Identification of genetic variants and gene expression relationships associated with pharmacogenes in humans

Huang, R. Stephanie; Duan, Shiwei; Kistner, Emily O.; Zhang, Wei; Bleibel, Wasim K.; Cox, Nancy J.; Dolan, M. Eileen

doi:10.1097/fpc.0b013e3282fe1745

Cited by 22 publications

(18 citation statements)

References 14 publications

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“…This has been demonstrated in prostate cancer and type I diabetes: such SNPs have been labeled ‘functionally interpolating SNPs or FitSNPs”[47, 48]. In addition there are clearly genetic influences upon gene expression levels, and so called ‘very important pharmacogenes (VIPs)’ have been previously shown to have expression patterns that are associated with genetic variation[49]. Other gene expression profiling studies, in cancer, have identified transcripts whose early expression correlates with good or poor response to MTX[50].…”

Section: Discussionmentioning

confidence: 99%

Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype

Moncrieffe¹,

Hinks

Ursu³

et al. 2010

Pharmacogenetics and Genomics

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Objectives-Little is known about mechanisms of efficacy of methotrexate (MTX) in childhood arthritis, or genetic influences upon response to MTX. The aims of this study were to use gene expression profiling to identify novel pathways/genes altered by MTX and then investigate these genes for genotype associations with response to MTX treatment.Methods-Gene expression profiling before and after MTX treatment was performed on 11 children with juvenile idiopathic arthritis (JIA) treated with MTX, in whom response at 6 months of treatment was defined. Genes showing the most differential gene expression after treatment were selected for SNP genotyping. Genotype frequencies were compared between non-responders and responders (ACR-Ped70). An independent cohort was available for validation.Results-Gene expression profiling before and after MTX treatment revealed 1222 differentially expressed probes sets (fold change >1.7, p< 0.05) and 1065 when restricted to full responder cases only. Six highly differentially expressed genes were analysed for genetic association to response to MTX. Three SNPs in the SLC16A7 gene showed significant association with MTX response. One SNP showed validated association in an independent cohort.Conclusions-This study is the first, to our knowledge, to evaluate gene expression profiles in children with JIA before and after MTX, and to analyse genetic variation in differentially expressed genes. We have identified a gene which may contribute to genetic variability in MTX response in JIA, and established as proof of principle that genes which are differentially expressed at mRNA level after drug administration may also be good candidates for genetic analysis.

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Section: Discussionmentioning

confidence: 99%

Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype

Moncrieffe¹,

Hinks

Ursu³

et al. 2010

Pharmacogenetics and Genomics

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“…drug response variation) between major human populations as well as between males and females. Interestingly, population differences in gene expression were observed in some of the important pharmacogenes using the HapMap LCLs [65], as maintained by the PharmGKB [53] VIP (Very Important Pharmacogenes) database. In addition, we set up a searchable database, SCAN (SNP and CNV Annotation Database, http://www.scandb.org), which can be useful for both gene-centric and SNP-centric queries for eQTLs using the exon array data (gene-level) on the CEU and YRI samples [51, 60].…”

Section: Lymphoblastoid Cell Line Resourcesmentioning

confidence: 99%

Use of Cell Lines in the Investigation of Pharmacogenetic Loci

Zhang

Dolan

2009

CPD

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Drug response and toxicity, complex traits that are often highly varied among individuals, likely involve multiple genetic and non-genetic factors. Pharmacogenomic research aims to individualize therapy in an effort to maximize efficacy and minimize toxicity for each patient. Cell lines can be used as a model system for cellular pharmacologic effects, which include, but are not limited to, drug-induced cytotoxicity or apoptosis, biochemical effects and enzymatic reactions. Because severe toxicities may be associated with drugs such as chemotherapeutics, cell lines derived from healthy individuals or patients provide a convenient model to study how human genetic variation alters response to these drugs that would be unsafe or unethical to administer to human volunteers. In addition to the traditional candidate gene approaches that focus on well-understood candidate genes and pathways, the availability of extensive genotypic and phenotypic data on some cell line models has begun to allow genome-wide association (GWA) studies to simultaneously test the entire human genome for associations with drug response and toxicity. Though with some important limitations, the use of these cell lines in pharmacogenomic discovery demonstrates the promise of constructing a more comprehensive model that may ultimately integrate both genetic and non-genetic factors to predict individual response and toxicity to anticancer drugs.

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“…In order to control for misrepresentation of individuals in such studies, either ancestry informative marker- or multilocus genotype-based clustering methods are generally used (Wilson et al, 2001; Estrela et al, 2008; Kosoy et al, 2009). Alternatively, by analyzing samples from populations of known ancestry, one can obtain a better understanding of comparative pharmacogenetic variation (Wang et al, 2007; Huang et al, 2008). Since ethnicity/race of individuals in both of our study groups, HIV-positive and HIV-negative, was self-identified, we performed genetic analyses of the 1236/2677/3435 SNP data from populations of known ancestry to compare our results.…”

Section: Introductionmentioning

confidence: 99%

Comparative description of haplotype structure and genetic diversity of MDR1 (ABCB1) in HIV-positive and HIV-negative populations

Benish

Rodrı́guez

Zimmerman

et al. 2010

Infection, Genetics and Evolution

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Human P-glycoprotein (P-gp), encoded by MDR1 (ABCB1), is an efflux transporter with a wide specificity for substrates/drugs, including HIV protease inhibitors which are commonly used in HIV/AIDS treatment. Three single nucleotide polymorphisms (SNPs) in MDR1 have been shown to affect P-gp expression and function, and may affect HIV/AIDS treatment outcome: 1236C>T [G412G, exon-12], 2677G>T/A [A893S/T, exon-21] and 3435C>T [I1145I, exon-26]. In the present study, our aims were (i) to compare the 3-SNP MDR1 haplotype structure and genetic diversity between North American HIV-positive and HIV-negative individuals belonging to four major ethnic groups and (ii) to determine whether the haplotype structure and genetic diversity observed in these ethnically admixed populations differ from that in ethnically non-admixed populations. For these aims, we analyzed a cohort of 447 HIV/AIDS patients (White [n = 193], Black [n = 235], Hispanic [n = 17], and Asian [n = 2]). Results obtained for these patients were compared with the results for (i) HIV-negative individuals (n = 356) and (ii) various HapMap and Environmental Genome Project populations. We observed that the genetic characteristics of MDR1 were largely consistent between HIV-positive and HIV-negative populations, but there were striking interethnic differences in the genetic characteristics of MDR1 in both populations. Although it appeared that the genetic characteristics of MDR1 were largely consistent between ethnically admixed and non-admixed populations, genetic characterization of the admixed populations remains to be done. Thus, our results provide useful comparative insights about the genetic characteristics of MDR1 that could be extrapolated across population groups worldwide. For a meaningful interpretation of these results regarding HIV/AIDS treatment outcome, MDR1 haplotype/diplotype structure data, genetic characterization of population admixture, and polymorphisms in other relevant drug transporter and/or metabolizing enzyme genes should be considered in future clinical studies.

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Identification of genetic variants and gene expression relationships associated with pharmacogenes in humans

Abstract: Using this information, one may identify genetic variants that are significantly associated with the expression of any set of genes of interest; or evaluate potential gene-gene interaction through SNP expression relationships.

Cited by 22 publications

References 14 publications

Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype

Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype

Use of Cell Lines in the Investigation of Pharmacogenetic Loci

Comparative description of haplotype structure and genetic diversity of MDR1 (ABCB1) in HIV-positive and HIV-negative populations

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