Pharmacogenetic and environmental determinants of response to HMG-CoA reductase inhibitors.

• Other Authors: Lui, Siu Hung.
• Format: Others
• Language: English; Chinese
• Published: 2007
• Subjects: Cytochrome P-450; Hypercholesteremia > Treatment; Statins (Cardiovascular agents); Anticholesteremic Agents; Cytochrome P-450 CYP2D6; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia > drug therapy
• Online Access: http://library.cuhk.edu.hk/record=b6074340; http://repository.lib.cuhk.edu.hk/en/item/cuhk-343969

A total of 146 Chinese patients with various degrees of hyperlipidaemia and high cardiovascular risk, suitable for treatment with rosuvastatin 10 mg daily and in whom it was possible to obtain baseline lipid profiles measured on no lipid lowering drug, were enrolled in to the study. The drug compliance was assessed by personal interview and 9 patients were excluded from the efficacy analysis because they stated their compliance was less than 80%. From the remaining 137 subjects, 62 had a clinical diagnosis of familial hypercholesterolaemia. Data for dietary intake were available in 121 of the 137 subjects. The average reduction in LDL-cholesterol in these subjects was 48.8 +/- 12.8% and as anticipated there was a wide range between individuals. The percentage reductions in LDL-cholesterol were significantly greater in the female than in the male subjects (-51.35 +/-10.89% vs. -46.38 +/-13.96%; p = 0.025), but this was no longer significant after adjustment for body weight. In patients with familial hypercholesterolaemia the absolute reductions in total cholesterol and LDL-cholesterol were significantly greater (p<0.001) than in those without familial hypercholesterolaemia, but the percentage reductions were not significantly different in the two groups. The increases in HDL-cholesterol and the decreases in triglycerides were significantly greater in the subjects with familial hypercholesterolaemia than in those without familial hypercholesterolaemia, both for the absolute changes and for the percentage changes. There were no significant effects on the percentage changes in lipids with rosuvastatin treatment due to age, measurements of body fatness, smoking or alcohol drinking status, or having hypertension or diabetes. === Polymorphisms in the CYP2D6 gene were analyzed and the subjects were divided into 4 groups as wild-type or extensive metabolisers, heterozygotes for CYP2D6*10 and wild-type, homozygotes for CYP2D6*10, and subjects with one allele for poor metaboliser status. The groups in this order would be expected to have decreasing activity of the CYP2D6 enzyme. There was a tendency for greater reduction in LDL-cholesterol in groups with lower CYP2D6 activity, most obvious in male subjects and this was significant in the patients with familial hypercholesterolaemia comparing the first 3 groups. The fourth group had a low number of subjects, which may have biased that result. In the subjects without familial hypercholesterolaemia, the % change in LDL-cholesterol was similar in all genotype groups, but the % reduction in triglycerides was numerically higher in the wild-type group than in groups with CYP2D6*10 alleles and the group with poor metaboliser status showed a lower % reduction. These differences were not significant and may be influenced by the baseline levels of triglycerides, which were not corrected for in this analysis. === The daily calorie intake and percentage of different macronutrient intake was obtained by using seven days food recall records. Dietary intake of most nutrients with higher in male than in female patients and was higher in the patients compared to gender-matched population data. Higher intake of most nutrients was associated with higher baseline triglyceride levels, but not LDL-cholesterol levels in all patients, and in lower HDL-cholesterol levels in the patients without familial hypercholesterolaemia. Higher intake of total calories was associated with less percentage reduction in LDL-cholesterol with rosuvastatin in the patients without familial hypercholesterolaemia and a similar non-significant tendency was seen with higher intake of total fat, saturated fat and cholesterol. === The study described in this thesis examined the role of the CYP2D6*10 polymorphism on the lipid response to rosuvastatin in addition to a number of phenotypic factors such as diet, gender, measures of obesity and other medical conditions. === These findings suggest that the CYP2D6 genotype may have some influence on the lipid response to rosuvastatin, but it appears to interact with other factors including, gender, diet and the presence of familial hypercholesterolaemia. (Abstract shortened by UMI.) === Lui, Siu Hung. === "February 2007." === Adviser: Brian Tomlinson. === Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0248. === Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. === Includes bibliographical references (p. 165-190). === Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. === Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. === Abstracts in English and Chinese. === School code: 1307.