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1
Kelempisioti, A. (Anthi). "Genetic risk factors for intervertebral disc degeneration." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526211350.
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Abstract Low back pain (LBP) is the leading cause of years lived with disabilities worldwide. Intervertebral disc (IVD) degeneration is a strong contributing factor to LBP. Recent studies have shown that genetic determinants contribute markedly to IVD degeneration but knowledge about the actual genes involved as well as their roles is still limited. The aim of this thesis work was to study genetic factors that may predispose to IVD degeneration. Using both family and case-control association study designs, variants in five genes showed association with IVD degeneration on magnetic resonance imaging (MRI) in a population-based sample and among patients with sciatica due to lumbar disc herniation (LDH). We performed a candidate gene association study of the known variants implicated in IVD degeneration in a Finnish cohort of 538 young individuals with a moderate degree of lumbar IVD degeneration on MRI. We were able to confirm the associations of variants in the IL6, SKT, and CILP genes, which provides further evidence for true associations. Based on our earlier linkage study in Finnish sciatica families, we performed a candidate gene analysis and identified IL17F as a potential candidate gene. To the best of our knowledge this is the first study to observe an association between this gene and discogenic sciatica. Both IL-6 and IL-17 are pro-inflammatory cytokines with elevated expression levels in herniated tissues, which suggest a role in IVD degeneration. Study of the role of genes coding for inflammatory mediators is of interest as it may contribute to the understanding of the overall inflammatory response of the disc. In addition, we reported on the involvement of SKT in the etiology of lumbar disc herniation (LDH) both in Japanese and Finnish case-control samples. Experimental studies in mice have shown that Skt homozygous mutants exhibit disc abnormalities resulting in a kinky tale phenotype. We hypothesized that the human homolog SKT could have long-term importance in the onset of IVD degeneration by making the discs more vulnerable. Finally, through linkage studies and in the subsequent association analyses, the role of CHST3 as a novel risk factor for IVD degeneration was identified. CHST3 encodes an enzyme that catalyzes the sulfation of chondroitin, and mutations in this gene are associated with spondylepiphyseal dysplasia and humerospinal dysostosis. In our study, we identified this gene using genome –wide linkage based on data from a Southern Chinese family and speculated that mild CHST3 reduction caused by the reported susceptibility SNP could result in disc degeneration in adults in conjunction with other risk factors. This thesis provides new information about the genetic background of IVD degeneration and new insights into the etiology of the disease. The specific roles of these genes in the IVD function and pathogenesis of sciatica are not clear however, and need to be elucidatedTiivistelmä Alaselkäkipu on yksi yleisimmistä sairauksista ja johtava syy työkyvyttömyyteen. Välilevyrappeuma myötävaikuttaa merkittävästi alaselän kipuun. Vaikka aiemmat tutkimukset ovat osoittaneet, että perintötekijöillä on vahva osuus välilevyrappeumaan, altistavat geenit ja niiden rooli tunnetaan huonosti. Tämän tutkimuksen tavoitteena oli arvioida tiettyjen perintötekijöiden osuutta välilevyrappeumassa ja tunnistaa taudille altistava geeni perheaineistossa aiemmin havaitulta kromosomialueelta. Aineistoina tutkimuksessa olivat perheaineistot sekä laajat potilas-kontrolliaineistot suomalaisesta ja aasialaisista väestöistä. Tutkimuksessa osoitimme, että perimän vaihtelut viidessä tutkitussa geenissä altistivat erilaisille välilevyrappeuman taudin muodoille. Tutkimus, jossa analysoimme aiemmin tunnistettuja alttiusgeenejä, vahvisti IL6, SKT ja CILP geenien vaihteluiden osuuden taudin alttiustekijöinä. Tutkimusaineistona oli pohjoissuomalainen syntymäkohortti, jossa välilevyrappeuma oli määritetty magneettikuvauksella (MRI). Suomalaisessa perheaineistossa tehdyn kokogenomin laajuisen kartoituksen pohjalta analysoimme IL17F geenin mahdollisena uutena alttiusgeeninä oireiselle välilevytaudille. Kahdesta geenin variantista koostuva haplotyyppi assosioitui tautiin merkitsevästi. Lisäksi osoitimme, että SKT-geenin tietty muutos altistaa välilevyn pullistumille sekä japanilaisessa että suomalaisessa potilasaineistossa. Hiirikokeissa on havainnoitu, että SKT-geenin homotsygootti mutaatio johtaa välilevy-poikkeamaan, joka edelleen aiheuttaa hiiren poikkeavan häntäilmiasun-. Hypoteesimme oli, että ihmisen SKT -geeni voi myötävaikuttaa välilevypullistuman kehittymiseen altistamalla välilevyt rappeumalle. Edelleen, laajassa usean populaation aineiston käsittävässä tutkimuksessa osoitimme CHST3-geenin muutoksen altistavan välilevyrappeumalle. Peittyvästi periytyvät muutokset tässä geenissä aiheuttavat perinnöllisiä harvinaisia luusairauksia. Tämä väitöstutkimus tarjoaa uutta tietoa välilevyrappeuman geneettisestä taustasta ja auttaa taudin syiden tutkintaa. Geenien rooli välilevyn toiminnassa ja muutosten vaikutus taudin kulkuun vaativat kuitenkin vielä lisätutkimuksia
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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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Al-Chalabi, Ammar. "Genetic risk factors in amytrophic lateral sclerosis." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321934.
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Burger, Marilize Cornelle. "Genetic risk factors for carpal tunnel syndrome." Doctoral thesis, University of Cape Town, 2014. http://hdl.handle.net/11427/12714.
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Includes bibliographical references.Carpal tunnel syndrome (CTS) is a common occupational injury that is caused by an increase in pressure within the carpal tunnel structure which, in turn, causes compression of the median nerve. Although several factors are believed to be associated with increased risk of CTS, the direct causes of this injury remain unknown and it is generally accepted that CTS, with the exception of acutely caused CTS, is a multifactorial condition. Although it is generally accepted that an increase in pressure within the carpal tunnel structure, which contains nine flexor tendons, causes compression of the median nerve, the involvement of these tendons and other connective tissue structures in the aetiology of CTS cannot be excluded. In support of this, pathology of these connective structures have been proposed as being comorbid conditions or a precursor of CTS, cause CTS and/or can lead to an increase in carpal tunnel pressure. Several studies have suggested that specific non-occupational risk factors, such as anatomical, systemic and chronic factors as well as mostly repetition- and force-related occupational risk factors are associated with CTS. Although genetic influences in the aetiology of CTS have been proposed, this area has received little attention. Common DNA sequence variants on the other hand have previously been reported to associate with common exercise-associated tendon, such as chronic Achilles tendinopathy, and ligament injuries. The aim of this thesis was to determine whether common DNA sequence variants within several genes that have been associated or implicated in the aetiology of exercise-related musculoskeletal soft tissue injuries, are associated with altered risk of CTS by using a genetic association case-control study approach.
