• Core Analytical Laboratory
• Pharmacometrics
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      Pharmacogenomics Initiatives       WNY Pharmacogenomics Program       Pharmacogenomics Update

Freshman Discovery Seminar Program: Spring 2008

Nishida et al. established an HPLC assay system to determine TPMT activity. Using this assay, the investigators looked at the metabolic capacity for 6-methylmercaptopurine in 44 Japanese subjects to assess its relationship to the genotype of TPMT in these subjects. The TPMT activity of the subjects with TPMT *1/ *3C was 40% lower than the mean value of subjects with TPMT *1/ *1. TPMT deficiency is associated with severe hematopoietic toxicity after administration of standard doses of 6-MP or azathioprine. The TPMT assay developed in this study enables inexpensive screening for TPMT activity and would be suitable for routine clinical use.

Reference

Nishida A, et al. Thiopurine S-methyltransferase activity in Japanese subjects: metabolic activity of 6-mercaptopurine 6-methylation in different TPMT genotypes. Clin Chim Acta. 2002;323(1-2):147-50.

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In this study, Hung et al. enrolled 235 patients, 91 of whom experienced a cutaneous adverse drug reaction (cADR) while being treated with carbamazepine. The goal of this study was to further investigate the susceptibility locus for carbamazepine-induced cADRs. Comparisons of allele or genotype frequencies between groups were performed and the association of haplotypes frequencies was tested. This study confirmed HLA- B*1502 itself is most likely the susceptibility gene for carbamazepine-induced Stevens-Johnson syndrome. The tight association of HLA- B*1502 and carbmazapine-induced cADRs provides a plausible basis for the development of such a test to identify individuals at risk for this potentially life-threatening condition.

Hung SI, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006;16(4):297-306.

http://thegenesherpa.blogspot.com/2007/12/toxic-epidermal-necrolysis-and.html

http://psychcentral.com/news/2007/12/05/biomarkers-aid-treatment-of-mental-illness/1614.html

Abacavir therapy is associated with significant drug hypersensitivity in approximately 8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allele. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701-negative recipients.

Rauch A, et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006;43:99–102.

http://enewschannels.com/2006/10/17/enc299_034821.php

The aim of our study was the evaluation of the effects of genetic and environmental factors on the lipid-lowering response to statin therapy in patients with molecularly defined FH. Atorvastatin 20 mg/day was prescribed in 49 patients with heterozygous FH. The lipid profile was examined before and after 12 weeks of therapy. The study population was divided into 2 groups according to the class of the LDLR mutation. In both groups, the percentage decrement in LDL-C and apoB levels were correlated with the initial LDL-C and apoB levels, respectively. Our data indicate that the class of the LDLR gene mutation affects the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. Specifically, patients with a class V mutation exhibit higher percentage decrease in LDL-C and apoB levels after statin therapy compared to patients sharing class II mutations.

Miltiadous G, et al. Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. Pharmacogenet Genomics. 2005;15(4):219-25.

http://www.bcbs.com/betterknowledge/tec/vols/22/22_07.html

Alzheimer's disease (AD) is a devastating neurodegeneration with a characteristic deficit in cholinergic neurotransmission. Treatment with acetylcholinesterase (AChE) inhibitors aims to reverse this deficit and does ameliorate the decline in cognition in some AD patients, although response is variable. To examine whether sequence variation in the gene encoding choline acetyltransferase (CHAT), which encodes the major catalytic enzyme of the cholinergic pathway, predicts response to AChE inhibitors. Alzheimer's disease patients (n=121) were treated with cholinesterase inhibitors and the effect of treatment on cognition was measured using the Mini Mental State Examination (MMSE). Six polymorphisms in CHAT were analysed for association with change in MMSE score. After correction for multiple testing, we found one SNP, rs733722, in a promoter region of CHAT, is associated with response of AD patients to cholinesterase inhibitors (P=0.03) and accounts for 6% of the variance in response to AChE inhibitors. Rs733722 represents a putative marker of response to AChE inhibitors in AD patients.

