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Singleton, Andrew B. "Genetic aspects of dementia." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299652.
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Curragh, H. J. "Aspects of genetic instability in lactobacilli." Thesis, Queen's University Belfast, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384494.
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Pennington, Catherine Margaret. "Genetic aspects of human prion diseases." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/24216.
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Introduction: Human prion diseases are progressive, fatal neurological conditions linked to conformational changes in the structure of the prion protein. Prion diseases may be sporadic (sporadic Creutzfeldt-Jakob disease or sCJD, Sporadic Fatal Insomnia), acquired (variant CJD, iatrogenic CJD, kuru) or genetic (genetic prion disease, gPD). gPD is due to a disease-specific point or octapeptide repeat insertion (OPRI) mutation in the prion protein gene (PRNP). Numerous different PRNP mutations have been described. In some cases of gPD the phenotype may closely resemble that of sCJD, and it can be impossible to distinguish sporadic from genetic cases without genetic screening. The clinico-pathological phenotype of gPD is highly variable, both between different mutations and even within families carrying the same mutation. This variability can be partly explained by a polymorphism at codon 129 of PRNP. Codon 129 encodes either methionine or valine, and the status of both the mutated and wild-type alleles may influence disease susceptibility and phenotype. Codon 129 may also affect the manifestations of sporadic and acquired prion disease. Homozygosity for methionine at codon 129 is over-represented in both sporadic CJD (sCJD) and variant CJD (vCJD); indeed all definite or probable clinical cases of vCJD seen to date have been homozygous for methionine. Other polymorphisms of PRNP have been found in a small number of patients with sporadic and variant CJD. The significance of these polymorphisms has not been fully investigated. It is likely that other, as yet unidentified, genetic factors also play a role in influencing susceptibility to prion diseases and the clinico-pathological phenotype. A recent genome wide association study of vCJD patients found codon 129 to be the main genetic risk factor for vCJD, but did identify other candidate loci that may contribute to disease susceptibility. Work is in progress to carry out genomic screens for other, novel polymorphisms in 309 patients with sCJD and 118 patients with vCJD. Aims: The aims of the work described in this MD thesis are: 1) To review all cases of gPD on the database of the National Creutzfeldt-Jakob Disease Research and Surveillance Unit. The clinico-pathological phenotype, investigative findings and family history will be reviewed in detail. The findings will be compared with those cases of gPD previously described, in particular with cases seen in other European countries. The incidence and prevalence of these diseases in the UK will also be assessed. 2) To review cases of sCJD and vCJD with novel PRNP polymorphisms of uncertain significance. The clinico-pathological phenotype will be reviewed in detail to attempt to establish if these novel polymorphisms exert any influence over disease susceptibility or phenotype. Results: 159 cases of gPD were identified between 1970 and 2009, representing 7.8% of the prion disease (of any type) cases referred to the NCJDRSU over this time period. 17 different PRNP haplotypes were identified: P102L-129M, P105L-129V, A117V-129V, S132I-129M, Y163X, D167G-129M, D178N-129M, D178N-129V, E200K-129M, D202N-129V, V210I-129M, Q212P-129M, 2-OPRI, 4-OPRI, 5- OPRI, 6-OPRI, 7-OPRI. The clinicopathological phenotypes were highly variable and often difficult to distinguish from sCJD. The highest number of cases was caused by the 6-OPRI, most of which belonged to a single kindred. Several cases in the 4-OPRI group were found to share an additional risk allele, rsl029273C. In may be that this mutation is not pathogenic unless this risk allele is also present. This raises the possibility that other as yet unidentified genetic risk factors exist which influence gPD susceptibility and clinicopathological phenotype. Overall 61.4% of cases tested had a positive cerebrospinal fluid (CSF) 14-3-3, 90.0% an elevated SI00b, 23.1% had Magnetic Resonance Imaging (MRI) of the brain showing basal ganglia or cortical high signal, and 18.1% had an electroencephalogram (EEG) showing triphasic periodic complexes. A positive family history of prion disease was present in 57.9% of cases. Discussion: The range of point mutations and OPRI seen in the UK is considerable, but the majority of cases were due to 6-OPRI, E200K, or PI 02L. The UK differs from the rest of the world in that E200K is not the commonest mutation, due to the presence of a large British kindred with the 6-OPRI. Even within the larger kindreds, the clinicopathological phenotype remained very variable. Some distinctive features which may act as pointers towards gPD were found, such as a linear pattern of PrPSc deposition in the cerebellum seen in E200K-129M cases. Analysing the data in the smaller groups should be done with caution, and further large international studies are needed in order to truly determine the influence of factors such as codon 129 status. As with other forms of prion disease, there is an excess of individuals with methionine homozygosity at codon 129. It is unclear whether or not PRNP mutations in cis with valine at codon 129 will result in prion disease at an older age or with a different phenotype, or if these are not actually pathogenic in this genetic context. In the case of 4-OPRI, it appears that an additional risk allele is required for the development of disease, and it remains to be seen if other additional genetic factors will be found to influence disease susceptibility and phenotype. A relatively small percentage of cases had EEGs showing periodic triphasic waves, or basal ganglia or cortical high signal on MRI. CSF SI00b was more sensitive than 14-3-3, the reverse of the pattern seen in sCJD. A pattern of a negative 14-3-3 and a very high SI00b should lead to suspicions of gPD. The current diagnostic criteria for gPD are relatively strict, and may exclude some individuals who have neuropathologically confirmed prion disease (without PRNP genotyping) and several second degree relatives with gPD. This is a potential problem, especially as the neuropathological appearances cannot be relied upon to distinguish sporadic from genetic disease. Particular attention should be paid to the family history and any subtle unusual neuropathological appearances to try and reduce the risk of gPD cases being missed. In conclusion, gPD remains a difficult condition to diagnose and study. Large systematic collaborative studies are essential to increase our understanding of these rare conditions.
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Bley, Tim. "Genetic aspects of labrador retriever myopathy /." [S.l.] : [s.n.], 2001. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Hayat, Roshanai Afsaneh. "Psychological and Behavioral Aspects of Receiving Genetic Counseling for Hereditary Cancer." Doctoral thesis, Uppsala universitet, Vårdvetenskap, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128870.
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The overall aims of this thesis were to investigate psychological and behavioral effects of receiving cancer genetic counseling for breast, ovarian and colorectal cancer and/or with a family history of these cancer types and to determine whether counselees’ informational needs were met. Study I was performed 3-7 years post-counseling. Participants (n=214) reported a relatively high level of anxiety but a low level of depression compared to cancer patients in general. However, there was no indication that the distress experienced was due to the counseling. Moderate changes in life and family relations, high level of adherence to recommended controls and satisfaction was reported. Study II was a randomized control trial (RCT) intervention study which involved 147 counselees. An increase in the level of knowledge and correct estimation of personal risk was reported in both the intervention and control groups, although this increase declined at later follow-up. Enhanced information led to significantly greater satisfaction with the given information, and the way of informing relatives. Most counselees had shared information with their at-risk relatives. Study III focused on sharing information with at-risk relatives among participants in study II and their relatives (n=81). Counselees were interviewed and answered a questionnaire, whilst their relatives only answered the questionnaire. Counselees reported positive/neutral feelings about communicating genetic information and mostly interpreted their relatives’ reactions as positive/ neutral. Also, approximately 50% of relatives reported positive/neutral reactions and were generally satisfied with the received information. Study IV was conducted in Sweden and Norway based on 235 counselees. Counselees expected counselors to be skillful and thoughtful, take them seriously and provide risk estimations and medical information. Most important issues to counselees were satisfactorily addressed by the counselors. Analyzing importance rankings resulted in five categories of needs: a need for facts, caring communication and medical information, need for understanding and support in sharing genetic information, practical care and medical/practical information. In conclusion, no adverse psychological or behavioral effect on counselees was observed. Apparently, genetic counseling is managed properly and counselors successfully address counselees’ needs. Providing extended information does not seem necessary, however, tailoring information to individual counselees needs may create a more effective counseling.