5
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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Mayosi, B. M. "Genetic determination of cardiovascular risk factors in families." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249502.
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Maude, Sophia Karen. "An investigation of genetic risk factors for migraine." Thesis, University of Aberdeen, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248576.
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Migraine manifests itself episodically with incidence ranging from one attack in a lifetime to one almost every day. Most migraineurs suffer from typical migraine with or without aura, that is inherited in a complex manner. A small number of migraineurs suffer from FHM, a condition that exhibits Mendelian inheritance. BFNC is another rare episodic disorder that exhibits Mendelian inheritance. In a four generational family the BFNC phenotype was linked to the KCNQ2 gene on chromosome 20q13.3. Blood samples and epidemiological information were collected from 214 migraine probands in the Grampian region. An Access database was created to hold these data which were subsequently input. The database was utilised to extract epidemiological information about the cohort for subsequent analysis. These data were compared to other studies to characterise the severity of the cohort. A total of six polymorphisms were analysed by association analysis for involvement in migraine. The first polymorphism to be analysed was the -141C Ins/Del polymorphism in the DRD2 gene on chromosome 11q22. This polymorphism was analysed by restriction digest. Statistical analysis excluded this polymorphism and the regions encompassed by linkage disequilibrium in the aetiology of migraine. The second and third polymorphisms were located in intron 1 of the ERa gene on chromosome 6q25. These two polymorphisms were identified by restriction digest. Individual and haplotype analysis excluded the involvement of both polymorphisms in the aetiology of migraine. The fourth, fifth and sixth polymorphisms were located in exon 47, exon 23 and exon 8 of the CACNA1A gene on chromosome 19p13. The polymorphisms were analysed by capillary electrophoresis, restriction digest and DASH, respectively. All three polymorphisms were excluded from the aetiology of migraine. A total of 12 hot spot exons were sequenced in the CACNA1A gene in one individual afflicted by FHM and two by HM. No mutations were presented in the exons sequenced.
8
Posthumus, Michael. "Genetic risk factors for anterior cruciate ligament ruptures." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3195.
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Includes abstract.Includes bibliographical references (p. 197-215).
The primary aim of this thesis was to identify candidate genes that may be associated with ACL ruptures, and then use a genetic association approach following a case-control study design to identify specific sequence variants (single nucleotide polymorphisms, SNPs) within these candidate genes which may predispose individuals to ACL ruptures. Candidate genes (COL1A1, COL5A1 and COL12A1) were selected based on the biological function of their encoded proteins (type I, type V and type XII collagen respectively) within the basic structural and functional unit of ligaments, namely the collagen microfibril.
9
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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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 detectedTiivistelmä 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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Beskow, Anna. "Genetic Risk Factors for Cervical Carcinoma in situ." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3318.
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Oncogenic human papillomaviruses (HPVs) are implicated in 99.7 % of cervical cancer cases but require the co-operation of other factors. To investigate potential genetic risk factors we have typed the HLA class II DRB1 and DQB1 loci in 478 women diagnosed with cervical carcinoma in situ and in 608 age-matched controls. Quantitative measurements of HPV 16, HPV 18/45 and HPV 31 were obtained. The DRB1*1501 and DQB1*0602 alleles were found to increase the risk of HPV 16 infection. Carriers of DRB1*1501 and DQB1*0602 were also shown to have an increased risk of a higher viral load compared to non-carriers. The DRB1*1301 and DQB1*0603 alleles were found to protect from HPV 18/45 and 31 infections as well as resulting in a lower viral load in carriers compared to non-carriers. Women with a high HPV 16, 18/45 or 31 viral load were more prone to long-term infections and women with a low HPV 16 viral load were more prone to short-term infections. Carriers of DRB1*1501 and DQB1*0602 alleles were also shown to have an increased risk of long-term infections compared to short-term infections. We also tested if an HPV susceptibility locus found for epidermodysplasia verruciformis (EV) was also linked to HPV susceptibility in cervical cancer. We did not find any linkage to this locus in a set of 77 families, each with at least three cases diagnosed with cervical carcinoma in situ. Other potential risk factors tested were HPV 16 E6 variants together with a p53 codon 72 polymorphism and HLA class II alleles. We found an association between the E6 L83V variant and the HLA DR4-DQ3 haplotype, as well as an increased frequency of Arg homozygosity of p53 in women infected with the L83V variant. These results show that alleles at HLA class II loci represents risk factors for persistent HPV infection and thereby also contribute to the risk of development of cervical carcinoma in situ.
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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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Vossen, Carolina Y. "Genetic risk factors for venous thrombosis : key players or minor risk modifiers ? /." [S.l. : s.n], 2005. http://catalogue.bnf.fr/ark:/12148/cb402235083.
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Beauchamp, Nicholas James. "Molecular genetic basis of inherited thrombophilia." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287349.
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Ferreira, Manuel A. R. "Genetic risk factors for allergic asthma in Australian families /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19164.pdf.
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Rantala, M. (Maire). "Dietary modification and genetic variability of atherosclerosis risk factors." Doctoral thesis, University of Oulu, 2000. http://urn.fi/urn:isbn:9514256522.
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Abstract
The risk factors for atherosclerosis and coronary heart disease
(CHD) are multiple and may interact with each other. Diet has a
significant role among the main risk factors for atherosclerosis,
as it regulates the levels of plasma lipids and lipoproteins, their
oxidative modification or protection from oxidation, blood pressure,
energy balance, and thrombogenesis. Nutrients can transfer their
effects directly through plasma concentrations or modify the cell
transduction or gene expression of important regulatory genes. The
response to dietary modification varies between individuals. The plasma
cholesterol response induced by dietary modification is at least
partly regulated genetically and some of the variation is explained
by other environmental factors.
