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Background and Objectives: Pharmacogenetics has the potential to maximize drug efficacy and minimize adverse effects of cardiovascular disease (CVD) but its translation into clinical practice been slow. However, recent advancements in genotyping and statistical methodologies have now provided robust evidence in the support of personalized medicine. This thesis addresses how the advancements in pharmacogenetics may help to gain novel insights into existing drug targets, inform and guide clinical decision-making and validate potential disease target pathways. Methods: This was achieved by exploring whether the COX-2 genetic variant (rs20417) is associated with a decreased risk of CVD outcomes, assessing whether bile acid sequestrants (BAS) are associated with a reduced the risk of coronary artery disease (CAD) using the principles of Mendelian Randomization and investigating whether genetic variants associated with dysglycaemia are associated with an increased risk of CAD. Results: We demonstrated that COX-2 carrier status was associated with a decreased risk of major cardiovascular outcomes. Furthermore, we also showed that BAS appear to be associated with a reduced risk of CAD and genetic variants associated with HbA1c and diabetes were associated with an increased risk of CAD. Conclusions: The convergence of technological and statistical advancements in pharmacogenetics have led to a more high-quality and cost-effective means of assessing the effect of CVD therapeutic agents. / Thesis / Doctor of Philosophy (PhD)

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The present thesis covers two aspects of statistical analysis applied to the genetics of human diseases. First, the significance of LOD-score results for the confirmation of linkage is addressed, with special emphasis on small pedigrees. A new analytical approach is presented for the linkage analysis of heterogenetic traits, using hereditary spastic paraplegia as a model, a disease well suited for the analyses. The critical significance values for confirmation of linkage are evaluated using Bayesian statistics, and empirical P-values for LOD score results are calculated using computer simulation methods. The presented analytical approach resulted in conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity. / The second part addresses linkage-disequilibrium based fine mapping in the French Canadian population. The performance of five linkage-disequilibrium based fine-mapping methods is evaluated using French Canadian chromosomes with one of three diseases found in this population: oculopharyngeal muscular dystrophy (OPMD), hidrotic ectodermal dysplasia (HED), and sensorimotor polyneuropathy with or without agenesis of the corpus callosum (ACCPN). The gene for OPMD was recently mapped and cloned, allowing us to evaluate the performance of the methods with the OPMD results, and to make predictions about the ACCPN and HED putative gene positions. In addition, a new approach to linkage-disequilibrium based fine mapping is presented using FrenchCanadian ascending genealogies. The method involves two steps. First, the likely founding couple of a mutation-bearing chromosome is identified using a computerised randomisation statistic. Then, using a delete-d jackknife resampling scheme, the distribution of gene mapping estimates is calculated from the count of ancestral recombinants and ancestral meioses joining the identified founding couple to the disease gene carriers. Gene mapping estimates are calculated from each marker individually, and confidence intervals of the estimates are derived from the jackknife distributions. The method, when applied to French Canadian families with OPMD, successfully confirmed the localisation of PABP2 responsible for OPMD and performed better than other linkage disequilibrium-based mapping models.

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Atopic asthma is a complex disease process that has a significant social, personal and economic burden across all ages. Leukotriene-receptors are involved in the cascade of inflammation that may result in symptoms of atopy and asthma. Two leukotriene receptors have been identified in the lung. The cysteinyl leukotriene receptor 1 and cysteinyl leukotriene receptor 2 genes (i.e., CYSLTR1 and CYSLTR2) have been sequenced, and a number of single nucleotide polymorphisms (SNPs) within these genes have been identified.The purpose of this study was to: (1) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, atopy, elevated IgE level, and eosinophilia, (2) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, asthma, and atopic asthma, and (3) Determine the degree of interaction between CYSLTR2 genetic variation and gender in atopic asthma.Nested within two sub-studies of the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) study, a prospective longitudinal cohort, 853 individuals were entered into this study. Study criteria included Non-Hispanic white adults, who consented to genetic testing in the two sub-studies. Tagging SNPs of the CYSLTR1 and CYSLTR2 genes were genotyped. Serum IgE status and eosinophilia were obtained from existing dataset. Questionnaires collected in the parent study were used to obtain demographic and clinical data.SNP rs321006 in the CYSLTR1 gene was associated with atopy among Non-Hispanic white women. Assuming a recessive model, among female Non-Hispanic white adults, the odds of having rs321073 CC genotype was 5.82 times higher among those with atopic asthma than those without atopic asthma. No gene by gender interaction was found between SNP of interest in CYSLTR2 and atopic asthma. Genetic association of SNPs rs321006 with atopy and rs321073 with atopic asthma are novel findings to date.Implications for nurses, clinicians, and scientists include better understanding of associations of these genetic variations with asthma, atopy, and atopic asthma that can generate further inquiry into other mechanisms of atopic asthma. These novel genetic associations with atopy and atopic asthma may have the potential for personalized medicine that might afford patients with appropriate treatment based on their genotype.