Harold D, et al. A single nucleotide polymorphism in CHAT influences response to acetylcholinesterase inhibitors in Alzheimer's disease. Pharmacogenet Genomics. 2006;16(2):75-7.

http://sahabatlansia.blogspot.com/2007/06/pharmacogenomic-approach-to-alzheimers.html

In this study the presence of a polymorphism associated with reduced or absent activity of TPMT was studied in 88 patients to look at the correlation of the genotype with the occurrence of bone marrow toxicity in a population of renal transplant patients being treated with azathioprine. The differences in relationship of either wild or mutant alleles with azathioprine toxicity were assessed by of Fisher’s exact test. SPSS software was used for Kaplan-Meier analysis as well as log-rank test. Seven of 12 patients with mutant alleles (58.3%) developed toxicity compared to 12 of 76 (16%) without one of these mutant alleles. This study shows that screening for TPMT genotype before initiating azathioprine therapy in renal transplant recipients may be a valuable tool in clinical decision making to reduce the risk of hematological side effects.

Pandya B, et al. Azathioprine toxicity and thiopurine methyltransferase genotype in renal transplant patients. Transplant Proc. 2002;34(5):1642-5.

http://www.sciencedaily.com/releases/2005/05/050505223749.htm

298 patients from St. Petersburg, Russia were enrolled in a study to estimate the frequencies of CYP2C9*2 and CYP2C9*3 alleles in the Russian population and to investigate an association between allelic variation and individual sensitivity to Warfarin treatment. A Chi square test was used to compare the percentages of patients with at least one INR above the upper target limit in carriers of wild-type, CYP2C9*2, and CYP2C9*3 alleles. The study found that CYP2C9*2 and CYP2C9*3 alleles were associated with increased risk of anticoagulation and these results may be useful for guiding Warfarin dosing.

Pchelina SN, et al. The frequency of cytochrome P450 2C9 genetic variants in the Russian population and their associations with individual sensitivity to warfarin therapy. Thromb Res. 2005;115(3):199-203.

http://www.nelm.nhs.uk/Record%20Viewing/viewRecord.aspx?id=585929

Ontology: Developing a Systematic Approach to Translational Pharmacogenomics Research Data Collection

Pharmacogenomics studies the involvement of inter-individual variations of DNA sequence in different drug responses. Knowledge Discovery in Databases (KDD) process is a means for discovering new pharmacogenomic knowledge in biological databases. However data complexity makes it necessary to guide the KDD process by representation of domain knowledge. Three domains at least are in concern: genotype, drug and phenotype. The approach described here aims at reusing whenever possible existing domain knowledge in order to build a modular formal representation of domain knowledge in pharmacogenomics. The resulting ontology is called SO-Pharm for Suggested Ontology for Pharmacogenomics.

Coulet A, et al. Suggested Ontology for Pharmacogenomics (SO-Pharm): Modular Construction and Preliminary Testing. On the Move to Meaningful Internet Systems 2006: OTM 2006 Workshops, Springer Berlin/Heidelberg, 2006.

Resource

http://toy.lbl.gov:9004/cgi-bin/detail.cgi?id=pharmacogenomics

Health Care Policy and Economics: Who Pays for Pharmacogenomics in Clinical Medicine?

This report models how the evolving field of pharmacogenomics, the science of using genomic markers to predict drug response, may impact drug development times, attrition rates, and costs. While there still remains an abundance of uncertainty around how pharmacogenomics will impact the future landscape of pharmaceutical and biological R&D, we identify several likely outcomes. We conclude pharmacogenomics has the potential to significantly reduce both expected drug development costs via higher probability of technical success, shorter clinical development times, and smaller clinical trials.

Vernon JA, Hughen WK. The Future of Drug Development: The Economics of Pharmacogenomics. NBER Working Paper No. W11875, 2005. Available at http://www.nber.org/papers/w11875

http://andyde.blogspot.com/2007/02/three-things-that-keep-big-pharma-ceos.html