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Parelli, Francisco Paulo Contador [UNESP]. "Papel de polimorfismos genéticos nos genes IL10, TNF e LTA na hanseníase." Universidade Estadual Paulista (UNESP), 2011. http://hdl.handle.net/11449/89944.
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Universidade Estadual Paulista (UNESP)
Visando contribuir para o melhor entendimento do papel dos polimorfismos em genes de citocinas na susceptibilidade para hanseníase, foi conduzido um estudo de associação do tipo caso-controle investigando polimorfismos de base única (SNPs) nas regiões promotoras dos genes IL10 (-819C>T, -1082A>G, -2763A>C, -2849A>G e -3575T>A) e TNF (TNF-308G>A) e no gene LTA (LTA+80C>A e LTA252A>G). Amostras de DNA genômico foram obtidas de 545 pacientes com hanseníase e 380 controles, provenientes do Estado de São Paulo. As genotipagens foram feitas pelas técnicas de PCR e polimorfismo de comprimento dos fragmentos de restrição (RFLP). Para as análises estatísticas foram calculadas as freqüências alélicas, de genótipos e de portadores para cada polimorfismo avaliado. As freqüências de haplótipos foram estimadas por meio do método de máxima verossimilhança. Desvios da lei do equilíbrio de Hardy-Weinberg foram testados empregando testes de Qui-quadrado. Modelos de regressão logística com cálculo de odds ratio (OR) e p-valor com ajustes para as co-variáveis gênero e etnia foram utilizados nas comparações das freqüências entre casos e controles. Em análise isolada, os polimorfismos TNF-308G>A e LTA252A>G não apresentaram associação significativa com a doença, já para o polimorfismo LTA+80C>A, os genótipos AA e CA mostraram-se marginalmente associados com OR de proteção (0,68 e 0,80, respectivamente e mesmo p-valor corrigido=0,07) para hanseníase per se. Confirmando ainda o sentido desta associação, a análise de carreador para o polimorfismo no locus LTA+80 mostrou associação com proteção para hanseníase per se para os carreadores do alelo A (OR=0,78; p-valor corrigido=0,04). Na análise de haplótipos, LTA+80A/LTA+252A/TNF-308G foi também associado com proteção (OR=0,74; p-valor corrigido=0,02). Para a região promotora do gene IL10, o SNP - 819C>T foi...
To the better understanding of the role of genetic polymorphisms at cytokines genes on leprosy susceptibility, we conducted a case-control association study investigating single nucleotide polymorphisms (SNPs) located at promoter region of IL10 (-819C>T, -1082A>G, -2763A>C, -2849A>G and -3575T>A) and TNF genes (TNF-308G>A) and LTA gene (LTA+80C>A e LTA252A>G) gene. Genomic DNA samples were obtained from 545 leprosy patients and 380 controls, from State of São Paulo. Genotyping were done by PCR followed by restriction fragments length polymorphisms (RFLP) analyses. For statistical analyses were calculated allelic, genotypes and carriers frequencies for each polymorphism. The haplotypes frequencies were estimated using maximum-likelihood estimation method. Chisquare tests for deviation from Hardy-Weinberg equilibrium were also performed. Logistic regression models for odds ratio (OR) and p-value calculations, with adjusting for the ethnicity and gender covariates, were performed in comparisons of frequencies. Isolated, TNF-308G>A and LTA252A>G were not significantly associated to the disease, while the CC and CA genotypes to LTA+80C>A locus were marginally associated with protection (0.68 e 0.80, respectively and identical corrected p-value=0.07) for leprosy per se. In the same line, carrier analysis for LTA+80 locus showed association with protection for leprosy per se for allele A carriers (OR=0.78; corrected p-value=0.04). In the haplotype analysis, LTA+80A/LTA+252A/TNF-308G was also associated to protection (OR=0.74; corrected p-value=0.02). From IL10 promoter region analysis, -819C>T SNP was associated with susceptibility to leprosy per se to TT (OR=1.58; p-value=0.05) and CT genotypes (OR=1.36; p=0.05). This association could be confirmed in the carriers analysis for -819T allele (OR=1.40; p-value=0.02 and OR=1.39; corrected pvalue= 0.03). From haplotypic analysis for IL10 ... (Complete abstract click electronic access below)
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Zhao, Wei, and 趙煒. "BRAF mutation and aberrant methylation of gene promoters in the pathogenesis of gastrointestinal tract adenocarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36718464.
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Stolk, Megan. "Characterisation of novel TAC3 a d TACR3 gene variants and polymorphisms in patients with pre-eclampsia /." Thesis, Stellenbosch : University of Stellenbosch, 2007. http://hdl.handle.net/10019.1/1748.
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Thesis (MSc (Genetics))—University of Stellenbosch, 2007.In South Africa, pre-eclampsia is the second highest cause of maternal deaths. The incidence of this disease in the Western Cape alone is 6.8% and places a large burden of health care facilities. The placenta and implantation thereof is thought to play the most significant role in the onset of this disease. Among the many theories for its aetiology, is the acknowledged two - stage theory. This is based on evidence that pre-eclamptic placentas demonstrate altered remodelling and invasion into the uterine endometrium and myometrium. The sub-optimal endometrium invasion leads to less oxygenation of the placental environment causing transient hypoxia. Consequently, the placenta is thought to release unknown factors into the maternal circulation which then culminates in clinical features associated with pre-eclampsia. Neurokinin B is thought to be one of these placental factors and subsequently binds to the NKB receptor in the maternal system. Endothelium-derived nitric oxide synthase has recently been shown to activate this receptor. The aim of this study was to investigate the role of neurokinin B (TAC3) and the neurokinin B receptor (TACR3) genes in the predisposition of pre-eclampsia and their interaction with eNOS in the South African coloured population together with a matched control cohort.
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Law, Bic-fai Fian, and 羅璧輝. "Molecular genetics of esophageal squamous cell carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B3660446X.
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Mells, George Frank Gannaway. "Investigation of the genetic basis of primary biliary cirrhosis : the PBC genetics study." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648610.
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Sjöstrand, Christina. "Clinical and genetic aspects on cluster headache /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-363-9/.