Aim The aim of this study was to investigate the most commonly used approaches to measure individual genome-wide heterozygosity (IGWH) and to investigate whether IGWH can be considered as a health risk factor or a protective factor in humans. Methods This study was based on two samples from isolated communities of Croatian Adriatic islands, with a total of 1,930 adult examinees from Islands of Vis (N=986) and Korcula (N=944). Examinees were genotyped with a total of 302,662 single nucleotide polymorphisms. Heterozygosity was estimated using five commonly calculated methods. Results Correlation coefficients between different heterozygosity methods were generally in the range of 0.7-0.8. A worsening in some phenotypic traits, including cholesterol and triglycerides as well as increased odds for osteoporosis and metabolic syndrome was recorded in cases of IGWH reduction. Nevertheless, in these cases heterozygosity explained a relatively low amount of variance, generally in range of 0.4-0.6% of total trait variance. Conclusion However, these results were significant in Vis Island sample, while in the replication sample, Korcula Island, most of the associations were not significant, possibly due to the overall lower amount of inbreeding and higher heterozygosity in Korcula Island sample. The results warrant further research in order to provide more information on the extent and importance of individual genome-wide heterozygosity, which might have an important role in communities which experience consanguinity on a greater scale. Two main shortcomings of the study include possible lack of power to detect inbreeding depression and the need to replicate the results in other populations.

Introduction: There is evidence to suggest that common genetic polymorphisms can modify the effect of environmental risk factors on colorectal neoplasia. Methods: Data on 1430 individuals were obtained from two chemoprevention trials, the Wheat Bran Fiber Trial (WBF) (1) and the Effects of Ursodeoxycholic Acid on Adenomatous Polyp Recurrence Trial (URSO) (2). Data were analyzed to test for gene-environment interactions between allelic variation in PPAR-γ (Pro12Ala, C1431T), body mass index (BMI) and waist circumference, and the biochemical biomarkers of metabolic syndrome. Simulated data were then used to determine if the sample size required to formally test the relationship between gene-exposure interactions could be reduced by using a genetically enriched study population. For this simulation aspect of the work, an established gene-drug interaction (i.e.: flavin monooxygenase 3 (FMO3) and sulindac) was used as a model system. Results: There was a borderline significant interaction between BMI and PPAR-γ for the Pro12Ala genotype (p(inter)=0.11) and significant interactions between BMI and the C1431T genotype (p(inter)=0.09). Results from the recursive partition model identified BMI (p = 0.007) and baseline fasting glucose levels (p =0.033) as significant predictors of colorectal adenoma recurrence for carriers of Ala12 and waist circumference as a significant predictor for the Pro12Pro12 carriers (p=0.002). Results from the simulated studies indicated that using genetically pre-screened and enriched populations can result in a 50% savings in the number of subjects required to test the candidate gene-drug interaction. Conclusions: These findings provide evidence that the effect of allelic variation in PPAR-γ on colorectal adenoma recurrence is modified by BMI and that component traits of metabolic syndrome differentially affect the risk of colorectal adenoma recurrence depending on genotype. In addition, using genotype as an inclusion criterion in future studies of adenoma recurrence will result in a smaller sample size required to test gene-environment interactions.

Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.

Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.