU Digital Commons, 2013. http://digitalcommons.fiu.edu/etd/992.
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The cause for childhood acute lymphoblastic leukemia (ALL) remains unknown, but male gender is a risk factor, and among ethnicities, Hispanics have the highest risk. In this dissertation, we explored correlations among genetic polymorphisms, birth characteristics, and the risk of childhood ALL in a multi-ethnic sample in 161 cases and 231 controls recruited contemporaneously (2007-2012) in Houston, TX. We first examined three lymphoma risk markers, since lymphoma and ALL both stem from lymphoid cells. Of these, rs2395185 showed a risk association in non-Hispanic White males (OR=2.8, P=0.02; Pinteraction=0.03 for gender), but not in Hispanics. We verified previously known risk associations to validate the case-control sample. Mutations of HFE (C282Y, H63D) were genotyped to test whether iron-regulatory gene (IRG) variants known to elevate iron levels increase childhood ALL risk. Being positive for either polymorphism yielded only a modestly elevated OR in males, which increased to 2.96 (P=0.01) in the presence of a particular transferrin receptor (TFRC) genotype for rs3817672 (Pinteraction=0.04). SNP rs3817672 itself showed an ethnicity-specific association (Pinteraction=0.02 for ethnicity). We then examined additional IRG SNPs (rs422982, rs855791, rs733655), which showed risk associations in males (ORs=1.52 to 2.60). A polygenic model based on the number of polymorphic alleles in five IRG SNPs revealed a linear increase in risk (OR=2.00 per incremental change; P=0.002). Having three or more alleles compared with none was associated with increased risk in males (OR=4.12; P=0.004). Significant risk associations with childhood ALL was found with birth length (OR=1.18 per inch, P=0.04), high birth weight (>4,000g) (OR=1.93, P=0.01), and with gestational age (OR=1.10 per week, P=0.04). We observed a negative correlation between HFE SNP rs9366637 and gestational age (P=0.005), again, stronger in males (P=0.001) and interacting with TFRC (PPinteraction=0.05). Our results showed that (i) ALL risk markers do not show universal associations across ethnicities or between genders, (ii) IRG SNPs modify ALL risk presumably by their effects on iron levels, (iii) a negative correlation between an HFE SNP and gestational age exists, which implicates an iron-related mechanism. The results suggest that currently unregulated supplemental iron intake may have implications on childhood ALL development.
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Fuller, Melissa Suzanne. "Primary Care Providers Believe Patient-Generated Family History Will Increase Ability to Assess Patient Risk." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218051698.
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Bradley, India. "Clinical Practices of Neurologists Related to Predictive Testing of Presymptomatic Patients At Risk for Huntington Disease." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406900839.
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Lluís, Ganella Carla 1984. "Genetic factors associated with coronary heart disease and analysis of their predictive capacity." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/84185.
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The main expansion of the discovery of genetic variants associated with complex diseases has occurred during the last decade. This expansion has been accompanied, and in some sense motivated, by the desire to use this information to improve the predictive capacity of many diseases with an unidentified familial component, including coronary heart disease (CHD), with the aim of translating this genetic knowledge into clinical practice. This doctoral thesis is structured in two lines of investigation that address distinct aspects of this issue, first to evaluate the possible role of genetic variation in a candidate gene in modulating CHD risk, and second to evaluate whether genetic information can be used to improve risk assessment tools used in clinical practice.
In the first research line (described in Part I), we investigate the contribution of genetic variation in one of the most widely-studied genes in cardiovascular genetics, ESR1, which encodes the Oestrogen receptor α protein. We provide a solid meta-analysis of evidence regarding the most widely-studied variant in this gene and we further explore the role of a broad range of common and uncommon variants in this gene in CHD risk. Using these approaches, we find no evidence of association between the genetic variants studied and CHD risk. However, although we can confidently accept that common genetic polymorphisms are not associated with cardiovascular disease, we cannot discard the possibility that other types of variation in this gene (for instance epigenetic variation) could modify susceptibility to cardiovascular disease, or that other elements of this pathway are associated with an increased risk of CHD. In this research I have provided a reliable answer to this long running unanswered question in cardiovascular genetics, allowing research to re-focus on other elements of this system or other pathways.