Apolipoprotein E (apo E) and apolipoprotein B (apo B) are
the key regulatory proteins in cholesterol and lipoprotein metabolism.
The genetic variation of apo E is associated with the plasma lipid
levels and the CHD risk. The polymorphic variation of the apo B
gene is also associated with increased plasma cholesterol and CHD
risk. Obesity is associated with increased morbidity and mortality.
Plasma lipid abnormalities, impaired glucose metabolism and increased
blood pressure caused by obesity are the main reasons for increased
CHD mortality among obese subjects.
To study the magnitude of the response to dietary modification,
genetically selected groups were investigated. Dietary modification
had a significant impact on plasma total, LDL, and HDL cholesterol
concentrations, and the individual response in plasma LDL cholesterol
varied from 3 to 100%. The role of genetic variation in
the apo E gene was not significant in the lipid response, but the
blood pressure response was more distinct among subjects with the ε 4
allele than those with the ε 3 allele. The determination
of apo B EcoRI and MspI gene polymorphisms revealed subjects with a
greater response to diet, a finding which may have clinical importance
in the future for the attempt to identify subjects for effective
dietary counselling.
The effect of caloric restriction on gene expression was studied
in obese gallstone patients. Moderate weight reduction during caloric
restriction was associated with reduced lipoprotein lipase gene
expression, while the cholesteryl ester transfer protein gene expression
remained unchanged. Some of the beneficial changes in plasma lipids
and lipoproteins during and after weight reduction may be followed
by altered transcription of their modifying genes.
Meta-analysis is a modern and generally accepted method. Many
clinical uncertainties can be solved by combining all the data available
to a quantitative and objective analysis. However, the use of meta-analysis
do not resolve the problem of the effect of publication bias.
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Karvonen, J. (Jarkko). "Genetic and immunological risk factors and carotid artery atherosclerosis." Doctoral thesis, University of Oulu, 2004. http://urn.fi/urn:isbn:9514272609.
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Atherosclerosis is a multifactorial disease with numerous genes and environmental factors affecting its intiation and progression. During the past years many candidate genes for atherosclerosis have been suggested, and it has also become evident that the immune system plays a part in atherogenesis. Early atherosclerotic changes can be effectively detected by measuring carotid artery intima-media thickness (IMT). In the present study the associations between IMT and polymorphisms of three candidate genes for atherosclerosis were studied: endothelial nitric oxide synthase (eNOS), apolipoprotein E (apoE) and paraoxonase-1 (PON1). To assess the role of immunological factors determining carotid atherosclerosis, CRP and circulating autoantibodies to oxidised LDL were studied in relation to IMT. The study population consisted of 519 hypertensive and 526 control subjects from a middle-aged population in Oulu, Finland. The results showed that the investigated polymorphisms of eNOS and PON1 genes were not associated with IMT, suggesting that these polymorphisms are not major risk factors for atherosclerosis in the general Caucasian population. A significant interaction between the apoE polymorphism and smoking in relation to IMT was observed among men, indicating that carriers of the ε4 allele may be particularly prone to the atherogenic effects of smoking. This interaction was especially clear in hypertensive subjects. CRP was strongly associated with IMT before adjusting for confounding factors. After the adjustment, this association diasppeared. The finding suggests that instead of early atherosclerosis CRP may be related to the later phases of the disease. This may partly explain the strong correlation between CRP and future cardiovascular events. IgM type of autoantibodies binding to oxidised LDL were inversely associated with IMT, and this finding remained after adjusting for previously known risk factors for atherosclerosis, implying a possible protective role for these antibodies in atherogenesis.
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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.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.
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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Mahlman, M. (Mari). "Genetic background and antenatal risk factors of bronchopulmonary dysplasia." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526219530.
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Abstract Advances over the past few decades in ante- and neonatal care have led to the survival of a growing number of premature infants of extremely low gestational age. However, the occurrence of serious diseases, particularly those affecting the most immature infants, remains high. Bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, is one such disease. Our current understanding of the molecular pathogenesis of BPD is incomplete; consequently, there are few preventive and therapeutic options for BPD. Moreover, it is challenging to predict the risk of BPD. Previous studies of BPD in twins revealed that the heritability of BPD is quite high. However, the individual genes that predispose premature infants to BPD are largely unknown. The aim of this study was to identify and study genes associated with BPD in order to investigate its pathogenesis. An additional aim was to add to knowledge of the risk of BPD in newborn premature infants, with an emphasis on twins. A candidate gene study found no consistent association between common polymorphisms of vascular endothelial growth factor receptor 2 and BPD. A second candidate gene study noted an association between the gene encoding Kit ligand and BPD. A genome-wide association study found a suggestive association between a locus close to the gene encoding C-reactive protein (CRP) and BPD, and in subsequent analyses, plasma levels of CRP during the first week of life predicted BPD. Finally, a nationwide register study found that the risk of BPD was lower in twins than in singletons. The results of this study add to what is known of the genetics and pathogenesis of BPD. They also provide new data on the risk of BPD, which may be used to improve early identification of infants for whom the risk of developing BPD is highTiivistelmä Ennenaikaisen syntymän ja keskoslasten hoidon kehittymisen myötä yhä useammat huomattavan epäkypsinä syntyneet lapset jäävät henkiin. Samalla erityisesti juuri näitä lapsia uhkaavien sairauksien esiintyvyys on pysynyt korkeana. Bronkopulmonaalinen dysplasia (BPD, keskosen krooninen keuhkosairaus) on yksi näistä sairauksista. BPD:n molekyylitasoinen tautimekanismi on vielä osin tuntematon, eikä BPD:tä tehokkaasti estävää tai siitä parantavaa hoitoa ole. Myös BPD riskin arvioiminen vastasyntyneen keskoslapsen kohdalla on vaikeaa. BPD on huomattavan perinnöllinen tauti. BPD:lle altistavista geeneistä on kuitenkin vasta vähän tietoa. Tämän tutkimuksen tavoitteena oli lisätä tietoa BPD:n tautimekanismista tutkimalla BPD:lle altistavia geenejä. Lisäksi tutkimuksessa tarkasteltiin BPD:n esiintyvyyttä ja syntymää edeltäviä riskitekijöitä erityisesti kaksosten osalta. Ehdokasgeenitutkimuksessa verisuonten endoteelikasvutekijää koodaava geeni ei assosioitunut toistuvasti BPD:hen. Kit ligandia koodaava geeni sen sijaan assosioitui. Koko genomin assosiaatiotutkimuksessa C-reaktiivista proteiinia (CRP) koodaavan geenin lähistöltä löydettiin BPD:hen mahdollisesti assosioituva alue. Lisäksi ensimmäisen viikon CRP-arvojen osoitettiin ennakoivan myöhemmin kehittyvää BPD:tä. BPD-riskin todettiin olevan matalampi kaksi- kuin yksisikiöisistä raskauksista syntyneillä lapsilla. Tutkimuksen tulokset lisäävät tietoa BPD:n perinnöllisyydestä ja sitä kautta BPD:n tautimekanismista. Tutkimus toi myös uutta tietoa BPD:n riskitekijöistä parantaen vastasyntyneen keskoslapsen BPD-riskin arviota
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Kraatari, M. (Minna). "The heritability and genetic risk factors of Modic changes." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220550.