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Grandinson, Katja. "Genetic aspects of maternal ability in sows /." Uppsala : Dept. of Animal Breeding and Genetics, Swedish Univ. of Agricultural Sciences, 2003. http://epsilon.slu.se/a390.pdf.
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Fransén, Karin. "Molecular genetic aspects of colorectal cancer development /." Linköping : Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med878s.pdf.
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Wierzbicki, Anthony S. "Refsum's disease : clinical, biochemical and genetic aspects." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413972.
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Steggles, Naomi. "Psychological aspects of genetic testing for cancer." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271020.
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Dornan, Susan. "Aspects of genetic instability in Lactococcus lactis." Thesis, Queen's University Belfast, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334525.
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Meredith, Christopher. "Molecular genetic investigation of autosomal dominant muscular dystrophy." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2001. https://ro.ecu.edu.au/theses/1509.
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This thesis contributes to the Human Genome Project by adding detail to the physical and genetic maps of the human genome, and by identifying a strong candidate gene for a form of distal myopathy. Genomic clones for the human skeletal muscle genes slow troponin (TNN/1), alpha actin (ACTA1), and (3-tropomyosin (TPM2) were isolated for use in the fluorescent in situ hybridisation localisation of these genes on the cytogenetic map of the human genome. The localisation of these genes made them potential candidates for inherited skeletal muscle diseases, including the muscular dystrophies investigated here. Microsatellite, VNTR and RFLP markers were used in a search for linkage to a novel form of distal myopathy segregating in a Western Australian family. The decadic logarithm of the likelihood ratio, or 'lod score' method, was used to determine linkage between markers and this distal myopathy gene. A 22.4 cM candidate region was identified at 14q11.2. This was the first localisation of a distal myopathy gene. The Human Genome Organisation Nomenclature Committee reserved MPD1, 'myopathy, distal 1 ', for this form of distal myopathy, now known as Laing myopathy. The MPD1 candidate region was excluded as the disease gene location for two other forms of distal myopathy. Silburn myopathy in 1994, which established the genetic heterogeneity of distal myopathy, and Felice myopathy in 1996. The exclusion of the MPD1 and French-Canadian OPMD candidate regions as disease gene locations for a putative-OPMD segregating in a Western Australian family, proved that this disease gene did not lie at 14q11.2. Testing an MPD1 muscle-specific candidate gene for the Laing myopathy mutation, the myosin heavy polypeptide 7 gene (MYH7), identified seven base changes between the MPD1 proband sequence and the published MYH7 eDNA sequence. All of these base changes were found in eight unrelated, unaffected Western Australians, therefore none of them were the Laing myopathy mutation. Two further differences to the published MYH7 sequence segregated exclusively with the MPD1 proband. One of these, the MYH7 G5073C (cDNA)/G23628C (gDNA) base change, caused a critical change to the MYH7 13-myosin heavy chain polypeptide product (13-MyHC). An A 1663P 13-MyHC substitution. G23628/C 23628 segregated with Laing myopathy in the Western Australian distal myopathy family. This segregation was confirmed by a single-strand conformation polymorphism test, then used to test 256 unaffected chromosomes. None possessed MYH7C23628. Two patients from European distal myopathy families phenotypically similar to Laing myopathy, the Voit and Scoppetta families, were tested for the presence of MYH7 gDNA G23628/C23628 heterozygosity. Both were homozygous MYH7 G23628. One of these patients (Voit) was also tested for MYH7 eDNA G5073/C5073 heterozygosity. She was homozygous MYH7 G5073. An analysis of the effect of the 13-MyHC A 1663P substitution at various levels of protein structure strengthened the candidature of MYH7 G5073C as the Laing myopathy mutation. It demonstrated the extreme rarity of the 13-MyHC A 1663P substitution; it showed that this substitution did have a detrimental effect on coiled-coil formation; and it identified ways in which the 13-MyHC A 1663P substitution could disrupt myofibrillogenesis or contractility. Future research directions are identified and the contribution of this work to evolving concepts in muscular dystrophy is evaluated.
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McCaskie, Pamela Ann. "Multiple-imputation approaches to haplotypic analysis of population-based data with applications to cardiovascular disease." University of Western Australia. School of Population Health, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0160.
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[Truncated abstract] This thesis investigates novel methods for the genetic association analysis of haplotype data in samples of unrelated individuals, and applies these methods to the analysis of coronary heart disease and related phenotypes. Determining the inheritance pattern of genetic variants in studies of unrelated individuals can be problematic because family members of the studied individuals are often not available. For the analysis of individual genetic loci, no problem arises because the unit of interest is the observed genotype. When the unit of interest is the linear combination of alleles along one chromosome, inherited together in a haplotype, it is not always possible to determine with certainty the inheritance pattern, and therefore statistical methods to infer these patterns must be adopted. Due to genotypic heterozygosity, mutliple possible haplotype configurations can often resolve an individual's genotype measures at multiple loci. When haplotypes are not known, but are inferred statistically, an element of uncertainty is thus inherent which, if not dealt with appropriately, can result in unreliable estimates of effect sizes in an association setting. The core aim of the research described in this thesis was to develop and implement a general method for haplotype-based association analysis using multiple imputation to appropriately deal with uncertainty haplotype assignment. Regression-based approaches to association analysis provide flexible methods to investigate the influence of a covariate on a response variable, adjusting for the effects of other variables including interaction terms. ... These methods are then applied to models accommodating binary, quantitative, longitudinal and survival data. The performance of the multiple imputation method implemented was assessed using simulated data under a range of haplotypic effect sizes and genetic inheritance patterns. The multiple imputation approach performed better, on average, than ignoring haplotypic uncertainty, and provided estimates that in most cases were similar to those observed when haplotypes were known. The haplotype association methods developed in this thesis were used to investigate the genetic epidemiology of cardiovascular disease, utilising data for the cholesteryl ester transfer protein gene (CETP), the hepatic lipase (LIPC) gene and the 15- lipoxygenase (ALOX15) gene on a total of 6,487 individuals from three Western Australian studies. Results of these analyses suggested single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were associated with increased plasma high-density lipoprotein cholesterol (HDL-C). SNPs in the LIPC gene were also associated with increased HDL-C and haplotypes in the ALOX15 gene were associated with risk of carotid plaque among individuals with premature CHD. The research presented in this thesis is both novel and important as it provides methods for the analysis of haplotypic associations with a range of response types, while incorporating information about haplotype uncertainty inherent in populationbased studies. These methods are shown to perform well for a range of simulated and real data situations, and have been written into a statistical analysis package that has been freely released to the research community.
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Bruiners, Natalie. "Molecular genetic analysis of preterm labour." Thesis, Stellenbosch : Stellenbosch University, 2007. http://hdl.handle.net/10019.1/17741.