In the second line, we explored the possible utility of genetic information obtained from genome-wide association studies (GWAS) in prediction of 10-year risk of CHD events by adding this information to cardiovascular risk functions. We have followed the recommendations proposed by the American Heart Association for evaluating the utility of novel biomarkers in clinical practice, and have demonstrated that although the magnitudes of the effects of these genetic variants on CHD risk are modest, there is a tendency towards improvement in the capacity of the risk functions to predict future CHD events. The translation of genetic information into clinical practice was one of the main motivations for the investment in genome-wide association studies, and my research represents one of the first efforts to explore this possibility.<br>L’expansió principal pel que fa al descobriment de variants genètiques associades amb malalties complexes s’ha dut a terme durant la última dècada. Aquesta expansió ha estat acompanyada, i d’alguna forma motivada, pel desig d’usar aquesta informació per millorar la capacitat de predicció d’aquelles malalties on hi és present un cert component familiar però en les que no es coneixien les variants que conferien un major risc de patir la malaltia, entre elles la cardiopatia isquèmica (CI). La present tesis doctoral està estructurada en dues línies d’investigació que avaluen el possible rol d’un gen candidat en la susceptibilitat de la CI i també avalua la millora en la capacitat de predicció d’un esdeveniment coronari de les eines usades habitualment en la pràctica clínica mitjançant la inclusió d’informació genètica.
Més concretament, la primera línea d’investigació es centra en la contribució de la variació genètica en un dels gens més estudiats en relació amb CI: el gen que codifica pel receptor d’estrogens alfa (ESR1). En aquesta línea hem proveït un sòlid meta-anàlisis entre la variant més àmpliament estudiada d’aquest gen i risc coronari i també hem explorat el paper de la majoria de les variants comunes descrites en aquest gen i risc de CI. Mitjançant cap dels anàlisis hem trobat evidència d’associació entre les variants genètiques en aquest gen i el risc de CI. No obstant això, i encara que podem acceptar que les variants genètiques comunes d’aquest gen no estan associades amb esdeveniments coronaris, no podem descartar que altres tipus de variació en aquest gen (com per exemple variació epigenètica) pugui estar modificant la susceptibilitat a patir un esdeveniment coronari, ni tampoc que altres elements de la mateixa cadena de senyalització estiguin associats amb la malaltia.
En la segona línea d’investigació, hem explorat el possible paper de les variants genètiques, obtingudes mitjançant estudis d’associació global del genoma (GWAS), en la millora de la capacitat de predicció a 10 anys dels esdeveniments coronaris, mitjançant la seva addició en les funcions de risc cardiovascular clàssiques. Hem seguit les recomanacions proposades per la American Heart Association per l’avaluació en la pràctica clínica de nous biomarcadors, i hem demostrat que, tot i que la magnitud de l’associació d’aquestes variants és modesta, hi ha una tendència cap a la millora de la capacitat de predicció de les funcions de risc.
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Antoine, Darlène. "Functional Regulation at the 9p21.3 Genetic Risk Locus in Coronary Artery Disease (CAD)." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/33148.
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The first genetic CAD risk locus to be identified by genome-wide association studies, single nucleotide polymorphisms (SNPs) at 9p21.3 predispose to increased risk of CAD. By bioinformatics scan analysis of the 9p21.3 locus; we interrogated the 59 linked SNPs over the 53,202bp to identify putative transcription factor-binding consensus sequences. We hypothesize that some genetic polymorphisms at the 9p21.3 locus are functional and will disrupt specific regulatory sequences within enhancers. Here, I investigated how polymorphisms affect TEAD-dependent regulation at the 9p21.3 locus, and also how polymorphisms affect GATA factor-dependent regulation at the 9p21.3 locus, using cultured HEK293 and primary human aortic smooth muscle cells (HAoSMCs) to transfect the pGL3-promoter plasmid constructs containing the reference or risk variant sequences (rs10611656, rs4977757, rs10757269, rs9632885). We showed by luciferase reporter assay that the risk allele of the SNPs disrupt activation by various TEAD transcription factors. We also performed electrophoretic mobility shift assay (EMSA) to test for allele-specific transcription factor binding that affect the family of TEAD transcription factors and the GATA factors. EMSA showed binding of TEAD3 and TEAD4, and differential binding for both GATA genotypes, and luciferase reporter assay confirmed that TEAD3 and TEAD4 activate the non-risk but not the risk allele, and for GATA factors no significant activation was shown. Our investigations lead us to conclude that rs10811656 and rs4977757 are functional and disrupt specific TEAD regulatory sequences within enhancers
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Reitz, Christiane. "Genetic and vascular risk factors for cognitive decline and cerebral small-vessel disease." [S.l.] : [The Author], 2006. http://hdl.handle.net/1765/13309.
