"March 2003" / Corrections inside front cover. / Includes bibliographical references (leaves 111-167) / x, 167 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003

"February 2004" / Bibliography: leaves 150-168. / 168 leaves : ill., plates ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2004

Includes bibliographical references (leaves [138]-186) / xiii, 186 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Describes the kinetics of the hepatic lipase mediated hydrolysis of phospholipids and triacylglycerol in spherical, apolipoprotein-specific reconstituted high density lipoproteins. The results show that apolipoproteins have a major impact on these processes. / Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 2001

"March 2003" / Corrections inside front cover. / Includes bibliographical references (leaves 111-167) / x, 167 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003

Thesis (Ph. D.)--University of Adelaide, Dept. of Medicine, 2004. / "February 2004." Includes bibliographical references (leaves 150-168).

Thesis (Ph. D.)--University of Chicago, Committee on Human Nutrition and Nutritional Biology, March 2001. / Includes bibliographical references. Also available on the Internet.

Reduced high-density lipoprotein cholesterol (HDL-C) concentrations are a major risk factor for cardiovascular disease. Intense interest recently has been in identifying the genetic factors that contribute to an aberrant HDL-C phenotype. Finding genetic factors associated with low HDL-C concentrations in New Zealanders was the major aim of this study, with a similar analysis aimed at finding factors associated with high HDL-C concentrations included. The study began with an investigation of a New Zealand family with HDL-C deficiency. The proband had virtually no HDL-C, and was homozygous for an R1068H mutation in the ABCA1 gene. Nineteen relatives were recruited into the study, and an analysis aimed at finding the underlying cause for the disparate HDL-C phenotypes amongst H1068 carriers initiated. A further investigation into HDL-C levels aimed to find other genetic factors that contribute to HDL-C in New Zealanders. Subjects were selected from those taking part in the Otago Vascular Disease study, and placed into three groups based on their HDL-C lipid measurement: low (n=154), mid (n=105), and high (n=102) HDL-C. Mutations in ABCAI and the apolipoprotein AI gene (APOAI) were identified in subjects with low HDL-C. Polymorphisms in ABCA1 and APOAI were also investigated as contributors to HDL-C concentrations. Seventeen SNPs in functionally relevant regions were genotyped in the three HDL-C groups. Five single polymorphisms and one polymorphism haplotype showed a statistically significant association with HDL-C concentrations. The final analysis investigated plasma lipoprotein compositions in individuals with low HDL-C to identify if other lipoprotein abnormalities concurred. Individuals with HDL-C below 0.65 mmol/L were almost invariably associated with triglyceride-rich VLDL and/or triglyceride-rich LDL. This finding may have relevance for an increased atherosclerotic risk for those with low HDL-C.

"September 2004" / Bibliography: leaves 236-262. / xxxi, 262 leaves : ill., plates (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2004

Three studies were conducted to determine whether the elevated plasma and HDL cholesterol levels observed in copper-deficient rats could be explained by the interaction of ¹²⁵I-HDL subfractions with liver membrane preparations in vitro. Rats from all studies were randomly divided into two dietary treatments, copper-deficient and adequate (0.7 mg and 8.0 mg Cu/kg diet, respectively). Deionized water and diet were provided ad libitum. After eight weeks, rats were exsanguinated, membranes prepared from livers, and plasma high density lipoproteins (HDL) isolated by ultracentrifugation and agarose column chromatography. Heparin-Sepharose affinity chromatography was used to isolate specific subfractions of HDL. The HDL subfractions derived from rats of each dietary treatment were iodinated and bound to either crude liver membranes or purified liver plasma membranes prepared from rats of both treatment groups. Total binding data and computer derived estimates (K(d) and B(max)) were used to compare differences between treatments. Binding data from all experiments conformed to a one-site model. In all cases, binding was saturable and EDTA and pronase insensitive. Treatment differences were observed in Study I (¹²⁵I-apo E-free HDL binding to crude liver membranes). Significantly lower total binding and B(max) were observed when lipoproteins and membranes from copper-deficient animals were used in the assay. Competition experiments from Studies II and III demonstrate that the different HDL subfractions competed effectively with one another for binding sites, indicating that apo E is not a determinant in binding of rat ¹²⁵I-HDL subfractions to purified liver plasma membranes.

Background Over the past few years, results refuting the causal role of HDL cholesterol (HDL-c) have been reported by a number of randomized controlled trials (RCTs) testing different ways of modifying HDL-c. Results from Mendelian randomization studies showed no difference in cardiovascular disease (CVD) risk among individuals with genetically different serum levels of HDL-c. The causal role of HDL-c in CVD is thus uncertain, raising the question as to whether HDL-c is a worthwhile target of public health interventions and medical treatments. The objective of these meta-analyses is to explore whether changes in HDL-c are symptomatic of prior causes instead of being a causal factor for CVD by first identifying two possible candidates—androgens and zinc—for the investigation of associations. Experimental evidence would then be investigated for whether either of them might underlie (i.e. confound) the observed association of HDL-c with CVD risk factors. Methods This study followed the PRISMA statement. A literature search was conducted through PUBMED, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Keywords of “androgens/testosterone”, “HDL”, “high-density lipoprotein”, “lipid”, “cholesterol”, “lipoprotein”, “CVD”, “cardiovascular”, “heart”, “cardiovascular disease” were used with the search period limited to January 2000 – June 2013 with only human RCTs conducted and reported in English. For locating studies concerning the effect of zinc, the keyword “zinc” was used instead of “androgens/testosterone”. Inclusion and exclusion criteria were applied during study screening and selection. The Cochrane Collaboration’s tool for assessing risk of bias was used for quality assessment. Heterogeneity across included studies was measured using I2 statistic and publication bias was assessed via funnel plots and the Begg’s Rank Correlation test. The “trim and fill” method was also used for the correction of funnel plot asymmetry. The meta-analyses were performed using The Comprehensive R Archive Network Program (Version R 3.0.0), using the function “metacont” from the “meta” package, where the pooled intervention effects were displayed using forest plots, with inverse variance weighting and random effects model. Results A total of twelve and ten RCTs were identified and included in the meta-analyses of androgens and zinc respectively. There were no consistent beneficial effects of androgens on CVD observed, as the results from CVD surrogate markers were inconclusive, despite showing significant overall reduction in HDL-c levels. However, as current findings suggest that lower HDL-c levels are associated with higher cardiovascular risk, it is possible that androgens may increase that risk by influencing HDL metabolism. On the other hand, zinc was associated with healthier CVD profile. This supports the notion of zinc as a cardioprotective agent. Nonetheless, conclusion failed to be drawn concerning the effect of zinc on HDL-c as there were contradictory results across included studies. Conclusion The meta-analyses suggest that androgens could be a factor which lowers HDL-c and thus increases cardiovascular risk, rather than HDL-c being the direct causative agent. This research may serve as a template for more extensive search for other potentially better candidates in this new study focus in cardiovascular epidemiology. / published_or_final_version / Community Medicine / Master / Master of Public Health