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Thesis (MSc)--University of Stellenbosch, 2007.ENGLISH ABSTRACT: The World Health Organisation (WHO) has defined preterm labour as the onset of labour before 37 completed weeks of gestation with an incidence ranging between 5-10%. Although patient care has improved, the rate of preterm birth has slowly been increasing and currently impacts significantly on maternal and fetal mortality and morbidity. The complex condition of preterm labour involves multiple etiologies and risk factors, which complicates the search for candidate markers and / or biomarkers. The aim of this prospective study was to investigate potential genetic associations with preterm labour. The study cohort consisted of consecutive first-time booking, low-risk primigravid pregnant women from a restricted geographical region. The study cohort comprised 421 [306 Coloured and 115 Black] pregnant women presenting at the Paarl Hospital Obstetric clinic. Subsequently, DNA was extracted from whole blood and investigated for a range of known polymorphisms in pro-inflammatory and anti-inflammatory cytokines, as well as the novel LGALS13 gene, for potential variants that may impact on pregnancy outcome. Screening techniques involve combinations of allele-specific PCR amplification, Multiphor SSCP/HD analysis, restriction enzyme analyses and DNA sequencing. A significant association was demonstrated between the IL-1RN*2-allele and adverse pregnancy outcome, mainly in the preterm labour and hypertension group. The presence TNFα-308 A-allele was associated with overall adverse pregnancy outcome and preterm labour. In addition to this, a novel IL-1RN allele was identified in the control group. Mutation screening and subsequent statistical methods revealed an association between a novel LGALS13 exonic variant, 221delT, and preterm labour in Coloured women. Two previouslydocumented intronic variants (IVS2-22A/G and IVS3+72T/A) demonstrated linkage disequilibrium, signifying evolutionary conservation of exon three. Additionally, two novel intronic variants, IVS2-36 G/A and IVS2-15 G/A, demonstrated no association with adverse pregnancy outcome. In this study we identified rare novel exonic variants; two non-synonymous variants in exon three (M44V, [N=2] and K87R, [N=1]) and a silent variant in exon four (P117P, [N=1]) - all identified in individuals from the control cohort. Within coding exon three, an interesting variant [“hotspot”] was identified, which represents six polymorphic bases within an 11bp stretch. No associations were demonstrated with these variants and pregnancy outcome. Furthermore, a previously documented 5' “‘promoter” variant, -98 A/C, was identified and demonstrated no association with adverse pregnancy outcome. However, subdivision of lateonset pre-eclamptic cases revealed a significant association with the A-allele and late-onset preeclampsia. Genotype-phenotype investigation demonstrated association between the IL-10 -1082 A/G, IL-4 C/T and 221delT loci and poor pregnancy progress which manifested as (i) delivery of infants weighing <2000g, (ii) before 37 weeks of gestation. The findings of this study will strengthen our understanding of the pathophysiology underlying pregnancy complications and facilitate the further development of effective treatment strategies to reduce maternal and fetal morbidity and mortality.
AFRIKAANSE OPSOMMING: Die Wêreld Gesondheid Organisasie (WHO) klassifiseer voortydse kraam as kontraksie voor 37 volledige weke, met ‘n insidensie tussen 5-10%. Alhoewel pasiënte-sorg verbeter het, neem die tempo van voortydse geboorte steeds toe, wat ‘n groot impak het op moederstrefte en fetale mortaliteit en morbiditeit. Die komplekse kondisie van voortydse kraam sluit veelvoudige oorsake en risiko faktore in, wat die navorsing van kandidaat en / of biologiese merkers kompliseer. Die doel van hierdie prospektiewe studie, was die potensiële navorsing van genetiese assosiasies met voortydse kraam. Die studie kohort bevat opeenvolgende eerste bespreking van lae risiko primigravida swanger vrouens vanaf ‘n beperkte geografiese omgewing. Die studie kohort beslaan 421 [306 Kleurling en 115 Swart] swanger vrouens teenwoordig by die Paarl Hospitaal Verloskunde kliniek. Vervolgens was DNS geëkstraeer van bloedmonsters en geondersoek vir ‘n verskeidenheid van bekende polimorfismes in pro-inflammatoriese en antiinflammatoriese sitokiene, insluitend die nuwe sifting van die LGALS13 geen potensiaal vir variante wat ‘n impak op swangerskap uitkomste sal hê. Die siftings tegnieke toegepas, sluit in ‘n kombinasie van alleel-spesifieke amplifikasie, Multiphor enkelstring konformasie polimorfisme / heterodupleks analise, restriksie ensiem verterings en volgorde bepalings tegnieke. ‘n Betekenisvolle assosiasie was gedemonstreer tussen die IL-1RN*2-alleel en nadelige swangerskap, beperk tot voortydse kraam en die hipertensie groep. Die teenwoordigheid van die TNFα-308 A-alleel was geassosieer met algehele nadelige uitkomste en voortydse kraam. Daarby, was ‘n nuwe IL-1RN alleel geïdentifiseer in die kontrole groep. Mutasie sifting en opeenvolgende statistiese metodes, het ‘n assosiasie getoon tussen ‘n nuwe LGALS13 koderende variant, 221delT, en voortydse kraam in Kleurling vrouens. Twee voorafbeskryfde introniese variante (IVS2-22 A/G en IVS3+72 T/A), het ‘n betekenisvolle bewys opgelewer dat daar koppelings-onewewig bestaan tussen hierdie variante, en toon evolusionêre konservasie van ekson drie. Addisioneel was twee nuwe introniese variante ontdek, IVS2-36 G/A en IVS2-15 G/A, wat geen assosiasie getoon nie. In hierdie studie het ons ‘n nuwe seldsame koderende variante geïdentifiseer in die kontrole groep, waarvan twee nie-sinonieme variante was in ekson drie (M44V, N=2 en K87R, N=1) en ‘n stil variasie in ekson vier (P117P, N=1). Geleë in die koderende area van ekson drie, was ’n interessante variant [“hotspot’] ontdek, waarvan ses basisse in ‘n 11 basis paar area polimorfies is. Geen assosiasie was getoon met hierdie variante en swangerskap uitkomste nie. Verder was ‘n voorafbeskryfde 5' ‘promotor’ variant, -98 A/C, geïdentifiseer wat geen assosiasie getoon met nadelige swangerskap uitkomste nie. Onderverdeling van laat-aanvangs preeklampsie, het getoon dat die A-alleel ‘n betekenisvolle assosiasie getoon het met die ontwikkeling van laat pre-eklampsie. Genotipe-fenotipe interaksies het ’n assosiasie getoon tussen die IL-10 -1082 A/G, IL-4 C/T en 221delT lokusse en nadelige swangerskap uitkomste, wat manifesteer as (i) kraam van suigelinge wat <2000g weeg, (ii) geboorte voor 37 weke. Die bevindings van hierdie studie sal ons basiese kennis verbeter oor die patologie beskrywend aan swangerskap komplikasies, asook die fasilitering en ontwikkeling van effektiewe behandelings strategieë, om moederstrefte en fetale mortaliteit en morbiditeit te verminder.
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Selemani, George Paul. "Genetic diversity and population structure of plasmodium falciparum from four epidemiological locations in Malawi." Thesis, Nelson Mandela Metropolitan University, 2014. http://hdl.handle.net/10948/d1021026.