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Carter, Sarah. "The potential value and regulation of genetic tests for complex disease risk factors." Thesis, University College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433791.
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Wanby, Pär W. "On certain genetic and metabolic risk factors for carotid stenosis and stroke /." Linköping : Kalmar : Linköping University ; Department of Internal Medicine, County Hospital of Kalmar, 2006. http://www.bibl.liu.se/liupubl/disp/disp2006/med942s.pdf.
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Assimes, Themistocles L., and Robert Roberts. "Genetics: Implications for Prevention and Management of Coronary Artery Disease." ELSEVIER SCIENCE INC, 2016. http://hdl.handle.net/10150/623131.
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An exciting new era has dawned for the prevention and management of CAD utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for coronary artery disease (CAD) confirm not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis
of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Lastly, genetic risk scores of CAD may serve not only as prognostic, but also as
predictive markers and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.
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Porter, Tenielle L. S. "Genetic determinants of rates of cognitive decline in preclinical Alzheimer’s Disease." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2018. https://ro.ecu.edu.au/theses/2114.
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In 2015 the number of people worldwide living with Dementia was 46.8 million, with approximately 50-75% of these cases being clinically defined as Alzheimer’s disease (AD). Despite extensive efforts, clinical trials have so far failed to yield a treatment that successfully addresses the underlying cause of AD. This lack of treatment has been suggested, in part, to be a result of late stage of intervention in current clinical trial design. For this reason, greater focus has been placed on preclinical trials and in turn both the identification of individuals at-risk for AD and, amongst these, those that are expected to decline over the course of a trial. While brain imaging to determine Aβ- amyloid burden has utility in identifying individuals with preclinical AD, further work needs to be conducted to determine what influences rates of change during these early disease stages. Of particular focus is the rate of decline in cognitive performance, as it is the primary outcome measure of efficacy in clinical trials. A number of genetic variants have been associated with cognitive performance, however additional research needs to be conducted to accurately understand the influence that genetic variation has on cognition in preclinical AD.
Aims
Initially the aim of this thesis was to assess the combined genetic influence of established AD risk genetic variants on preclinical cognitive performance, specifically using AD-risk effect-size weighted polygenic risk scores (PRSs) (Chapter 2). It was then aimed to evaluate the effects on cognitive rates of change in preclinical AD of genes with a priori evidence for association with cognition, both individually (Chapter 3) and then when combined (Chapter 4). The results of the preceding chapters informed the final aim which was to determine a novel method of weighting individual variants in genes associated with AD-risk and/or cognition, for use in a genetic risk score that would improve the prediction of preclinical cognitive rates of change (Chapter 5).
Methods
All studies presented in this thesis utilised data from the highly characterised Australian Imaging, Biomarkers and Lifestyle Study of Aging (AIBL). The AIBL study is a longitudinal cohort study collecting data at 18-monthly intervals, currently consisting of 7.5 years of follow up. Individuals investigated in this thesis had been Positron Emission Tomography (PET) imaged to determine neocortical amyloid burden. Further, all individuals were classified as Αβhigh or Αβlow based on tracer specific cut offs. In addition, a subset of these samples underwent lumbar puncture for CSF collection at the study baseline, and Aβ42, total-tau and phospho-tau were quantified. Finally, based on the AIBL neuropsychological test battery, three cognitive composites previously developed were calculated for all participants. The cognitive composites investigated were; verbal episodic memory, a statistically driven global cognition composite, and the Pre-Alzheimer’s Cognitive Composite.
The AD-risk weighted PRS (Chapter 2) consisted of 22 genetic variants associated with AD classification, and was calculated by weighting individual variants based on their previously published associations with risk for AD. A statistically derived Cognitive Genetic Risk Profile (Cog-GRP), specifically driven by verbal episodic memory, was developed using a decision tree analysis (Chapter 4). Finally, a 27 genetic variant cognition weighted PRS (cwPRS), was developed and tested in a preclinical AD sample (Chapter 5). For the cwPRS, effect sizes for decline in a verbal episodic memory were determined individually for all variants in a reference sample. The resulting effect sizes were then used to calculate the cwPRS for each participant in a test sample (Chapter 5). For both the AD-risk weighted PRS (Chapter 2) and the cwPRS (Chapter 5), PRS calculations were conducted with both the inclusion and exclusion of the major genetic risk factor for, Apolipoprotein E (APOE).
