Introdução. A etiologia da leucemia linfocítica aguda (LLA), câncer mais comum na infância, não é completamente conhecida. Objetivo. Examinar a associação de infecções na infância e características maternas com a LLA em crianças residentes no Estado de São Paulo. Métodos. Estudo caso-controle com 241 casos recrutados em oito hospitais do Estado de São Paulo e diagnosticados com LLA de janeiro de 2003 a fevereiro de 2009. Os 598 controles foram selecionados na base de Declarações de Nascidos Vivos da Fundação Sistema Estadual de Análise de Dados. Entrevistas com a mãe ou responsável pela criança foram realizadas no hospital para os casos e no domicílio para os controles utilizando-se questionário semelhante. A análise dos dados foi conduzida com três grupos distintos: Grupo 1 - todos os subtipos de LLA, entrevistas com as mães ou outros responsáveis pelas crianças; Grupo 2 - todos os subtipos de LLA, entrevistas com as mães; Grupo 3 - LLA de precursores B, entrevistas com as mães. Para estimar o risco de LLA associado com as variáveis relacionadas a infecções e características maternas odds ratios (OR) e intervalos com 95 por cento de confiança (IC 95 por cento ) foram calculados por meio de análise de regressão logística multivariada não condicional. Três modelos de regressão logística foram conduzidos: a) com ajuste por sexo e idade da criança; b) com ajuste por sexo, idade da criança e escolaridade materna; c) com ajuste por todas potenciais variáveis de confusão via stepwise forward selection. Resultados. Os resultados correspondentes ao Grupo 3 e Modelo 3 de análise revelaram proteção para LLA em crianças com histórico de episódios de gripe (categoria frequentemente versus não OR = 0,27; IC 95 por cento 0,15-0,48), episódios de dor no ouvido (categoria raramente versus não OR = 0,48; IC 95 por cento 0,25-0,90), frequência à creche (categoria mais de 24 meses versus nunca OR = 0,37; IC 95 por cento 0,17-0,77), e contato com cães no primeiro ano de vida (categoria sim versus não OR = 0,76; IC 95 por cento 0,45-1,27). Foi observado tênue aumento do risco de LLA em crianças com mães que referiram consumo de álcool no passado (OR = 1,29; IC 95 por cento 0,62-2,68) e ainda bebe (OR = 1,53; IC 95 por cento 0,97-2,41) em comparação àquelas cujas mães referiram nunca ter consumido álcool. Baixo nível educacional das mães foi associado com aumento do risco de LLA em crianças (categoria 0 a 4 anos versus 12 e mais OR = 2,71; IC 95 por cento 1,26-5,81). Conclusões. Os resultados mostraram que exposição a infecções na infância, frequência à creche e contato com cães no primeiro ano de vida exercem papel protetor para LLA, por outro lado, o consumo de álcool e o baixo nível educacional das mães aumentaram o risco de LLA em crianças / Introduction. The etiology of acute lymphoblastic leukemia (ALL), the most common cancer in childhood, is not completely known. Objective. To examine the association of childhood infections and mother characteristics with ALL in children living in São Paulo. Methods. Case-control study with 241 cases recruited in eight hospitals in the state of São Paulo and diagnosed with ALL from January 2003 to February 2009. The 598 controls were selected from the São Paulo Birth Registry. Interviews with the mother or guardian were conducted in the hospital for cases and at home for controls through a similar questionnaire. Data analysis was performed in three distinct groups: Group 1 - all subtypes of ALL, interviews conducted with the mother or other childs guardian; Group 2 - all subtypes of ALL, interviews conducted with the mother; Group 3 - precursor B ALL, interviews conducted with the mother. In order to estimate the risk of ALL associated with variables related to infections and mother characteristics odds ratios (OR) and 95 per cent confidence interval (95 per cent CI) were calculated by unconditional multivariate logistic regression. Three logistic regression models were conducted: a) with adjustment for sex and age of child; b) with adjustment for sex, age of child and maternal education; c) adjusted