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In malaria-endemic regions, Plasmodium falciparum (P. falciparum) infection is characterized by extensive genetic/antigenic diversity. Describing this diversity provides important information about the local molecular epidemiology of infecting P. falciparum parasites. Intriguingly, one of the major obstacles to the development of an effective malaria vaccine has been the genetic polymorphisms exhibited by P. falciparum genes encoding targets of human immune system. This situation has necessitated the development of polyvalent vaccines with wide antigenic coverage that would increase the likelihood of vaccine efficacy that covers wide geographical areas of malaria endemic countries. Limited reports are available on the population genetic diversity and structure of P. falciparum in Malawi, and this is of particular concern as the country has put in place several interventions to combat the disease. The primary aim of the research project was to determine the genetic diversity and population structure of P. falciparum isolates and comparing complexity from four different epidemiological settings in Malawi using msp-2 gene polymorphisms. Samples were collected from four epidemiological locations in the north, centre and southern regions of Malawi. The diversity and genetic differentiation of P. falciparum populations were analyzed based on the highly polymorphic block 3 msp-2 gene. One hundred and twenty patient samples who presented with signs and symptoms of malaria and who had microscopically confirmed P. falciparum infection were enrolled in the study after they had satisfied the inclusion criteria. Parasite DNA was extracted from the blood spot on to filter paper and analyzed by genotyping the msp-2 gene using allele-specific nested PCR. A total of 28 msp-2 block 3 fragments, defined by the size and the allelic types were detected in the 102 patients. The length variants of the PCR product ranged from 240basepairs (bp) to 450bp for the K1/FC and 410bp to 780bp for the 3D7/IC allelic families. Isolates of the 3D7 alleles were predominant in the population (59 percent), compared to isolates of the K1/ FC27 alleles (41 percent) and for 3D7 and K1 most of the isolates were monoclonal infections. In comparisons between the sites, we observed the highest prevalence of mixed infection in Mwanza (46.7 percent) followed by Dwangwa (23.3 percent) compared to Bolero (16.7 percent) and Mitundu (16.7 percent). The difference in prevalence of mixed infections between Mwanza and the other sites was statistically significant (p=0.041). There was also a non-significant trend towards a higher mean genotype number per isolate in the children aged >5 years compared to those below 5 years of age. These data suggest differences in prevalence rates of mixed infections in different geographical/epidemiological settings in Malawi. Further studies are needed to confirm, with larger sample sizes, the observation of a non-significant trend towards higher multiclonality of infection in older children in malaria endemic areas of Malawi.
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Lo, Yee-nga, and 盧懿雅. "Effect of t(11;14)(p13;q32) translocation on the expression of PDHX, the telomeric gene on chromosome 11p13, in mature B-cell malignancies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632505.
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Wright, C. M. "The prognostic significance of microsatellite instability in sporadic stage C colorectal cancer." Thesis, The University of Sydney, 2008. https://hdl.handle.net/2123/28955.
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Identification and understanding of the molecular events involved in colorectal
cancer (CRC) pathogenesis should lead to better comprehension of the disease
process, hopefully leading to better prognostic stratification, and as a result more
targeted treatment regimens and improved patient outcomes. A sub group of
sporadic CRC exhibit microsatellite instability (MSI). MSI is seen when the
fidelity of DNA replication is impaired. Cancers may be categorized as MSI-high
(MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS), according to the
degree of MSI exhibited.
This research project was designed to analyse the association between MSI—H and
MSI-L, clinicopathological features and survival in an unselected group of
patients with sporadic Australian Clinicopathological Stage (ACPS) C / American
Joint Committee on Cancer (AJCC) stage III CRC, i.e. patients with lymph node
metastases at the time of surgical resection of their cancer. The criteria used to
determine MSI, specifically the type and number of microsatellite markers used,
were also reviewed.
255 patients who underwent resection for sporadic ACPS stage C CRC were
studied; none of these patients received chemotherapy. Archival normal and
tumour DNA were extracted and amplified by polymerase chain reaction using a
radioactive-labelling technique and a panel of internationally recognised
microsatellite markers. MSI-H was defined as instability in 2 40% of 7 markers,
MSI-L as instability at > 0% but < 40% of 11 markers, and M88 as no instability.
Twenty one MSI-H and 33 MSI-L CRC were identified. Significant results
included that MSI-H tumours are more commonly right sided (p < 0.00001);
larger (p 5 0.0005); more likely to be high grade (p = 0.049); and, after adjustment
for age, sex and other pathology variables, associated with improved survival (p =
0.015). No difference was found between the biological characteristics of MSI-L
and MSS CRC. MSI-L CRC showed a trend towards poorer cancer-specific
survival than MSS CRC but this difference did not reach statistical significance.
Although dependent on the number and type of microsatellites used, similar trends
in the results were seen when different criteria were used to determine MSI.
This study has contributed to the rapidly expanding literature on CRC
carcinogenesis and, at the time completed, was one of the first to show an
association between MSI-H and improved survival in clinicopathological stage C
CRC patients who had not received chemotherapy. It supports the view that
identification of MSI status in patients with sporadic ACPS C / AJCC stage III
tumours may help stratify patients according to prognosis and should be
considered in therapeutic decision making and future trials of adjuvant therapy.
However to accurately determine the clinical usefulness of MSI more precise
standardisation of the definition and methodologies used to identify M81 is
required.
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Guo, Youling, and 郭友玲. "Genetic and genomic mapping of common diseases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50533861.
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Genome-wide mapping of susceptibility genes was conducted in two complex disorders of hypertension and epilepsy, allowing the dissection of the genetic architecture of these common diseases and related quantitative traits. The study performed comprehensive genetic analyses in a genome-wide scale, using different structure of data – sib-pairs and case-control samples.
To identify genes influencing hypertension and blood pressure, a combined linkage and association study was conducted using over half a million SNPs genotyped in 328 siblings. Regions of significant linkage were identified for blood pressure traits on chromosomes 2q22.3 and 5p13.2, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P < 7 10-5) for hypertension. One candidate gene, PDC, was replicated in the family-based association tests.
A two-stage genome-wide association study (GWAS) was performed in a total of 1,087 cases and 3,444 controls, to identify common susceptibility variants of epilepsy in Chinese. The combined analysis identified two association signals in CAMSAP1L1, rs2292096 [G] (P=1.0×10-8, OR =0.63) and rs6660197 [T] (P=9.9×10-7, OR=0.69), which are highly correlated, achieving genome-wide significance. One SNP (rs9390754, P = 1.7 × 10-5) in GRIK2 was refined as a previously-implicated association. In addition to SNPs, the assessment of CNVs in GWAS was performed, which could provide valuable clues to discover genes contributing to the heritability of epilepsy. A genome-wide scan for epilepsy through the use of DNA pooling also provides an alternative approach to reducing the substantial cost and thus increase efficiency in large-scale genetic association studies.
The genome-wide mapping studies in families and unrelated individuals are complementary and together offer a comprehensive catalog of common variations and structural variants implicated for both quantitative and qualitative traits.published_or_final_version
Psychiatry
Doctoral
Doctor of Philosophy
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Tai, Lai-shan, and 戴麗珊. "Molecular genetic characterizations of human non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31375315.
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李耀華 and Yiu-wah Lee. "Molecular genetic analysis of the polyol pathway in diabetic and galactosemic cataracts." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1995. http://hub.hku.hk/bib/B31234276.