In all studies, linear mixed models were used to investigate associations between genetic factors, independent or in combination, and longitudinal rates of cognitive performance.
Results
In CN older adults the AD-risk weighted PRS, both including and excluding APOE, was positively correlated with brain and blood biomarkers, specifically; brain Aβ burden, CSF total-tau and phospho-tau (Chapter 2). When investigating cognitive performance, specifically in CN Αβhigh participants, significant associations with baseline and longitudinal cognition were only observed in the AD-risk weighted PRS with APOE (Chapter 2).
When investigating gene variants previously reported to influence cognition, in CN Αβhigh participants, no independent associations were observed for any variant (Chapter 3). However, in the same sample, after interaction with APOE e4, significant associations were observed for variants in the Kidney Brain Expressed Protein (KIBRA) and Spondin-1 (SPON1) genes (Chapter 3). The combination of variants investigated in Chapter 3, with additional variants, resulted in the development of the Cog-GRP (Chapter 4). The Cog-GRP was able to delineate four groups: APOE ε4+ Risk, APOE ε4+ Resilient, APOE ε4- Risk, APOE ε4- Resilient, with the ε4+ Risk group reporting significantly faster decline in cognition than all other groups (Chapter 4).
Finally, a PRS encompassing a combination of AD-risk genes (Chapter 2) and cognitive-risk genes (Chapters 3 and 4), weighted by episodic memory (cwPRS), was reported to be associated with preclinical longitudinal cognitive performance (Chapter 5). Further, these associations were observed irrespective of the presence or absence of APOE in the calculation of the cwPRS (Chapter 5).
Conclusions
The work presented in this thesis provides an in depth investigation of genetic influences in preclinical AD, particularly on cognitive performance. Importantly, it supports the hypothesis that there is are differences between the genetic architectures of AD-risk and AD progression. The results presented here support the use of combinatory approaches when investigating genetic influence. Finally, reported here is a novel method for PRS weighting, with the ability to predict preclinical cognitive performance in the presence and absence of APOE. Further investigation is required in cohorts with comparable data to the AIBL study, to validate the methods explored in this thesis, allowing for their eventual use in a clinical setting.
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Bombard, Yvonne. "The nature and extent of genetic discrimination among persons at risk for Huntington disease." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/7525.
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Huntington disease (HD), the “Dancing Mania” of the Middle Ages, has always been a
particular target of social stigma and discrimination. With the discovery of a polymorphic DNA
marker linked to HD in 1983, individuals at-risk for HD were able to learn whether or not they
had inherited the causative HD mutation and possibly escape its stigma and discrimination. For
those who had inherited the HD mutation increased discrimination became a real possibility.
Genetic discrimination (GD) refers to the differential treatment of asymptomatic
individuals or their family based on genetic differences. It has been over twenty years since the
introduction of predictive testing (PT) for HD, yet little is known about the nature and extent of
GD and whether PT actually results in increased levels of GD. The objective of this dissertation
was to use qualitative and quantitative methods to investigate the nature and extent of GD
among persons at-risk for HD.
Qualitative findings provide insight into how individuals interpret, personalize and
manage GD. Results from the national survey indicate that 40% of respondents reported at
least one experience of GD. Reported experiences occurred most often in reference to life and
disability insurance, and among family and friends. Surprisingly, there were few reports of GD in
employment, health care and government settings. Experiences were not significantly
associated with PT. However, the proportion of respondents who reported GD was 16% higher
among persons who have the HD mutation than among those that do not and untested
respondents. Interestingly, respondents’ family history (FH), rather than their PT result, was the
major reason given for their experiences as well as an important predictor of GD. Psychological
distress was a health outcome of GD.
This is the first study to investigate the nature and extent of GD among an asymptomatic
tested and untested population. This dissertation provides evidence that GD is a frequently
reported experience and a source of distress for persons at-risk for HD. These findings provide
insight for policy, identify areas where more education and support is needed, and provide
direction to genetic professionals supporting their clients as they confront issues of GD.