for all potential confounders through stepwise forward selection. Results. The results corresponding to Group 3 and Model 3 revealed protection for ALL in children with episodes of influenza (category often versus no OR = 0.27; 95 per cent CI 0.15-0.48), episodes of earache (category rarely versus no OR = 0.48; 95 per cent CI 0.25-0.90), daycare attendance (category over 24 months versus never OR = 0.37; 95 per cent CI 0.17-0.77), and contact with dogs in the first year of life (category yes versus no OR = 0.76; 95 per cent CI 0,45-1.27). Slight increase was observed in the risk of ALL in children with mothers who reported alcohol consumption in the past (OR = 1.29; 95 per cent CI 0.62-2.68) and still drink (OR = 1.53; 95 per cent CI 0.97-2.41) compared to those whose mothers reported never having consumed alcohol. Low educational level of the mothers was associated with increased risk of ALL in children (category 0-4 years versus 12 and over OR = 2.71; 95 per cent CI 1.26-5.81). Conclusions. The results provided evidences that exposure to infections in the childhood, daycare attendance and contact with dogs in the first year of life have a protective role in ALL, on the other hand, alcohol consumption and low education level of mothers increase the risk of ALL in children

Introdução. Considerando-se a incidência e os reflexos na qualidade de vida, os tumores de cabeça e pescoço constituem-se em relevante problema de saúde pública. A medida de efeito dos principais fatores de risco, tabaco e álcool, no risco de acometimento de cânceres de cabeça e pescoço tem sido pouco relatada no Brasil. Objetivo. Verificar as variações de risco decorrentes do tabagismo e do consumo de bebidas alcoólicas no câncer de cabeça e pescoço nas regiões Sudeste, Sul e Centrooeste do Brasil. Sujeitos e Métodos. Estudo caso-controle de base hospitalar conduzido entre setembro de 1998 e maio de 2003, com base em 1.594 casos diagnosticados com carcinoma espinocelular de cabeça e pescoço, confirmados histologicamente, em hospitais das cidades de São Paulo e Rio de Janeiro (Sudeste), Porto Alegre e Pelotas (Sul), Goiânia (Centro-oeste), e 1.292 controles. Os pacientes foram entrevistados por meio de questionários com informações sobre características e hábitos, bem como dados clínicos e laboratoriais para o diagnóstico de câncer de cabeça e pescoço. A OR (odds ratio) e IC 95 por cento (intervalo com 95 por cento de confiança) para câncer de cabeça e pescoço associados ao tabaco e álcool foram estimados por regressão logística não condicional. O modelo foi ajustado por idade, sexo, escolaridade, consumo de frutas e legumes. Resultados. Na região Centro-oeste observaram-se riscos mais expressivos para tabagismo, ex-fumantes (OR 3,5; IC95 por cento 1,6-7,4) e fumantes (OR 13,6 IC95 por cento 6,4-28,6), com efeito dose-resposta para frequência e tempo de consumo na exposição cumulativa, de 1-9 maços-ano (OR 1,9; IC 95 por cento 0,8-4,4) à 40 maços-ano e mais (OR 8,6; IC95 por cento 4,2-17,5). No consumo de bebidas alcoólicas, observou-se riscos mais elevados para consumidores atuais na região Sul (OR 4,7 IC95 por cento 2,8-7,9); na exposição cumulativa o efeito dose-resposta para frequência de consumo foi nítido a partir da categoria 0-4,99g/ml/dia nas regiões Sudeste, Sul e Centro-oeste. Conclusões. As diferenças que puderam ser observadas no risco para tumores de cabeça e pescoço decorrentes do tabagismo e consumo de bebidas alcoólicas, sugerem diferenças no perfil de consumo nas regiões Sudeste, Sul e Centro-oeste, provavelmente, relacionados ao uso de tipos de preparo do tabaco e consumo de diferentes tipos de bebidas alcoólicas / Introduction. Considering the incidence and reflections on the quality of life, the head and neck tumors constitute an important public health problem. The extent of effect of the main risk factors, tobacco and alcohol, in risk of involvement of head and neck cancers has been rarely reported in Brazil. Objectives. Check the variations the risks caused by smoking and alcohol consumption in head and neck