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Abstract Low back pain (LBP) is a highly prevalent musculoskeletal condition and the leading cause for workplace absenteeism. Lumbar disc degeneration (DD) is considered as a contributing factor to LBP. The role of genetic factors in the development of lumbar DD has been demonstrated to be significant, with heritability estimates ranging from 64% to 81%. Modic change (MC), a distinct phenotype of lumbar DD, is a subchondral and vertebral bone marrow change revealed only by magnetic resonance imaging (MRI). MC has been associated with LBP in both clinical samples and the general population. The genetic background of MC is largely unknown, and the heritability of MC has not previously been assessed. The aim of this study was to assess the heritability of MC using a twin study, identify predisposing genetic factors for MC in a family-based design using whole-exome sequencing and to identify genetic loci associated with MC using genome-wide association study (GWAS) meta-analysis. An additional aim was to study the prevalence, incidence and morphology of MC. The data consisted of two general population samples, the Northern Finland Birth Cohort 1966 (NFBC1966) and TwinsUK from the United Kingdom, as well as two Finnish families from the Oulu region. MC was found to be partly heritable with a heritability estimate of 30%. Two novel candidate genes, HSPG2 and MAML1, were found co-segregating with MC in two Finnish families. Both genes are important in the growth and differentiation of chondrocytes. Finally, a genetic locus on chromosome 9 was found to be significantly associated with MC using genome-wide meta-analysis of NFBC1966 and TwinsUK. These results showed that genetic factors play a role in the development of MC. In conclusion, this thesis increased the knowledge on the genetics of MC. However, the specific roles of these genes need to be studied furtherTiivistelmä Alaselkäkivun kansaterveydellinen merkitys on suuri, sillä jopa 84% aikuisista kärsii siitä elämänsä aikana. Selkäkivun vuoksi Suomessa kertyy yli 2 miljoona sairauslomapäivää vuodessa. Välilevyrappeumaa pidetään merkittävänä tekijänä alaselkäkivun synnyssä ja perinnölliset tekijät selittävät välilevyrappeuman synnystä jopa 74%. Modic-muutokset ovat selkärangan välilevyjen päätelevyjen ja subkondraalisen luun muutoksia, jotka voidaan havaita ainoastaan magneettikuvauksella. Niitä pidetään välilevyrappeuman alatyyppinä. Modic-muutosten on osoitettu olevan yhteydessä alaselkäkipuun, mutta etiologia tunnetaan huonosti. Perinnöllisyyden osuutta Modic-muutoksien synnyssä ei ole aiemmin tutkittu ja niiden taustalla vaikuttavat geneettiset tekijät ovat pääasiassa tuntemattomia. Tämän tutkimuksen tavoitteena oli arvioida perinnöllisyyden osuutta Modic-muutoksissa kaksoisaineistossa, tunnistaa Modic-muutoksille altistavia geneettisiä muutoksia perheaineistossa käyttäen eksomisekvensointia ja tunnistaa genomin alueita, jotka assosioituvat Modic-muutoksiin. Tutkimus perustui kahteen väestöperäiseen aineistoon: Pohjois-Suomen Syntymäkohorttiin 1966 ja TwinsUK-kaksosaineistoon Yhdistyneistä kuningaskunnista sekä kahteen pohjois-suomalaiseen perheeseen. Tutkimuksessa osoitettiin, että Modic-muutokset ovat perinnöllisiä ja, että perinnölliset tekijät selittävät noin 30% niiden ilmenemisestä. Lisäksi tutkimuksessa tunnistettiin kaksi uutta alttiusgeeniä; HSPG2- ja MAML1-geenit. Molemmilla geeneillä on tärkeä rooli rustosolujen kasvamisessa ja erilaistumisessa. Tutkimuksessa myös tunnistettiin kromosomista 9 genomin alue, joka assosioituu Modic-muutoksiin. Väitöskirjassani osoitettiin, että perinnöllisillä tekijöillä on merkitystä Modic-muutosten synnyssä. Kokonaisuudessaan tämä väitöskirja kasvattaa ymmärrystä Modic-muutoksista, mutta lisätutkimusta aiheesta tarvitaan
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Byrne, Karl Smith. "Lifestyle, biochemical, and genetic risk factors for prostate cancer." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:eb6da30a-c986-4eeb-b270-667c82fe3497.
