Cardiovascular disease (CVD) is an inclusive term encompassing several disorders of the circulatory system that together account for the majority of global non-communicable disease (NCD) mortality. Major thrombotic events, due in part to impaired fibrinolysis, are a unifying characteristic of several CVDs. Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of fibrinolysis, and PAI-1 levels associate with CVD susceptibility and severity in several populations. The main objectives of this dissertation were to evaluate the genetic impact of common single nucleotide polymorphisms (SNPs) on inter-individual variation in PAI-1 levels in a Ghanaian population, and present a novel method to identify candidate genes for prioritization in future studies. We discovered novel associations between single variants in the arylsulfatase b (ARSB), carboxypeptidase A2 (CPA2), and leukocyte receptor cluster member 9 (LENG9) and median PAI-1 levels. Quantile regression analyses directed at the upper quartile of the PAI-1 distribution was performed to uncover novel variants with significant impact on this clinically relevant portion of the PAI-1 distribution. Upper quartile regression analyses revealed significant associations between single variants in period circadian clock 3 (PER3), a discovery that supports previous evidence of the involvement of the circadian pathway in regulation of PAI-1 levels in Caucasian populations as well as model organisms. This finding suggests that the significance of the circadian pathway as a whole may be generalizable across populations, even though gene effects may be population specific. We present a novel approach; Multi-lOcus based selection of Candidate genes (MOCA), which incorporates multi-variant association signals into the prioritization of genes for further evaluation. MOCA identified four significantly associated loci; these loci included 28 novel candidate genes for PAI-1 levels. Each MOCA identified locus was located within previously identified CVD and/or PAI-1 related quantitative trait loci (QTL).

Personalized medicine, the individualization of clinical care based, in part, upon an individuals genetic background, can be thought of as a three step process: scientific discovery, validation, and clinical implementation. Women and individuals of diverse ethnic/racial backgrounds are at risk of widening health disparities unless additional emphasis is placed upon these subjects for future research. Genetic association studies were used to identify genetic variants that contribute to the timing of the reproductive lifespan in women, endometrial cancer, and elevated serum thyroid stimulating hormone levels. A rapid evidence review was performed to validate previously reported variants associated with hypothyroidism and consider the analytic evidence that genetic testing of asymptomatic adult women leads to improved health outcomes. The ethical, legal, and social impacts of personalized medicine implementation were evaluated from the perspectives of both the health care system and the general public.

This study developed a food preference survey to estimate adolescents willingness to consume energy-dense foods and sugar-sweetened beverages. Five focus group interviews with 13 to 19 year-old students were conducted, and items representing energy-dense foods, energy-dilute foods, sweetened beverages, and unsweetened beverages were determined (5 per category). The final survey was administered to 234 students. Willingness to consume items was assessed using a 7-point Likert Scale (1, representing Extremely Unwilling to 7, indicating Extremely Willing). Exploratory Factor Analysis using Principal Axis factoring with a Promax (oblique) rotation revealed two factors. Factor one included French fries, Kool-Aid, glazed donuts, cookies, lemonade, and pizza (23.9% of the variance). Factor 2 included nuts or peanut butter, low-fat or fat-free yogurt, grapes, and bananas (13.8% of the variance). Cronbachs alpha was 0.770 for factor 1 and 0.664 for factor 2.

Alzheimers Disease is an irreversible, degenerative disease of the brain that accounts for a majority of dementia cases each year, in both the general population and in patients with Down Syndrome. The advancement of in vivo imaging modalities that detect the neuropathologies associated with both Down Syndrome and Alzheimers Disease present new opportunities to explore these diseases in living human subjects. Imaging biomarkers not only permit earlier, more accurate patient diagnosis, but quantitative, neuropathology-based traits derived from imaging modalities offer increased power to detect associations with large-scale genetic data. This field of investigation has been termed imaging genetics. Imaging genetics studies aim to identify novel risk genes and elucidate gene function and novel mechanisms of disease pathology and etiology. In this dissertation, I have conducted imaging genetics studies of the neuropathologies of Alzheimers Disease and Down Syndrome in order to increase our understanding of the genetic etiology underlying these pathologies. Furthermore, new biomarkers of these pathologies are still needed. Thus, a magnetic resonance imaging sequence which has been shown to detect amyloid beta plaque in mice is explored in human studies in this dissertation. This work contributes novel findings to the body of research aimed at early identification of patients at risk of Alzheimers Disease.

Typescript. / Thesis (Ph. D.)--University of Hawaii, 1969. / Bibliography [142]-147. / ix, 147 l illus

Thesis (MSoSc(AppliedSocialResearch))--University of South Australia, 2003.

Thesis (M. P. H.)--University of Hong Kong, 2007.

Thesis (M. P. H.)--University of Hong Kong, 2007. / Also available in print.

Diss. Stockholm : Handelshögsk., 2001.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 8 uppsatser.