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Edström, Elder Elisabeth. "Pheochromocytoma and abdominal paraganglioma : clinical and genetic aspects /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-116-0/.
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Välimäki, Stiina. "Growth of parathyroid glands : genetic and functional aspects /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-704-5.
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Alimov, Andrei. "Molecular genetic aspects of renal cell carcinoma development /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-559-X/.
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Masienė, Ramunė. "Genetic and physiological aspects of flax morphogenesis induction." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2014. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2013~D_20140123_134439-50527.
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Research objective. Investigation of consistent patterns of the induction of flax morphogenesis process, assessment of genetic and physiological aspects of this process and optimization methodologies. Proposition: 1. MOrphogenesis capacity of flax isolated explants depends on a genotype only, but on a composition of a medium and the cultivar type (fibre flax or linseed)also. 2. Cells of different organs of the same genotype have different morphogenic capacity. 3. Combining hormonal ratio with the affect on explats by exogenic factors enables targeted control of the morphogenesis process in vitro.Darbo tikslas - ištirti linų morfogenezės proceso indukcijos dėsningumus, įvertinti šio proceso genetinius ir fiziologinius aspektus bei optimizuoti regeneravimo metodikas. Ginamieji disertacijos teiginiai: 1. Linų izoliuotų eksplantų morfogeninė galia priklauso ne tik nuo genotipo, maitinamosios terpės sudėties, bet ir nuo veislės tipo (pluoštiniai ar sėmeniniai). 2.To paties genotipo skirtingų organų ląstelės turi skirtingą morfogeninę galią. 3.Derinant hormoninį balansą su eksplantų paveikimu egzogeniniais veiksniais galima kryptingai valdyti morfogenezės procesą in vitro.
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Standen, Graeme N. "Some aspects of genetic recombination in Drosophila melanogaster." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282210.
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Ratip, Siret. "Clinical, genetic and psychosocial aspects of the thalassaemias." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338876.
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Knight, A. I. "Genetic aspects of an alkane degrading Acinetobacter sp." Thesis, Cranfield University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376214.
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Stanescu, H. C. "Clinical, genetic and molecular aspects of membranous nephropathy." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318132/.
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Membranous Nephropathy (MN) is one of the leading causes of end-stage renal disease (ESRD). MN is an autoimmune disease in which autoantibodies target antigens at the level of the glomerular basement membrane. The nature of these antibodies and the reason why they develop are not fully understood. One of the strategies towards a better understanding of the disorder is genetic analysis, of which two approaches have been attempted: linkage mapping, based on a family suggestive for X-linked transmission of the MN trait; and whole genome association mapping, based on three case-control cohorts. The first cohort (335 cases and ethnically matched controls from the UK) was genotyped using SNP markers and analysed in an exploratory study which led to the identification of two highly significant loci of association. Two cohorts (146 biopsy proven MN cases and ethnically matched controls from the Dutch research group in Nijmegen and 75 biopsy proven cases and ethnically matched controls from the French research group in Paris) were used to successfully replicate the results. The two loci which we identified and independently confirmed are located on chromosome 2 and on chromosome 6. The chromosome 2 locus includes the PLA2R gene, confirming the hypothesis of Beck et al. which identified PLA2R as a key antigen in idiopathic MN by using an immunological approach [1]. The chromosome 6 locus lies within the extended Human Leukocyte Antigene (HLA) system locus, with the highest significance for association reached by alleles of HLA-DQA1. Our results suggest that the susceptibility to membranous nephropathy is associated to genetic variants at the level of both PLA2R1 and HLA loci. The causative variants could be some of the polymorphisms captured by the genotyping array which was analysed or, more likely variants (single nucleotide or copy number variant type) situated nearby (and therefore in linkage disequilibrium).
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Deshmukh, Harshal. "Genetic epidemiology studies of aspects of diabetic complications." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/bdbeee0f-7507-411f-914f-95a889afa6d0.
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Introduction Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), present in approximately 25%-40% of patients with long-standing diabetes and conferring additional risk of cardiovascular disease and mortality. Variations in the clinical presentations of DKD, heritability estimates from family-based studies and, more recently, the results from Genome-wide Association Studies (GWAS) demonstrate a heritable component of DKD. However, as is the case with the most of complex disorders, identifying causal genetic variants contributing to DKD has proven difficult. An important step in identifying variants associated with DKD in diabetes will involve integration of patient populations across multiple DKD cohorts, investigating rarer variants and by addressing the heterogeneity in DKD disease phenotypes in diabetes. Methods In this thesis, I reviewed the existing literature in genetic epidemiology in diabetic kidney disease. I then estimate chip-based heritability of DKD sub-phenotypes and replicated the association of known SNPS associated with renal function and upstream risk factors for diabetic kidney disease (BP, HbA1c) in patients with Type 2 Diabetes. I performed first GWAS for soluble receptor for advanced glycation products (sRAGE) a biomarker implicated in the pathogenesis of DKD. Finally, I performed GWAS for various DKD phenotypes on Type 1 Diabetes cohort (EURODIAB) and Type 2 Diabetes cohort (Go-DARTS) and helped with joint metaanalysis with DKD cohorts in SUMMIT consortium investigating genetic determinants of DKD. Results First, I showed that some DKD sub-phenotypes (like macro-albuminuria and ESRD) might be more heritable than others are and demonstrate that usefulness of estimation of chip-based heritability for complex trait by GCTA can be limited in the absence of large sample sizes. Second, I investigated the known genes for renal function (eGFR) and upstream risk factors for diabetic kidney disease (BP, HbA1c) in patients with Type 2 diabetes and showed that cumulative genetic risk for BP and HbA1c is associated with DKD. Third, I replicated the association of known loci associated with eGFR (UMOD GCKR and SHROOM3) in patients with Type 2 diabetes and showed that albuminuria affects the association of these variants with renal function. Fourth, I conducted a GWAS for sRAGE, an important biomarker associated with DKD, and identified novel variants in ITGA1 and HLA-DQA1 associated with circulating sRAGE levels. Finally, I performed GWAS for various DKD sub-phenotypes, and assisted in GWAS meta-analysis with SUMMIT consortium and identified potential novel genetic determinants for diabetic kidney diseases. Conclusion In conclusion this thesis has shown that a) estimation of chip based heritability of various DKD sub-phenotypes using GCTA has limited utility and requires GWAS studies with extremely large sample sizes b) the genetic determinants of renal function (eGFR) can interact with albuminuria in patients with T2D c) there are yet unidentified genetic markers associated with DKD and have identified potentially novel genetic markers associated with sRAGE (an important biomarker for DKD) and DKD itself which can be investigated in future studies for their reproducibility and functional consequences.
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Rask-Andersen, Mathias. "Obesity Genetics : Functional Aspects of Four Genetic Loci Associated with Obesity and Body Mass." Doctoral thesis, Uppsala universitet, Funktionell farmakologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-204449.