cancer in the Southeast, South and Midwest regions of Brazil. Subjects and Methods. A case-control hospitalbased, conducted between September 1998 and May 2003, based on 1.594 cases diagnosed with squamous cell carcinoma of the head and neck, histologically confirmed, in hospitals in the cities of São Paulo and Rio de Janeiro (Southeast), Porto Alegre and Pelotas (South), Goiania (Midwest), and 1.292 controls. Patients were interviewed using questionnaires with information about characteristics and habits, as well as clinical and laboratory data for the diagnosis of head and neck cancer. The odds ratio (OR) and IC95 per cent (confidence interval 95 per cent ) of head and neck cancer associated with tobacco and alcohol were estimated by unconditional logistic regression. The model was adjusted for age, sex, education, consumption of fruit and vegetables. Results. In the Midwest region we observed more significant risks for smoking, former smokers (OR 3,5; IC95 per cent 1,67,4) and smoking (OR 13,6; IC95 per cent 6,4-28,6), with doseresponse effect for frequency and time consumption in the cumulative exposure, from 1-9 pack-years (OR 1.9, IC95 per cent 0,84,4) to 40 pack-years and more (OR 8,6; IC95 per cent 4,2 17,5). In alcohol consumption was observed increased risks for current consumers in the South (OR 4,7; IC95 per cent 2,8 7,9); in the cumulative exposure dose-response effect for frequency of consumption was clear from the category 0-4,99 g/ml/day in the Southeast, South and Midwest regions. Conclusions. The differences in risk were observed for cancers of the head and neck caused by smoking and alcohol consumption suggest differences in the consumption profile in Southeast, South and Midwest regions, probably related to the use of types of tobacco and consumption of different types of alcoholic beverages

Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.

This dissertation consists of three projects in matched case-control studies. In the first project, we employ a general bias preventive approach developed by Firth (1993) to handle the bias of an estimator of the log-odds ratio parameter in conditional logistic regression by solving a modified score equation. The resultant estimator not only reduces bias but also can prevent producing infinite value. Furthermore, we propose a method to calculate the standard error of the resultant estimator. A closed form expression for the estimator of the log-odds ratio parameter is derived in the case of a dichotomous exposure variable. Finite sample properties of the estimator are investigated via a simulation study. Finally, we apply the method to analyze a matched case-control data from a low-birth-weight study. In the second project of this dissertation, we propose a score typed test for checking adequacy of a functional form of a covariate of interest in matched case-control studies by using penalized regression splines to approximate an unknown function. The asymptotic distribution of the test statistics under the null model is a linear combination of several chi-square random variables. We also derive the asymptotic distribution of the test statistic when the alternative model holds. Through a simulation study we assess and compare the finite sample properties of the proposed test with that of Arbogast and Lin (2004). To illustrate the usefulness of the method, we apply the proposed test to a matched case-control data constructed from the breast cancer data of the SEER study. Usually a logistic model is needed to associate the risk of the disease with the covariates of interests. However, this logistic model may not be appropriate in some instances. In the last project , we adopt idea to matched case-control studies and derive an information matrix based test for testing overall model adequacy and investigate the properties against the cumulative residual based test in Arbogast and Lin (2004) via a simulation study. The proposed method is less time consuming and has comparative power for small parameters. It is suitable to explore the overall model fitting.