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Despite considerable research there are no established risk factors for prostate cancer beyond age, family history, ethnicity, genetic factors, and insulin-like growth factor I. However, evidence from existing studies of risk factors for prostate cancer suggest that many lifestyle and biochemical exposures, and genetic variants may be risk factors for prostate cancer. Exposures investigated in this thesis are: vasectomy status, microseminoprotein-beta (MSP), human kallikrein 2 (HK2), and the lactase persistence SNP, rs4988235. Additionally, this thesis contains an analysis of how germline polymorphism, including rs4988235, may determine the intake of dairy produce. Vasectomy has been implicated as a risk factor for total and aggressive prostate cancer. However, vasectomy was not associated with risk of prostate cancer overall (hazards ratio (HR): 1.05; [95% CI 0.96-1.15]), with risk for high grade or advanced stage tumours (1.01; [0.84-1.21] & 0.83; [0.64-1.07], respectively), or for death from prostate cancer (0.88; [0.68-1.12]) in 84,753 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). A previous prospective study in the Multi-Ethnic Cohort found a significant protective association of MSP with prostate cancer. In a nested case-control study (1,871 cases & 1,871 controls) plasma MSP concentrations in EPIC were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen (PSA) concentration (odds ratio (OR) for highest versus lowest fourth of MSP = 0.65; [95% CI 0.51-0.84], p-trend = 0.001). No heterogeneity in this association was observed by tumor stage or histological grade. Mendelian randomisation (MR) analyses suggest a causal protective association of MSP with prostate cancer risk (OR per unit increase in MSP for MR: 0.96; [95% CI 0.95-0.97]). Although HK2 has previously been found to improve discrimination for prostate cancer in predictive models, there has been no large prospective investigation of the association of HK2 with prostate cancer in men without elevated PSA. However, in EPIC plasma HK2 concentrations were not associated with prostate cancer risk independent of circulating concentrations of PSA in a nested case-control study (2,867 cases & 2,867 controls) (OR for highest versus lowest fourth of HK2 before adjustment for PSA = 7.09; [95% CI 5.82-8.65], p-trend = 0.001 vs. after adjustment for PSA = 1.29; [0.98-1.67], p-trend = 0.1). Further, there was no evidence that including HK2 in a model of prostate cancer risk based on PSA and age improved discrimination for prostate cancer overall or for high grade tumours (overall area under the curve (AUC): 0.816 vs. 0.816 or high-grade AUC: 0.752 vs. 0.752). The lactase persistence SNP, rs4988235, has previously been investigated in the estimation of prostate cancer risk as a marker of dairy intake. In these analyses rs4988235 was not associated with prostate cancer risk overall (per-allele OR: 1.01; [95% CI 0.99-1.04]), with risk for high grade or advanced stage tumours (0.99; [0.95-1.04] and 0.99; [0.93-1.04], respectively), or for death from prostate cancer (0.96; [0.90-1.03]) in the PRACTICAL consortium, a large (48,471 cases & 29,866 controls) prostate cancer genetics consortium. Further, in UK Biobank (up to 41,514 men) rs4988235 was only associated with the intake of dairy milk (difference between CC and TT: 19.9 g/d; [12.8-26.9]) and not the intake of other dairy products (yogurt, ice cream, and cheese). It is possible that alternative germline polymorphisms may determine differences in the intake of dairy milk, which may be useful for future MR studies into prostate cancer risk. However, no SNPs were genome-wide significant in relation to the intake of dairy milk in a discovery GWAS in the UK Biobank (22,041 men). Further, putative associations for SNPs significant at the lower tentative genome-wide significance threshold (p < 10-5) were not replicated when investigated in an independent sample of men from the UK Biobank (50,701 men). In conclusion, there is no strong evidence that vasectomy, HK2, or the lactase persistence SNP as a marker of dairy intake, are associated with prostate cancer risk. Given the null GWAS for dairy milk intake, rs4988235 remains the strongest known genetic determinant of dairy milk intake. Lastly, observational and MR results provide compelling evidence that MSP is a potentially causal protective factor for prostate cancer risk. Future research should focus on replicating the putative causal association of MSP with prostate cancer and better understanding the purported role of MSP in tumour suppression or pathogen defense.
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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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Ruth, Katherine Sarah. "Identification of genetic and non-genetic factors contributing to female reproductive ageing." Thesis, University of Exeter, 2015. http://hdl.handle.net/10871/19189.
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The aim of my work was to identify additional genetic and non-genetic factors influencing female reproductive ageing in humans. Although approximately 50% of population variation in age at menopause is due to genetics, less than 3% of variation had been accounted for by common genetic variants. Of non-genetic risk factors, only smoking had consistently been found to have a strong effect on age of menopause. In the wider context of female reproduction, our understanding of the role of genetics in determining sex hormone levels was limited. By combining the results of research in these different areas, I hoped to improve our knowledge of the biology of female reproductive ageing. Chapter 1 is an introduction in which I discuss the biology of menopause, describe relationships with health and present current knowledge regarding non-genetic and genetic risk factors influencing menopause age. Chapter 2 is an analysis of the associations between non-genetic risk factors occurring in early life with early menopause. We identified an association between multiple births and early menopause, connecting events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life. Chapter 3 is a genome-wide association study to identify genetic variants associated with levels of nine sex hormone related phenotypes. We highlighted loci of relevance to reproductive function, which suggested overlaps in the genetic basis of hormone regulation. Chapter 4 is a genome-wide association study of menstrual cycle length. We showed that a common genetic variant related to follicle stimulating hormone levels and age at menopause is associated with several reproductive traits including length of menstrual cycle. Chapter 5 is an investigation of the relationship between differences in length of normal FMR1 triplet repeat alleles and timing of menopause. We found no association between the length of normal FMR1 alleles and timing of menopause, contradicting the results of smaller studies and replicating a null result in another large study. Chapter 6 is large genome-wide meta-analysis to identify common and low-frequency genetic variants associated with age at menopause. We identified 44 regions containing 54 independent common signals and two rare missense alleles of large effect. Finally, in Chapter 7 I evaluate how this work has benefitted our knowledge of female reproductive ageing and describe directions for future research.
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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.Figure 4 on page 17 is publshed with kind permisson from The Journal of Physiology (http://jp.physoc.org/).
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Varghese, Jajini Susan. "Genetic and life-style determinants of mammographic density." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610197.
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Mira, Marcelo Távora. "A study of host genetic risk factors for leprosy susceptibility /." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84296.
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Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is the leading cause of non-traumatic neuropathies in the world. Although a genetic component for leprosy susceptibility has been demonstrated by several studies, the exact nature and extent of this component is still unknown. Here, we applied linkage and association analysis in a combined candidate region and genome-wide approach to further investigate the nature of host genetic factors controlling leprosy susceptibility. First, we used 20 Vietnamese multiplex leprosy families to perform linkage analysis on selected genomic candidate regions harbouring genes previously known to be either linked or associated with leprosy phenotypes. We found significant evidence for linkage between markers of the TNFA gene located on chromosomal region 6p21 and clinical subtype of the disease (P = 0.00021). Next, we performed a genome-wide scan in a sample of 86 Vietnamese multiplex leprosy families. We identified a new leprosy "per se" susceptibility locus on chromosome 6q25--q27 (LOD = 4.31, P = 5 x 10-6). Linkage results were reproduced by family-based association analysis in an independent sample of 208 Vietnamese simplex leprosy pedigrees (P = 5.9 x 10 -5). A linkage homogeneity test confirmed chromosomal region 10p13 as modifier for paucibacillary leprosy in the Vietnamese population. Finally, we applied SNP-based association analysis to construct a high density linkage disequilibrium (LD) map of chromosome 6q25--q27. We identified genetic polymorphisms clustered in a 80 Kb LD block overlapping the 5-prime regulatory region shared by two genes, Parkinson's disease susceptibility gene PARK2 and PACRG, as risk factors for leprosy "per se" in the Vietnamese population (OR = 3.15--5.72). All associated SNPs can be distributed in three frequency haplotypes, with two SNPs capturing all the association information between the PARK2/PACRG 5-prime regulatory region and leprosy in the Viet
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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.published_or_final_version
Biochemistry
Doctoral
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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Nibali, Luigi. "Analysis of genetic polymorphisms as risk factors for Aggressive Periodontitis." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444871/.