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Obesity is a complex disorder which has reached epidemic proportions in many parts of the world. Twin studies have demonstrated a high heritability for obesity. The subsequent appli-cation of genome wide association studies (GWAS) in the last decade have identified at least 32 genetic loci associated with body mass and obesity. Despite these great advances, these loci are almost exclusively completely naïve in a functional context. Genetic variations within the gene encoding the fat mass and obesity associated gene (FTO) are the strongest and most consistently observed genetic variants associated with obesity and body mass throughout various studied populations from all parts of the world. The identification of association of FTO with obesity has spurred immense interest in the function of the FTO protein and the functional consequences of its variants. However, the implications of genetic variants at other genetic loci on protein molecular function and body mass development remain undetermined. This thesis aims to examine more closely four of the genetic loci associated with obesity; in proximity of, or associated with: FTO, TMEM18, MAP2K5 and STK33, in two cohorts of children of European descent: a case-control of clinically obese children and normal weight controls from the Stockholm area; and a cross sectional cohort of Greek children. These smaller cohorts allow for studies of more specific effects of genetic variants as individuals in these cohorts can be more carefully studied. TMEM18 gene expression was also studied in the rat-brain where a positive correlation was observed between the body weight of the animal and TMEM18 expression. We also employed next generation sequencing to more carefully study obesity-associated genetic loci related to FTO and TMEM18. We utilized a novel strategy in this project to study genetic variation in the entire FTO- and TMEM18 genes, as well as in the GWAS-identified BMI-associated loci located downstream from TMEM18. This analysis was performed on a case-control cohort of Swedish children (n = ~1000). Through this analysis, we were able to observe genetic variants within intron 1 of the FTO gene to be the main genetic variants asso-ciated with obesity at this locus. We also observed, for the first time, obesity-associated genetic variants within the gene encoding TMEM18. To analyze the potential functional context of FTO we used an in silico approach, utilizing public information databases on mRNA co-expression and protein-protein interaction. Based on our findings, we speculate on a wider functional role of FTO in extracellular ligand-induced neuronal plasticity, possibly via interaction or modulation of the BDNF/NTRK2 signaling pathway.
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Hu, Xiaotong, and 胡曉彤. "Novel IGH translocations in gastric non-Hodgkin's B-cell lymphoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38688098.
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Tong, Tin-wing, and 唐天穎. "Investigation of transcript expression of PRKAR2A, DUSP1, STMN2 and MAPT genes in nasopharyngeal carcinoma, ovarian cancer and benignovarian tumor." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632700.
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Mohammed, Javid P. "Isolation of Tripsacum dactyloides genes using putative apomixis genes from Pennisetum ciliare." Virtual Press, 2008. http://liblink.bsu.edu/uhtbin/catkey/1409586.
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In the present study, DNA sequences associated with an apomixis gene inPennisetum ciliare were isolated from a distantly related grass species, Tripsacum dactyloides. Primers were developed for two bioinformatics-identified candidate genes (Pca2l and Pca24) for apomixis in Pennisetum ciliare. Homologous gene sequences were successfully isolated from both diploid (2n=36) and tetraploid (4n=72) Tripsacum using the primers and polymerase chain reaction (PCR) amplification. Bioinformatics analysis of the purified, cloned and sequenced PCR products revealed that the isolated homolog of the Pca2l gene varies significantly between the diploid and the tetraploid Tripsacum. Comparative genome analyses against Oryza, Zea, Arabidopsis, Pennisetum, Tripsacum and the National Center for Biotechnology Information (NCBI) nucleotide collection (nr) have shown that the PCR-generated sequences are reproductive specific. Analysis of the Trip2lT3c sequence was shown to be a Rab2 homolog with an e-value of 9e-23. Further proteomics analyses of the putative gene products have revealed that the Pca2l and the Tripsacum sequences may be partially conserved, with the Trip2lT3c sequence more highly conserved than the Trip21D3a.Department of Biology
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Brown, Gerald Francis. "Novel aspects of grass carp GHR gene regulation." Thesis, Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41897080.
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Cheung, Chin-ling, and 張展寧. "Genetic analysis of nasopharyngeal cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44659866.
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Tang, Sze-man, and 鄧詩敏. "Genetic dissection of Hirschsprung's disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B44037922.
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Cheng, Guo, and 程果. "Genetic study on biliary atresia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196442.
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Biliary atresia (BA) is a rare and severe cholestatic disease in neonates characterized by an idiopathic inflammatory process affecting both intra- and extra-hepatic bile ducts, causing cholestasis and ultimately leading to obliteration of the biliary tract. Through a previous genome-wide-association-study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 gene. But disease pathogenesis and genetic architecture of BA is still obscure.
We mapped the 10q24.2 association locus with 107 single nucleotide polymorphisms (SNPs) on 339 Han Chinese patients and 401 matched controls, follow-up studies of the association signals were performed. We revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [logistic regression p=5.32x10-11; odds ratio, OR:2.38; confidence interval, CI:(2.14-2.62)]. No deleterious rare variants (RVs) residing on the risk haplotype were found, dismissing the theory of “synthetic” association. Moreover, the BA-associated potential regulatory SNPs correlated ADD3 gene expression (linear regression p=0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the general population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus. Our finding suggested the complexity of BA genetic architecture and role of environmental effects in the disease.
We then revisited BA GWAS dataset and annotated the association signals with expression quantitative trail loci (eQTL) information available on normal adult livers. We did not see excessive enrichment of BA associated SNPs in liver eQTLs. We speculate that the liver eQTLs currently available relate to adulthood liver function and are not necessarily involved in liver development, adaptation to oxidative stress, or inflammation changes seen in BA pathophysiology.
To investigate whether rare alleles can predispose to BA, we called copy number variations (CNVs) from the GWAS Affymetrix gene chip 5.0. We obtained 86 BA private CNVs distributed among 131 BA patients were compared to the CNV profile of 11,943 database samples and 846 hypertension disease samples. Assuming that pathogenic CNVs interrupt dosage-sensitive genes, we prioritized the dosage-sensitive genes and the pathogenic CNVs by integrating multiple lines of evidence. Through gene set enrichment analysis we found that the ‘core’ genes affected by BA CNVs were members of the Calcium signaling pathway, which has been involved in the pathogenesis of polycystic liver and kidney diseases. Further we initiated the survey on rare coding variants in BA through Exome sequencing 23 BA liver genomes, while patients’ blood DNA and parental DNA would be examined in the validation stage to validate de novo mutations, including somatic mosaicism in liver. We found inherited deleterious mutations in polycystic liver and kidney disease genes in BA patients, and the role of these mutations in BA pathogenesis is being investigated.
Functional validation of the BA variants identified in this study is compulsory given the overall obscurity of BA pathogenesis. Together, this study presents a comprehensive catalog of both common and rare variants implicated in BA. We hope that our findings will contribute to enriching the BA-associated genetic network.published_or_final_version
Surgery
Doctoral
Doctor of Philosophy
43
Xue, Fan, and 薛凡. "Identification of SNP markers on 1p36 and analysis of the association of EPB41 with mandibular prognathism." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B45824514.
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Wong, Hoi-man Emily, and 黃凱敏. "Genome-wide association analyses on complex diseases: from single-nucleotide polymorphism to copy numbervariation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B50534099.
