Pharmacogenomics: Challenges and Opportunities

Roden, Dan M.

doi:10.7326/0003-4819-145-10-200611210-00007

Cited by 228 publications

(141 citation statements)

References 79 publications

(71 reference statements)

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“…Moreover, refinement and further improvement of the prediction model are warranted. Additional research may also focus on the contribution of other factors such as inflammatory cytokine levels, because variability in drug response may also reflect changes in the complex biologic milieu in which drugs interact with their target molecules (53).…”

Section: Discussionmentioning

confidence: 99%

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Wessels

Kooij

Cessie

et al. 2007

Arthritis & Rheumatism

222

152

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Objective. To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).Methods. Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS <2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.Results. The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of <3.5 had a true positive response rate of 95%. Scores of >6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.Conclusion. This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.

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Section: Discussionmentioning

confidence: 99%

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Wessels

Kooij

Cessie

et al. 2007

Arthritis & Rheumatism

222

152

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“…Specifically, all possible pairwise SNP comparisons were used to compute R 2 and D′ values [25]. Data for all pairwise SNP comparisons with R 2 values ≥ 0.7 are listed in Supplemental Table 3.…”

Section: Linkage Disequilibrium and Haplotype Analysismentioning

confidence: 99%

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Feng

Lee

et al. 2008

Molecular Genetics and Metabolism

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Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT2 encodes a protein 73% identical in amino acid sequence to BHMT, but the function of BHMT2 remains unclear. We set out to identify and functionally characterize common genetic variation in BHMT and BHMT2. Specifically, we sequenced exons, exon-intron splice junctions and the 5′-flanking regions (5′-FRs) of BHMT and BHMT2 using 240 DNA samples from four ethnic groups. Twenty-five single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, and 39 SNPs, including 4 nonsynonymous, were observed in BHMT and BHMT2, respectively. BHMT wild type (WT) and variant allozymes were expressed in COS-1 cells. Variant allozymes showed no significant differences from WT in levels of enzyme activity or immunoreactive protein, but there were statistically significant differences in apparent K m values. Luciferase reporter gene constructs were created for the three most common BHMT 5′-FR haplotypes, and significant variation was observed in the ability of these constructs to drive transcription. Although BHMT2 mRNA has been observed in human liver and kidney, expression of the protein has not been reported. We were unable to express BHMT2 in mammalian cells, and the protein aggregated after bacterial expression. Furthermore, BHMT2 was rapidly degraded in a rabbit reticulocyte lysate, but it could be stabilized by cotransfection of COS-1 cells with BHMT and, after cotransfection, it coprecipitated with BHMT. These studies have defined common genetic variation in BHMT and BHMT2 and functionally characterized BHMT SNPs. They may also help to explain why BHMT2 has not previously been defined functionally.

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“…Moreover, it is likely that in the future a panel of genetic markers, or even a whole-genome scan, will form the basis of treatment tailoring, potentially leading to a stronger benefit of tailored therapy. 29,48 Third, the effects of discounting across time and the modest survival benefits of increasing the 6-month quit rate lead to clustering of the mean cost and LY outcomes, and consequently our comparisons are sensitive to model parameters and assumed costs when varied in combination. In some cases, the differences between treatments were too small to distinguish statistically even with the large number of subjects we simulated, leading to ambiguity in the determination of which treatments are dominated.…”

Section: Discussionmentioning

confidence: 99%

“…27 Nevertheless, it is understood that the cost-effectiveness of a genetically tailored drug treatment plan will depend on a number of factors: the distribution of the relevant genetic variants, the costs of genetic testing and subsequent treatment and the effectiveness of the tailored therapy compared to a 'one-size-fits-all' approach. 28,29 In this article, we describe a model of tobacco dependence treatment that allows us to simulate cost and effectiveness outcomes to assess the value of pharmacogenetic testing using data on pharmacogenetic effects observed in tobacco dependence treatment trials. 7 Estimates of pharmacogenetic effects in these trials are within the range of those observed for a variety of psychiatric medications.…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment

et al. 2008

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We evaluated the cost-effectiveness of a range of smoking cessation drug treatments, including varenicline, transdermal nicotine (TN), bupropion and the use of a genetic test to choose between TN and bupropion. We performed Monte Carlo simulation with sensitivity analysis, informing analyses with published estimates of model parameters and current prices for genetic testing and smoking-cessation therapy. The primary outcomes were discounted life-years (LY) and lifetime tobacco-cessation treatment costs. In the base case, varenicline treatment was optimal with an ICER, compared to bupropion, of $2985/LY saved. In sensitivity analyses, varenicline was in all cases (and bupropion in most cases) admissible; only under favorable assumptions was the genetically tailored approach competitive. Our data suggest that an untailored approach of treatment with either bupropion or varenicline is a cost-effective form of tobacco dependence treatment, but a tailored approach for selecting between TN and bupropion can be cost-effective under plausible assumptions.

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Pharmacogenomics: Challenges and Opportunities

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Cited by 228 publications

References 79 publications

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment

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