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This PhD consisted of a series of studies aiming at detecting genetic risk factors for Aggressive Periodontitis (AgP). AgP is a destructive disease of the periodontium affecting around 1% of the population and leading to early tooth loss. Microbiological and environmental factors are thought to act on a genetically susceptible host to determine AgP. We conducted a case-control association study on 224 AgP patients (both Generalised AgP and Localised AgP) and 231 healthy controls to detect differences in genotype distributions of 13 single nucleotide polymorphisms (SNPs). The selected SNPs included FcR and FPR, NADPH oxidase, IL-6, TNF-a and VDR polymorphisms. Further studies on subsets of patients were conducted to detect associations between these SNPs and classical features of AgP: disease severity, familial aggregation, presence of periodontopathogenic bacteria and neutrophil hyperactivity. The NADPH p22phox 242 polymorphism was associated with the AgP trait and with disease severity. The IL-6 -174 SNP was associated with LAgP and with increased detection of periodontopathogenic bacteria. The FcyRIIIb NA polymorphism was associated with GAgP, while FcyR haplotypes were linked with AgP in Blacks and FcyRIIa was associated with familial aggregation of the AgP phenotype. The VDR Taq-I polymorphism showed a trend for association with AgP in smokers. The overall results of the study provide two possible pathogenic pathways leading to AgP: one is mediated through an excessive inflammatory response triggered by the presence of specific bacteria in individuals with hyper-responsive genotypes (NADPH p22phox 242 T allele, FcyRIIIb NA1 homozygosity, IL-6 -174 G homozygosity) the second is initiated by an increased susceptibility to bacterial colonization (FcyRIIa R homozygosity). In conclusion, this study supports the importance of genetic factors in Aggressive Periodontitis and hypothesizes possible pathogenic mechanisms.
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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 antimetaboliteLes 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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Cheah, Sern Yih. "Understanding the risk and functional importance of schizophrenia genetic factors." Thesis, Queensland University of Technology, 2016. https://eprints.qut.edu.au/101340/1/Sern%20Yih_Cheah_Thesis.pdf.
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This thesis investigated the role of genetics in schizophrenia. Particular schizophrenia risk genes were examined to determine their role in the development of specific schizophrenia symptoms. These genes were further studied to determine how they interact to cause schizophrenia symptoms. One important schizophrenia risk gene (BDNF) was studied in detail to determine its effect on gene expression and epigenetic changes in brains of schizophrenia individuals. This thesis has contributed to a better understanding of the role of genetics in the development of particular symptoms of schizophrenia. The results presented in this thesis may ultimately lead to more accurate diagnosis and targeted treatment for schizophrenia leading to more effective treatments with less side-effects.
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McCormack, R. M. "Identification of genetic factors contributing to the development of type 1 (insulin-dependent) diabetes mellitus in the Northern Ireland population." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246427.
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Tannenbaum, Rebecca L. "Risk Factors Associated with Prematurity in Patients Diagnosed with Hypospadias." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1368024479.
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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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Park, S. "An investigation of genetic risk factors in primary open-angle glaucoma." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18777/.
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Primary open-angle glaucoma (POAG) is a multifactorial disease with a strong genetic component. Notably however, few genes have been robustly associated with POAG in the general population. Genes in which mutation causes anterior segment angle anomalies, including LMX1B and FOXC1 are associated with a high incidence of glaucoma to about 33-75% and are strong candidates for glaucoma susceptibility. In addition, growth factors including TGFβ2 and BMP4 act in concert to maintain a balance between extracellular matrix (ECM) deposition and degradation and may play a role in glaucoma pathogenesis through misregulation of ECM synthesis of the trabecular meshwork (TM). Furthermore, OPTN E50K mutation, a known genetic locus for POAG, has been shown to account for a high percentage of 13.5% of familial normal-tension glaucoma (NTG) in individuals of white British origin. In this study, the contribution of variation at the LMX1B, FOXC1, TGFβ2 and BMP4 loci to risk of glaucoma was investigated in a case-control genetic association study in a cohort of white British descent recruited in the North-East of England comprised of 272 patients with high-tension glaucoma (HTG), 37 patients with NTG, 58 patients with ocular hypertension (OHT), and 276 normal controls. The role of OPTN E50K mutation in these unrelated white British individuals with POAG was also examined. No significant associations were identified for FOXC1, TGFβ2 and BMP4. The OPTN E50K mutation was also absent in this cohort. The study identified a significant under representation of two LMX1B haplotypes [ATG; P = 5.0E-4 (permutation P = 0.01), GCAGAC; P = 5.0E-4 (permutation P = 0.0150)] among the POAG individuals compared to the control population, consistent with a 0.3 fold decreased risk of developing POAG. A replication study involving a second cohort of 222 NTGs and 108 HTGs recruited in London showed a similar distribution of the ATG haplotype (P = 0.0047) but did not withstand permutation testing. In conclusion, LMX1B haplotypes may influence susceptibility to develop POAG in the white British population, suggesting altered LMX1B function predisposes to glaucomatous damage.
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Schader, Lindsey Marie. "Comparison of Genetic Risk Factors Between Two Type II Diabetes Subtypes." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/595048.