Antro tipo cukrinis diabetas yra viena iš aktualiausių dabartinės medicinos problemų, kurios etiopatogenetinis pagrindas ypač glaudžiai siejasi su visuomenės papročiais ir gyvenimo būdu (WHO, 2006). Su gyvenimo būdu susietų rizikos veiksnių plėtra XX amžiuje įgavo epideminio pobūdžio metabolinių sutrikimų išraišką tarp atskirų, bet sąlyginai identiškai gyvenančių, individų grupių (King H. et al., 1998; Wild S. et al., 2004). Nepalankių socialinių ir ekonominių veiksnių įtaka ypač skatina metabolinių sutrikimų, kurie pasireiškia kaip metabolinis sindromas ir 2 tipo cukrinis diabetas, gausėjimą. Pasirinkus hipotezę, kad šiuolaikinės civilizacijos įpirštas gyvenimo būdas yra palankus 2 tipo cukrinio diabeto manifestavimui, prognozuojama, kad 2030 metais šia liga sirgs apie 366 milijonai planetos gyventojų (Wild S. et al., 2004). Metabolinių sutrikimų visuma įvardinta kaip „cukrinis diabetas” tampa vis dažnesne regėjimo sutrikimų, aklumo, kojų amputacijų, inkstų funkcijos nepakankamumo, blogos gyvenimo kokybės, prarasto darbingumo bei ankstyvesnio mirtingumo priežastimi. Tai – liga, esanti penktoje vietoje pagal mirtingumą po užkrečiamų, širdies ir kraujagyslių ligų, vėžio ir nelaimingų atsitikimų (Roglic G. et al., 2005). Lietuvoje cukrinio diabeto problema tampa vis aktualesnė, didėja sergančiųjų šia liga skaičius. Jei 1966 m. šalyje tebuvo suskaičiuotas 3561 sergantysis cukriniu diabetu (Sideraite Š., 1998), tai 1997 m. sausio 1 d. jau buvo užregistruoti 26896 sergantieji šia... [toliau žr. visą tekstą] / Diabetes mellitus is one of the main health issues in Lithuania. Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, resulting from defects in insulin secretion, insulin action or both. The disease is associated with significant increased risk of long–term microvascular and macrovascular complications. The number of cases of diabetes worldwide in 2000 among adults 20 years of age is estimated to be 171 million. Diabetes is becoming a world pandemic with an estimated increase till 366 million cases by 2030, especially in developing countries. The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity . The aim of our study to assess clinical, laboratory data, risk factors and quality of life of new type 2 diabetes mellitus cases. A case–control study included 234 cases with newly confirmed diagnose of type 2 diabetes mellitus in 2001 and 468 controls who were free of the disease. Cases and controls were matched by gender and age (+5 yr.). Ratio of case and controls was 1:2. Two questionnaires were used in this study (1st one – to collect information on possible risk factors of type 2 diabetes mellitus, the 2nd one – EQ–5D questionnaire – to measure quality of life for patients with newly diagnosed type 2 diabetes mellitus). Variables were retained in models as confounders when inclusion changed the value of the odds ratio (OR) by more than 10% in any exposure category. The... [to full text]

<p>Härtill 5 uppsatser</p> / digitalisering@umu

DM is a serious and complex public health problem in the U.S. The CDC (2013) estimated that 25.8 million people, or 8.3% of the U.S. population, were suffering from DM in 2011. DM can significantly affect patient’s quality of life. Additionally, DM places a significant economic burden on the U.S. healthcare system. Over the past two decades, DMPs have emerged as a promising intervention to improve health outcomes for patients suffering from chronic conditions, such as DM, and to bend the cost curve. DMP’s aim is to improve communication and follow-up so that patients can better manage their chronic condition(s) to avoid costly hospital stays and emergency room visits (Fireman, Bartlett, & Selby, 2004). The Georgia region of Kaiser Permanente (KPGA) is a fully integrated health system that serves 260,000 members at 28 medical offices along with two specialty offices in the metropolitan Atlanta area. The Center for Care Partnership, the population care division of KPGA, administers a chronic disease management program (DMP), Healthy Solutions (HS). HS exists to improve and maintain the health of chronically ill KPGA members, including patients diagnosed with diabetes mellitus (DM), by providing health coaches via telephone who counsel members on their specific chronic disease and aid members in starting or maintaining a physician approved self-care management plan. In order to determine the impact HS has on KPGA members with DM, an evaluation plan was created to evaluate the impact HS has on members’ glycated hemoglobin (A1C), blood pressure, and emergency department (ED) utilization. This capstone thoroughly details the proposed evaluation plan created for HS by using Robert Milstein and Scott Wetterhall’s six-step framework for program evaluation. Additionally, further evaluation questions are suggested and discussed in order to provide a more complete picture of program performance to stakeholders.