Full textAbstract:
Complex diseases, unlike Mendialian diseases, are often characterized by genetic heterogeneity and multifactorial inheritance, involving defects in genes from the same or multiple alternative pathways. Many congenital diseases and psychiatric disorders are complex diseases, and incur heavy health care burden on the society. With the advancement in high-throughput genotyping technologies and the availability of the human single nucleotide polymorphism (SNP) catalogue, genome-wide association study (GWAS) has been widely used to investigate the genetic component of complex diseases. Copy number variations (CNV) can also be identified using the data from the same SNP array.
Aiming to identify more disease susceptibility loci for complex diseases, separate GWAS using a case-control design were conducted on anorectal malformations (ARMs) and schizophrenia. ARMs are rare congenital diseases with heterogeneous phenotypes which could probably be explained by the genetic heterogeneity among patients, while schizophrenia is a common psychiatric disorder that is well known for its multigenic inheritance. The GWAS studies on ARM and schizophrenia included 4,369 (patients: N=363; controls: N=4,006) and 1,231 Han Chinese (patients: N=381; controls: N=850) respectively. The two studies were mainly focused on investigating the contribution of rare CNVs to the diseases, involving analyses on global CNV burden, rare CNV association, protein-protein interaction (PPI) network,
pathway and chromosomal aberrations. The associations of SNPs with ARMs were also examined. Apart from elucidating the genetic components in these two diseases, a systematic analysis on four CNV detection programs (CNV partition, PennCNV, QuantiSNP and iPattern) was also undertaken. In the study of schizophrenia, a new approach in CNV filtering which was based on latent class analysis was adopted to gather information from multiple CNV prediction programs.
The study of ARMs revealed 79 genes which were disrupted by CNVs in patients only. In particular, a de novo duplication of DKK4 (an antagonist of WNT signaling) was identified, and addition of Dkk4 protein was demonstrated to cause ARMs in mice. Another 10 genes uniquely disrupted in ARMs patients are also related to WNT signaling. Interestingly, this pathway was also significantly inferred by CNV in patients with schizophrenia. A different set of genes related to WNT signaling was disrupted in ARMs patients and patients with schizophrenia. WNT signaling is crucial for the development of multiple parts in the embryo. The contribution of different WNT signaling pathways at different development stages may vary. Apart from the WNT signaling pathway, other genes with biological relevance were also implicated in the two studies through gene-network and pathway analyses. The results from these two GWAS studies support our existing understanding of complex diseases that defects in various interacting genes could contribute to the same disease.
In summary, the CNV results from the two studies have demonstrated the genetic heterogeneity nature of these two complex diseases. The findings also uncovered a set of putative disease candidate genes, which can be used as reference materials for future genetic research for ARMs and schizophrenia.published_or_final_version
Psychiatry
Doctoral
Doctor of Philosophy
45
Cookson, William Osmond Charles Michael. "The genetics of atopy and atopic asthma." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670273.
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Meijer, Inge A. "Genetic analysis of the hereditary spastic paraplegias." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102811.
Full textAbstract:
The Hereditary Spastic Paraplegias (HSP) comprise a group of neurodegenerative diseases characterized by progressive lower limb spasticity. This disease, with a prevalence ranging from 1 to 20 in 100,000 individuals, is currently untreatable. The neuropathological hallmark is axonal degeneration of motor neurons in the corticospinal tract. However, the mechanisms of pathogenesis underlying this neurodegeneration remain poorly understood. Over the last decade, genetic studies of HSP have identified 33 loci including 14 genes. The main objective of this dissertation was to identify and characterize genes in a large North American HSP cohort. Mutation analysis of the two most common genes implicated in HSP, SPG3 and SPG4, led to the detection of nine novel mutations, including an ancestral SPG4 mutation in five French Canadian families. This screen also allowed for the molecular characterization of the p.del436N mutation in SPG3, which suggests a previously unidentified dominant-negative mechanism. Furthermore, a novel deletion in the VPS9 domain of the ALS2 gene was identified in a family with severe infantile onset HSP. In addition, linkage analysis and whole genome scan efforts resulted in the successful mapping of two novel HSP loci, SPG27 and SAX1. SAX1 represents the first locus for autosomal dominant spastic ataxia, a complicated form of HSP, with a common ancestor in Newfoundland. Finally, a positional candidate gene strategy at the SPG8 locus identified three missense mutations in a novel gene encoding strumpellin. Two mutations failed to rescue an axonal phenotype induced by morpholino knock-down of the SPG8 gene in zebrafish. Our efforts to identify and characterize HSP genes determined the underlying genetic cause in 36% of our cohort. These genetic causes include two novel loci and a novel gene. The findings are a major contribution to the characterization of the pathophysiology of HSP and significantly broaden the knowledge in the field of motor neuron disease. Analysis of the 15 known HSP genes suggests a common disease mechanism involving disrupted axonal membrane protein trafficking. Unraveling this mechanism will elucidate the functional maintenance of neurons in the corticospinal tract and will facilitate the development of therapies for HSP and related diseases.
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Charlier, Johan. "Monitoring gene level biodiversity - aspects and considerations in the context of conservation." Doctoral thesis, Stockholms universitet, Zoologiska institutionen, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-62796.
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The objectives of this thesis relate to questions needed to be addressed in the context of genetic monitoring for implementing the Convention on Biological Diversity for the gene level. Genetic monitoring is quantifying temporal changes in population genetic metrics. Specific goals of this thesis include i) synthesizing existing information relevant to genetic monitoring of Swedish species, ii) providing a genetic baseline for the Swedish moose, iii) evaluating the relative performance of nuclear versus organelle genetic markers for detecting population divergence, iv) actually monitoring the genetic composition, structure, level of variation, and effective population size (Ne) and assessing the relation between Ne and the actual number of individuals for an unexploited brown trout population. The concept of conservation genetic monitoring is defined and Swedish priority species for such monitoring are identified; they include highly exploited organisms such as moose, salmonid fishes, Norway spruce, Atlantic cod, and Atlantic herring. Results indicate that the Swedish moose might be more genetically divergent than previously anticipated and appears to be divided into at least three different subpopulations, representing a southern, a central, and a northern population. The relative efficiency of nuclear and organelle markers depends on the relationship between the degree of genetic differentiation at the two types of markers. In turn, this relates to how far the divergence process has progressed. For the monitored brown trout population no indication of systematic change of population structure or allele frequencies was observed over 30 years. Significant genetic drift was found, though, translating into an overall Ne-estimate of ~75. The actual number of adult fish (NC) was assessed as ~600, corresponding to an Ne/NC ratio of 0.13. In spite of the relatively small effective population size monitoring did not reveal loss of genetic variation.
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譚麗華 and Lai-wa Tam. "Genetics and development of the oral apparatus in 'paramecium tetraurelia'." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1985. http://hub.hku.hk/bib/B31207431.
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周妙芬 and Miu-fun Chau. "The role of the micronucleus in the development of the oral apparatus of paramecium." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1987. http://hub.hku.hk/bib/B31208101.
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Lai, Yau-lin Caroline, and 黎幼蓮. "Genotyping of gestational trophoblastic disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hdl.handle.net/10722/209581.
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