Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Thesis (M.P.H.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / Source: Masters Abstracts International, Volume: 46-03, page: 1501. Adviser: Jimmy L. Perkins. Includes bibliographical references.

Thesis (Ph.D.)--Indiana University, 2008. / Title from screen (viewed on June 4, 2009). Department of Pharmacology and Toxicology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): David A. Flockhart. Includes vita. Includes bibliographical references (leaves 124-139).

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Whilst antidepressants are widely prescribed, there is a large degree of variation between patients in terms of treatment outcomes. Furthermore, the mechanisms by which these drugs exert their effects remain unclear. In this thesis, genetic biomarkers of antidepressant outcomes have been explored, in order to better understand the molecular mechanisms underpinning effective antidepressant treatment. The research presented here use data from the GENDEP project, which is a large pharmacogenetic study of depressed patients receiving antidepressant treatment. Firstly, the pharmacological underpinnings of antidepressant-associated side effects were used to categorise these side effects and conduct a candidate gene analysis. Whilst a significant association between variation within the HTR2C gene and serotonergic side effects was found, the observation was not replicated in a second sample. Secondly, the role of variability in drug metabolism rates in treatment outcomes was investigated. Examining genotypic information on the cytochrome P450 enzymes, no associations with treatment response, side effects or study discontinuation were observed. Furthermore, serum concentrations of antidepressant were unrelated to treatment response or overall burden of side effects, predicting only a minority of specific side effects. Thirdly, transcriptomic changes with drug administration were explored in relation to treatment efficacy. Two genes were identified where changes in expression levels were significantly associated with treatment response amongst patients taking nortriptyline. Furthermore, using a network-based approach, changes in gene expression across one module of coexpressed genes showed significant correlation with symptom improvement; this biological network generalised across different antidepressant medications. Finally, genomic and transcriptomic data were combined, in an examination of the genetic control of gene expression. This analysis then was used to gain an insight into the molecular processes that link genotype to phenotype. The evidence presented within this thesis, when considered in combination with existing literature, highlights that antidepressant efficacy is a complex trait, influenced by many genes of small effect. Nevertheless, by layering together different levels of information, we can begin to dissect the molecular mechanisms involved in antidepressant action.

published_or_final_version / abstract / Microbiology / Master / Master of Philosophy

No description available.

There have been many scientific developments in the last century including the atomic bomb and DNA sequencing. Moreover, when human genome was sequenced in the early 2000s, it opened a new avenue to study disease and human development. Genetic tests have become an integral part for cancer diagnosis. Still, cancer therapy is decided based on the tumor genotype, the very definition of pharmacogenetic testing. More specifically, pharmacogenetics or pharmacogenomics is defined as variations in genes that can affect drug response. There has been great deal of research into pharmacogenetics and its potential fields for application. One such field is cardiology and cardiovascular disease. There are some promising researches that indicate genetic influence over drug response, such as the role of CYP2C19 over metabolism of a drug used for treating acute coronary disease and other cardiovascular issues. This is a great tool in the transition toward personalized medicine; however there are some logistical and social concerns over genetic tests; test administration, result accuracy and validity, data storage and security. Also, many patients were concerned with confidentiality, payment method and timely intervention. Also, implementation plans should include all areas, not just cities. Although there is potential for pharmacogenetic testing, many challenges have to be considered and addressed to ensure public confidence and proper use of the technique. Pharmacogenetics is a step towards individualized or personalized medicine; in-depth research prior to implementation will help tackle any challenges that may arise.

Nicotine is the primary substance in tobacco causing addiction. In humans the majority (70-80%) of nicotine is inactivated to cotinine in a reaction predominantly catalyzed by CYP2A6 (80-90%), with a minor possible role for CYP2B6. Substantial interindividual variability is observed in the rate of nicotine’s inactivation to cotinine and this variation contributes to differences in smoking behaviors (e.g. cigarette consumption). Twin studies suggest an important genetic contribution to the variability in nicotine metabolism. However in 2004, genetic variation in CYP2A6 and CYP2B6 accounted for only a small portion of the variability suggesting gaps in our knowledge. Our objective was to identify additional genetic and non-genetic sources of variability in CYP2A6 expression/activity, CYP2B6 expression, and nicotine to cotinine metabolism in vivo and/or in vitro. Participants included individuals from different world populations phenotyped for CYP2A6 activity either following oral nicotine administration or using metabolite ratios derived from baseline smoking. Genotyping and sequencing were utilized to identify and characterize multiple new CYP2A6 alleles. In total 17 novel CYP2A6 alleles were identified, many of which were found predominantly among individuals of black African descent and exhibited lower CYP2A6 activity. In addition, human livers were assessed for CYP2A6 and CYP2B6 expression and nicotine to cotinine metabolism. The mechanisms underlying the lower CYP2A6 activity associated with some of the variant CYP2A6 alleles included either a reduction in hepatic CYP2A6 protein expression, an alteration of CYP2A6’s structural property, or a combination of both. DNA methylation was not associated with altered hepatic CYP2A6 expression/activity. Livers from female donors were associated with higher CYP2A6 and CYP2B6 protein expression compared to male livers, while age did not influence the expression of either CYP. Finally, CYP2B6 and its prevalent altered function genetic variant (CYP2B6*6) did not influence nicotine to cotinine metabolism. Identification of factors that contribute to the variability in CYP2A6 and nicotine metabolism is important to improve future association studies between CYP2A6 genotype, nicotine metabolism, and smoking behaviors. In addition, this information could provide the potential to personalize therapy in order to improve the clinical efficacy of nicotine, particularly as a smoking cessation aid.