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Type 2 Diabetes (T2D) is an extremely heterogeneous disease, and the heritability of T2D is not fully accounted for. This study seeks to determine T2D subtypes based on clinical features before T2D diagnosis, and to test whether genetic risk factors differ between the subtypes. A sample of 13,459 White, GWAS study participants was obtained from FRAM, MESA, and ARIC. This sample consisted of 832 cases (individuals who developed T2D during follow-up) and 12,066 controls (did not develop T2D). K-means clustering was used to cluster individuals in the cases dataset based on metabolic and anthropometric characteristics. Cox proportional hazards models were used to test whether T2D genetic risk factors differed between the groups. The clustering analysis resulted in two clusters with cluster one consisting of a higher percentage of women with higher WHR, lower HDL, and higher FI as compared to cluster two. There were no statistically significant differences between the genetic risk factors of the two clusters. The most significant differences in genetic risk factors were associated with adiposity, suggesting some interaction between adiposity genes and the characteristic phenotypes of each cluster on T2D development. Further research is needed to replicate subtypes and to find significant genetic associations.
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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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Kopplin, Laura J. "The Identification of Genetic Risk Factors for Age-Related Macular Degeneration." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1251752708.
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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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Lai, Pui Man Rosalind. "Understanding the Genetic Susceptibility and Epidemiologic Risk Factors of Intracranial Aneurysms." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:15821583.
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Background and Objectives
Intracranial aneurysms affect up to 3% of the population and carry a high mortality and morbidity prognosis when presented with aneurysm rupture and spontaneous subarachnoid hemorrhage (SAH). Despite its severity on patient prognosis and cost to society, the pathologic mechanism of cerebral aneurysm formation and rupture remains unclear. The roles of genetics and epidemiology have been implicated to play major roles in the pathogenesis of aneurysm and patient outcome after SAH. Our studies serve to investigate both the genetic and epidemiologic factors associated with cerebral aneurysms through studying genome-wide association study (GWAS) of mitochondrial genes and the Nationwide Inpatient Sample (NIS) database.
Methods
For our genetic study of cerebral aneurysms, we analyzed data from two existing GWAS databases targeting the nuclear-encoded mitochondrial gene loci. We identified single nucleotide polymorphisms (SNPs) within 500kb of 794 candidate nuclear-encoded mitochondrial proteins using the human mitochondrial protein and MitoProteome databases. Plink was used to identify SNPs associated with cerebral aneurysms and a meta-analysis approach was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) of the two combined studies. In addition, gene expression analysis using three gene omnibus (GEO) databases (GSE15629, GSE26969, GSE46337) was used to identify differential expression of the genes associated with the significant SNPs.
For our epidemiologic study of cerebral aneurysms, we analyzed patients using the NIS database from 2001 to 2010. Multivariate linear and logistic models were used to analyze the association between 1) cerebral aneurysm rupture and climatic factors, 2) cerebral aneurysm outcome and hospital teaching status, and 3) cerebral aneurysm outcome and patient insurance status.
Results
Genetic studies:
A new genome-wide significant SNP on chromosome 19 (rs7937, OR=2.71, 95%CI 1.81-4.05, p=3.46x10-5) was found to be associated with the formation of cerebral aneurysms. The expression of the gene associated with this SNP, RAB4B, was also found to be elevated in our subsequent differential gene expression analysis (RAB4B, OR=1.74, 95%CI 1.23-2.47, p=0.02).
Epidemiologic studies:
There were 38,843 hospitalizations for the treatment of unruptured and ruptured aneurysms. In the analysis of SAH rupture with meteorological pattern, decreased sunlight and lower relative humidity were associated with increased rate of admission (p<0.001). In ruptured cerebral aneurysms, the odds ratio of in-hospital death and non-routine discharges were 0.69 (95% CI 0.54-0.88) and 0.77 (95% CI 0.60-0.99) in teaching hospitals, independent of hospital aneurysm procedure volume. This difference was accentuated in patients who underwent microsurgical clipping. In the analysis of patient outcome with insurance status, the adjusted odds of in-hospital mortality were higher for Medicare (OR 1.23, p<0.001), Medicaid (OR 1.23, p<0.001), and uninsured patients (OR 1.49, p<0.001) compared with those with private insurance.
Conclusion
In our genetics analysis of cerebral aneurysms, we demonstrated that mitochondrial genes may play an important role in the pathogenesis of cerebral aneurysm formation, and further research is necessary to confirm and validate the relationship between RAB4B and cerebral aneurysm formation. Our nationwide study was the first to suggest the association between decreased sunlight and lower relative humidity with admission of ruptured cerebral aneurysms. Furthermore, the studies also showed that both the hospital teaching status and patient insurance status have significant associations with the outcome cerebral aneurysm rupture.
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Kopplin, Laura J. "The indentification of genetic risk factors for age-related macular degeneration." Cleveland, Ohio : Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1251752708.
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Bruenig, Dagmar. "Genetic, biomarker and psychological factors for risk and resilience of PTSD." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/112180/1/Dagmar_Bruenig_Thesis.pdf.
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This thesis systematically investigated molecular risk and protective markers of Posttraumatic Stress Disorder (PTSD). PTSD poses a significant health and societal burden in Australia, especially in at-risk groups such as military personnel. The molecular aetiology of the disorder is poorly understood and it is unclear why many people recover quickly after trauma exposure while others continue to suffer. The thesis significantly contributes to the field of stress and resilience research by identifying novel markers for replication and adding to the knowledge-base of molecular markers for resilience, a burgeoning research field. This area of research is important to develop prevention and early intervention strategies.
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Wade, Walsh Margo. "Women Receiving Genetic Counseling for Breast Cancer Risk: Cancer Worry, Psychological Distress, and Risk Recall Accuracy." Thesis, University of North Texas, 1999. https://digital.library.unt.edu/ark:/67531/metadc2185/.
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This follows an earlier study of the same data set, which, through its findings, presented new questions that are investigated in this study. Both studies used a prospective controlled design, wherein women receiving genetic counseling for breast cancer risk were randomized into two groups. Subjects receiving an audiotaped recording of their genetic consultation (tape group) were compared to subjects who also had a genetic consultation but did not receive an audiotaped recording of it (no-tape group). Participants were drawn from attendees at the genetic clinics of two London hospitals and included 115 women with a family history of breast cancer. Cancer worry and psychological distress were assessed before genetic consultation (baseline), and at one- and six-month follow-ups by post. Objective risk was estimated by the geneticist during the consultation, and subjective risk was assessed at one month follow-up. The goals of the current study were to investigate relationships between cancer worry, psychological distress, and recall of genetic risk for breast cancer in a sample of women receiving genetic counseling for breast cancer risk, and to investigate the role sociodemographic variables on cancer worry, psychological distress, or risk recall for these women. Results for this sample of women with a family history of breast cancer found that there were consistent relationships between cancer worry, psychological distress, objective risk, and subjective risk before and after genetic consultation. This suggests that women=s psychological responses are appropriate to their level of cancer risk. There were no differences found between the tape and no-tape groups for objective or subjective risk, or for nearness of recall accuracy or degree of under-/over-estimation. Provision of an audiotaped recording of the genetic consultation did not appear to enhance recall of risk information. The role of sociodemographic variables on the psychological and risk variables assessed in this study was very minor. Age was mildly correlated with cancer worry, and employment was predictive of cancer worry only at baseline.