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study’s results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study’s results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

Background: Parkinson’s disease (PD) is a complex disease with a multi-factorial aetiology, comprising both genetic and environmental risk factors. The disease pathology is progressive and neurodegenerative where dopaminergic nerve cell death occurs predominantly in the substantia nigra pars compacta (SNpc) with the subsequent loss of the dopamine neurotransmitter in the basal ganglia. The most significant risk factors for PD include an advancing age and a family history of the disease, while environmental and lifestyle risk factors such as pesticide exposure and smoking are widely accepted as risk altering exposures. Currently up to 10% of PD is attributed to Mendelian inherited PD at one of 13 PARK loci in 9 genes. The pursuit of common susceptibility alleles for idiopathic PD has proven challenging with only a few loci reproducibility associated with an altered risk. The aim of this thesis is to study, using a candidate gene case-control design, the potential role of genetic variants in PD. The APOE candidate gene was hypothesized to modify the risk of PD as it is a proven modifier of Alzheimer’s disease (AD). The common pathological finding in PD of elevated levels of iron within the SNpc is proposed to increase the oxidative state of the nerve cells and predispose the dopaminergic neurons to apoptosis. Therefore, susceptibility alleles within the candidate genes that regulate iron metabolism and homeostasis are hypothesized to alter iron metabolism and predispose to iron-induced neurodegeneration in PD. Missense variants and common “tagging” SNPs with the HFE, Transferrin and Transferrin Receptor genes are investigated extensively in this thesis. Finally, autosomal recessively inherited PD can result from mutations in the parkin gene at the PARK2 locus. The final hypothesis explored in this thesis suggests that non-deleterious missense variants in the parkin gene modify the risk for developing sporadic PD. Further genetic variation in the parkin gene such as exon rearrangements is a frequently reported mutation where heterozygosity for these rearrangements may increase the risk of PD. Heterozygous deletions or duplications of exons in the parkin gene provide technical challenges for their detection. In this thesis a novel assay for the detection of these mutations is investigated. Methods: Genotyping was performed using PCR-RFLP for genetic variants in the APOE (E2 and E4 alleles), HFE (C282Y, H63D and S65C), Transferrin receptor (TfR; S142G), Transferrin (Tfn; P570S and G258S), IREB2 genes (L159V) and the parkin gene (S167N, R366W and V380L) in a cohort of 425 PD cases and 387 controls recruited from throughout Queensland, Australia. A tagged SNP high-throughput genotyping approach was then employed to try to replicate single SNP associations in 6 iron-related genes using a cohort of 1034 PD cases and 774 controls. These genetic variants were analysed for direct association with PD risk, age of onset effects as well as potential gene x gene (GxG) and gene x environment (GxE) interactions. Additionally, a quantitative PCR assay was developed to detect heterozygous deletions and duplications within the parkin gene and utilised to screen 43 YOPD cases for these mutations. Results: The initial study of the HFE C282Y variant revealed a significant protective association with PD in the two independent cohorts studied. Further study did not reveal significant associations with PD for the other HFE variants or missense variants within the Tfn and TfR genes. When analysed for GxE interactions, the C282Y, P589S and G277S variants showed evidence for an increased risk of PD in synergy with pesticide and herbicide exposure. Carriers of the risk variant and with toxin exposure were at two-fold increased risk of PD, although the number of individuals in this category was small. A further investigation of the role of common genetic polymorphisms in iron genes revealed only one of the 20 SNPs genotyped using high-throughput multiplex methods, remained significantly associated with PD after correction for age and sex. The rs198855 SNP is downstream of the HFE gene and further implicates a role for HFE in PD. The APOE E4 allele demonstrated modifying effects for the age of PD onset, restricted to the female cases. Analysis of the parkin missense variants also demonstrated a modifying effect on the age of PD onset in carriers of the S167N variant, with putative interactions between the APOE E4 allele, a family history of PD and toxin exposure that further reduced the age of onset. Twenty individuals of the 43 YOPD cases screened demonstrated heterozygous parkin exon rearrangements using the novel qPCR method. Conclusions: Non-synonymous variants within iron-related genes or the parkin gene putatively interact with herbicide and pesticide exposure to increase the risk of PD or modify the phenotype, highlighting the need for future studies to address the multi-factorial aetiology of PD in their study design and analysis. This thesis provides evidence for the association between genetic variation within the HFE locus and PD and for the APOE E4 allele as a modifier of PD.