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Munz, Matthias [Verfasser]. "Identification of genetic risk factors predisposing to the inflammatory oral disease periodontitis / Matthias Munz." Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1187244384/34.
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Karimiani, Ehsan Ghayoor. "Defining disease risk groups through the quantification of genetic heterogeneity across single leukaemia cells." Thesis, University of Manchester, 2012. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:163858.
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Chronic myeloid leukaemia (CML) is typified by the BCR-ABL fusion gene. Primitive CML cells are less responsive to treatment and have high BCR-ABL mRNA and protein expression. BCR-ABL may also be required for cell adhesion, which may possess increased resistance. Previous studies have analysed bulk cell populations but the significance of BCR-ABL expression heterogeneity at the single cell level is unknown. In this study, the K562 CML cell line was used. Surface-adherent (K562/Adh) and non-adherent (K562/NonAdh) cell populations from standard suspensions were generated through 4 months of passages. Isolated K562/Adh and K562/NonAdh were used for the detection and quantification of BCR-ABL DNA, mRNA and protein levels across single and bulk cell populations, using fluorescent in situ hybridisation (FISH), RT-qPCR, flow cytometry and proximal ligation assay (PLA). Cell viability was measured for both Adh and NonAdh cells grown in the presence of a tyrosine kinase inhibitor (Imatinib) using the Cell Proliferation Kit (XTT).The passage of K562 cells demonstrated a small fraction (5% + 2.1%) of K562/Adh cells adhering to the plastic surface of the culture flask. Genomic BCR-ABL gene amplification was present in K562 cells, but displayed no significant difference between K562/Adh and K562/NonAdh cell types (P=0.8227). RT-qPCR showed up-regulation of BCR-ABL mRNA in K562/Adh cells, compared to K562/NonAdh in single and bulk cells (p<0.0001). In addition, a microfluidic platform was developed for measuring the BCR-ABL fusion gene. The proximal ligation Assay (PLA) and flow cytometry showed higher expression of phospho-BCR-ABL protein in K562/Adh cells than K562/NonAdh (63.42% and 23.1%). Imatinib significantly inhibited the growth of K562/NonAdh; whereas the treatment of K562/Adh had less effect (p<0.005), suggesting resistance of K562/Adh to Imatinib. These results provide some evidence, at both single and bulk cell levels, for the existence of an adherent subpopulation of K562 cells with higher BCR-ABL mRNA and phosphorylated protein which are resistant to Imatinib, suggesting the possibility of a similar subpopulation of cells in CML which may cause clinical resistance.
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Bellis, Claire. "Use of the Isolated Norfolk Island Population for Cardiovascular Disease Risk Trait Genetic Analysis." Thesis, Griffith University, 2009. http://hdl.handle.net/10072/368099.
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Cardiovascular disease (CVD) is a major public health issue and a disorder that accounts for over half of all deaths in Western countries. Many important risk factors for cardiovascular disease have been identified, with environmental factors, such as diet, smoking, bodyweight, blood pressure, lipid levels and exercise involvement, have shown to be important in cardiovascular predisposition. However, CVD and its associated risk traits display both environmental and genetic components. A family history has been shown to one of the most important risk factors for disease development, emphasising the role of genetic predisposition. This study aimed to investigate the role of genetic and environmental risk factors in this common life threatening disorder including a focus on blood pressure, lipid and body mass variation. To investigate these factors a unique isolated founder effect population from Norfolk Island was studied.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>Griffith Institute for Health and Medical Research<br>Griffith Health<br>Full Text
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Guyatt, Anna Louise. "Complex genetic loci and their association with disease risk traits in population-based cohorts." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.742995.
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Hartman, Mikael. "Risk and prognosis of breast cancer among women at high risk of the disease /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-303-0/.
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So, Hon-cheong, and 蘇漢昌. "Genetic architecture and risk prediction of complex diseases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B4452805X.
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Nishio, Kazuko, Sakurako Nakamura, Yoshitaka Sekido, Toshimitsu Niwa, and Nobuyuki Hamajima. "Associations between Disease Risk and Eight Polymorphisms Adopted for Genotype Announcements at Nagoya University Hospital." Nagoya University School of Medicine, 2004. http://hdl.handle.net/2237/5404.
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