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Mokone, Gaonyadiwe George. "Risk factors for Achilles tendon injuries : an emphasis on the identification of specific genetic factors." Doctoral thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/3270.
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Includes bibliographical references.This main purpose of this thesis was therefore to investigate whether any specific genes on the tip of the long arm of chromosome 9 were associated with Achilles tendon injuries, using a case-control study design. The specific objectives were: (i) to identify all genes located in the 9q32-q34.3 locus in close proximity to the ABO gene, that could be involved in tendon injuries (Chapter 2) and (ii) to investigate the possible association of the identified candidate genes (COL5A1 and TNC with both Achilles tendon rupture and chronic Achilles tendinopathy (Chapter 3 and 4) and (iii) finally to investigate the possible interaction of these two genes with tendon function, namely the muscle-tendon unit flexibility (chapter 5) and structure, namely the morphological changes of the Achilles tendon (Chapter 6).
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Stone, Hillarey. "Enrichment of Transcriptional Regulators at Steroid Sensitive Nephrotic Syndrome Genetic Risk Loci." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin160199291391191.
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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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Osterstock, Jason Barrett. "Genetic epidemiology and familial risk factors for paratuberculosis seropositivity in beef cattle." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2435.
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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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Kytövuori, L. (Laura). "Genetic causes and risk factors associated with phenotypes occurring in mitochondrial disorders." Doctoral thesis, Oulun yliopisto, 2017. http://urn.fi/urn:isbn:9789526215815.
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Abstract Finding the genetic causes leading to phenotypes of mitochondrial diseases is challenging because of heterogeneity of the disorders and variety of the underlying biochemical defects. In adults, many of the manifestations of mitochondrial diseases cannot be distinguished from the neurodegenerative processes associated with old age. A single mutation or mutations within the same gene can result in a broad range of disorders. Conversely, clinically similar, monogenic disorders may be caused by genes which are governing entirely different cellular pathways. This study investigated the genetic etiology underlying certain symptoms which are characteristic for mitochondrial syndromes, or mimics of the mitochondrial ones. In the first project, we presented the contribution of genetic variation in the Wolfram Syndrome 1 gene to the risk of diabetes mellitus and sensorineural hearing impairment. We also estimated the frequency of a rare pathogenic variation in WFS1. The second project detected a link between the complex phenotype of age-related hearing impairment and the WFS1 gene. Monogenic forms of ARHI are extremely rare and we succeeded in recognizing one Mendelian form of the trait. The third project confirmed the Mitofusin 2 gene causality in the outlier phenotype of Charcot-Marie-Tooth disease. The fourth project described a Finnish family with two affected siblings with adult-onset ataxia, diabetes mellitus, and hypergonadotropic hypogonadism. The found novel mutation in mtDNA, m.8561C>G, was located in the overlapping region of two mitochondrial genes and resulted in an impaired assembly and dysfunctional energy production of mitochondrial ATP synthase. This thesis expands our knowledge about complex neurological phenotypes and identifies not only some causative genes but also outlier phenotypes, which should be noted in clinical practiceTiivistelmä Perintötekijät mitokondriaalisten ja niiden kaltaisten tautien taustalla ovat vaikeasti tunnistettavissa. Tautien kirjo on valtava, ja niihin johtavat biokemialliset syyt ovat moninaisia. Aikuisten mitokondriotaudit voivat jäädä diagnosoimatta, koska oireet voivat peittyä vanhenemiseen liittyviin neurodegeneratiivisiin prosesseihin. Sama mutaatio tai eri mutaatiot samassa geenissä voivat johtaa kliinisesti täysin erilaisiin ilmiasuihin. Toisaalta, kliinisesti samankaltaiset taudit voivat olla geneettisesti ja solubiologiallisesti kirjavia. Tässä tutkimuksessa selvitetään geneettistä etiologiaa tiettyjen mitokondriaalisille ja niiden kaltaisille taudeille tyypillisten oireiden taustalla. Ensimmäisessä osajulkaisussa tunnistetaan geneettisiä riskivariantteja Wolfram Syndrome 1 -geenissä diabeteksen ja kuulonaleneman taustalta. Lisäksi tutkimuksessa estimoidaan harvinaisen tautia aiheuttavan variaation määrää kyseisessä geenissä. Toinen projekti esittelee suomalaisen perheen, jossa myöhään alkaneen kuulonaleneman, ikäkuulon, geneettinen syy paljastuu WFS1-geenistä, jota ei aiemmin ole liitetty kyseiseen ilmiasuun. Yhden geenin aiheuttamat ikäkuulotapaukset ovat todella harvinaisia, koska ikäkuulo on monimutkainen kokonaisuus, johon ympäristötekijöillä on suuri vaikutus. Kolmas osajulkaisu kuvaa potilastapauksia, joiden ilmiasu on epätyypillinen Charcot-Marie-Toothin neuropatia. Tautigeeni on tunnettu Mitofusin 2, mutta sen aiheuttaman taudinkuvat ovat yleensä vakavampia ja varhain alkaneita. Viimeinen osajulkaisu kuvaa suomalaisen perheen, jonka kahden oireisen sisaruksen taustalta löytyy mitokondriaalisen DNA:n uusi mutaatio, joka sijaitsee kahden geenin alueella muuttaen niiden molempien lopputuotetta. Mutaation, m.8561C>G, osoitetaan vaikuttavan mitokondriaalisen ATP-syntaasin rakentumiseen ja energiatuotantoon. Tämä väitöskirja laajentaa geneettistä tietoisuutta neurologisten tautien taustalla ja esittelee uusia geneettisiä syitä ja ilmiasuja, jotka tulisi huomioida kliinisessä työssä terveydenhuollossa
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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.