Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes
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University of Cincinnati / OhioLINK
2008
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin12033937002021-10-01T05:11:01Z Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes Jian, Zhengwen Biology Genetics Toxicology single nucleotide polymorphism (SNP) regulatory SNP (rSNP) linkage disequilibrium (LD) allelic expression imbalance(AEI) CYP1A1 CYP1A2 expression variation Variation in activity of cytochrome P450s is one of the major factors responsible for interindividual difference in drug clearance rate which may cause serious toxicity or inefficacy of clinically used drugs. Such variation was reported to be determined at mRNA level for major P450 genes albeit it to a various degree. Little is known about mechanisms underlying the huge expression variation of most P450 genes among individuals. Identification of genetic variants affecting expression levels of P450 genes can lead to a cost-effective personalized medicine. This dissertation aims to 1) determine the genetic diversity and genetic structure of the CYP1A1_1A2 region; 2) search for determinants of interindividual variation in expression level of seven cytochrome P450 genes; 3) identify cis-acting genetic variants affecting the expression level of CYP1A1 and CYP1A2. Single nucleotide polymorphisms in a 39.6kb segment encompassing the whole CYP1A1 and CYP1A2 genes and the spacer region were identified. The linkage disequilibrium structure, haplotypes and tagSNPs in this region were determined. A humanized BAC-transgenic mouse line was established as a in vivo platform to study activity of different haplotypes of the human CYP1A1_1A2 region. Four factors were identified as major determinants of interindividual variability in expression level of P450 genes in human liver with various contribution for each P450 gene. These four factors include (1) the functional efficacy of global regulators affecting expression level of most active genes; (2) the expression level of specific P450 regulators; (3) exposure to environmental factors responsible for activation or modulation of activity of specific P450 regulators; (4) the presence of cis-acting genetic variants in P450 genes. At least four major cis-acting regulatory SNPs (rSNP) were demonstrated to exist in regulation of CYP1A1 or CYP1A2 expression. One of the four rSNPs was CYP1A1-940C>T (rs4646418), which is located in a G-rich domain about 1kb upstream of the CYP1A1 transcription initiation site, but affects both CYP1A1 and CYP1A2 expression. Another three SNPs – CYP1A1+2573C>T (rs4646422); CYP1A2-2217G>A (rs2069521); CYP1A2+734A>C (rs762551) – were identified to be top candidates as cis-acting genetic variants affecting the expression level of either CYP1A1 (by +2573C>T) or CYP1A2 (by -2217G>A; +734A>C). 2008-04-23 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1203393700 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1203393700 restricted--full text unavailable until 2022-09-30 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biology Genetics Toxicology single nucleotide polymorphism (SNP) regulatory SNP (rSNP) linkage disequilibrium (LD) allelic expression imbalance(AEI) CYP1A1 CYP1A2 expression variation |
| spellingShingle |
Biology Genetics Toxicology single nucleotide polymorphism (SNP) regulatory SNP (rSNP) linkage disequilibrium (LD) allelic expression imbalance(AEI) CYP1A1 CYP1A2 expression variation Jian, Zhengwen Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes |
| author |
Jian, Zhengwen |
| author_facet |
Jian, Zhengwen |
| author_sort |
Jian, Zhengwen |
| title |
Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes |
| title_short |
Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes |
| title_full |
Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes |
| title_fullStr |
Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes |
| title_full_unstemmed |
Genetic Diversity and Expression Variation in Human Cytochrome P450 Genes |
| title_sort |
genetic diversity and expression variation in human cytochrome p450 genes |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2008 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1203393700 |
| work_keys_str_mv |
AT jianzhengwen geneticdiversityandexpressionvariationinhumancytochromep450genes |
| _version_ |
1719486485480079360 |