Pharmacogenomics - Genome-wide association studies in pharmacogenomic... [Pharmacogenet Genomics. 2010] - PubMed result

Pharmacogenomics
1. Recent developments of pharmacogenomics in the treatment of colorectal cancers
Astier A
Ann Pharm Fr 2010 Jul;68(4):233-53

Ann Pharm Fr. 2010 Jul;68(4):233-53. Epub 2010 May 24.

[Recent developments of pharmacogenomics in the treatment of colorectal cancers]
[Article in French]

Astier A.

UMRS CNRS 7054, faculté de médecine Paris XII, 94000 Créteil, France. : prof.astier@gmail.com

Abstract
Colorectal cancer (CCR), which is one of the most common causes of cancer, has benefited from the major advances in the understanding of the intracellular signaling pathways implicated in the initiation, growing and local and metastasis dissemination of tumor, which have occurred during the 20 past years. The pharmacogenomics approach, especially the determination of the genetic polymorphisms, tries to find prognosis and predictive biomarkers permitting to identify patients who could benefit from a particular treatment or those exhibiting higher risks of toxicity. Among the numerous biomarkers, which have been studied, few are currently in use in clinical practice. The phenotyping of DPD and UGT1A1 activities, and to a lesser extent, its genotyping, appears as the most useful tool in terms of prediction of toxicities induced by two major drugs: 5-FU and irinotecan. For oxaliplatin, the determination of the polymorphisms of reparases and detoxification systems such as GSTpi seems interesting, but its exact place should be more defined. It is in the field of targeted therapies that the pharmacogenomics approach seems to be the more relevant. KRAS mutation is a dramatic example of single nucleotide polymorphism, which is able to identify a priori patients that could receive or not an anti-EGFR monoclonal antibody such as cetuximab or panitumumab. It is obvious that pre-clinical identification of molecular biomarkers predictive of the sensitivity of the drug targets, which subsequently implicate the selection of patients and the rational evaluation of responses, will be the cornerstone of any clinical trials concerning targeted therapies. Besides the determination of drug target polymorphisms, it is also important to consider those related to the distribution and metabolism. In this area, the determination of enzymatic activities should recover its place besides the genomic profiling. Copyright 2010 Elsevier Masson SAS. All rights reserved.

PMID: 20637356 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/20637356?dopt=Abstract


2. Genome-wide association studies in pharmacogenomics: successes and lessons
Motsinger-Reif AA, et al.
Pharmacogenet Genomics 2010 Jul
open here please:
Genome-wide association studies in pharmacogenomic... [Pharmacogenet Genomics. 2010] - PubMed result

Pharmacogenet Genomics. 2010 Jul 15. [Epub ahead of print]

Genome-wide association studies in pharmacogenomics: successes and lessons.
Motsinger-Reif AA, Jorgenson E, Relling MV, Kroetz DL, Weinshilboum R, Cox NJ, Roden DM.

aDepartment of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina bDepartment of Neurology, Ernest Gallo Clinic and Research Center cDepartment of Bioengineering and Therapeutic Sciences, School of Pharmacy and Medicine, University of California, San Francisco, California dDepartment of Pharmaceutical, St Jude Children's Research Hospital, Memphis eOffice of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee fDepartment of Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Mayo Clinic, Rochester, Minnesota gDepartment of Medicine, Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.

Abstract
OBJECTIVE: As genotyping technology has progressed, genome-wide association studies (GWAS) have matured into efficient and effective tools for mapping genes underlying human phenotypes. METHODS: Recent studies have shown the utility of the GWAS approach for examining pharmacogenomic traits, including drug metabolism, efficacy, and toxicity. RESULTS: Application of GWAS to pharmacogenomic outcomes presents unique challenges and opportunities. CONCLUSION: In the current review, we discuss the potential promises and potential caveats of this approach specifically as it relates to pharmacogenomic studies. Concerns with study design, power and sample size, and analysis are reviewed. We further examine the features of successful pharmacogenomic GWAS, and describe consortia efforts that are likely to expand the reach of pharmacogenomic GWAS in the future.

PMID: 20639796 [PubMed - as supplied by publisher]


3. Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant
Hawwa AF & McElnay JC
Expert Opin Drug Saf 2010 Jul

Expert Opin Drug Saf. 2010 Jul 15. [Epub ahead of print]

Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant.
Hawwa AF, McElnay JC.

Queen's University Belfast, Medical Biology Centre, School of Pharmacy, Clinical and Practice Research Group, 97 Lisburn Road, BT9 7BL Belfast, UK.

Abstract
Importance of the field: Tacrolimus is the most commonly used immunosuppressive agent following solid-organ transplantation in children. Its clinical use, however, is complicated by side effects (mainly nephrotoxicity), narrow therapeutic index and pharmacokinetic variability which can result in an increased risk of treatment failure or toxicity. Studies examining interindividual differences in the expression of the ABCB1 (ATP-binding cassette, subfamily B, member 1) gene (which encodes the drug transporter, P-gp) and its genetic polymorphisms have attempted to elucidate variations in tacrolimus response and disposition in children. Areas covered in this review: This review explores pharmacogenetic knowledge developed over the last decade regarding the impact of ABCB1 polymorphisms on tacrolimus toxicity and dosage requirements in children. What the reader will gain: A better understanding of the role of ABCB1 genetic polymorphisms (and corresponding haplotypes) and ABCB1 expression levels in various tissues and organs on tacrolimus outcomes in children with liver transplant. Take home message: Pharmacogenetics offers significant potential for optimising tacrolimus use. ABCB1 donor genotypes and ABCB1 expression level in the intestine and leukocytes may be useful in dosage selection. Large prospective studies are, however, required to further explore the potential of genetic testing in identifying children who are at risk of toxicity and to better individualise tacrolimus therapy.

PMID: 20629603 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20629603?dopt=Abstract


4. Pharmacogenetics and human genetic polymorphisms
Daly AK
Biochem J 2010 Jul;429(3):435-49

Biochem J. 2010 Jul 14;429(3):435-49.

Pharmacogenetics and human genetic polymorphisms.
Daly AK.

Institute of Cellular Medicine, Newcastle University Medical School, UK. a.k.daly@ncl.ac.uk

Abstract
The term pharmacogenetics was first used in the late 1950s and can be defined as the study of genetic factors affecting drug response. Prior to formal use of this term, there was already clinical data available in relation to variable patient responses to the drugs isoniazid, primaquine and succinylcholine. The subject area developed rapidly, particularly with regard to genetic factors affecting drug disposition. There is now comprehensive understanding of the molecular basis for variable drug metabolism by the cytochromes P450 and also for variable glucuronidation, acetylation and methylation of certain drugs. Some of this knowledge has already been translated to the clinic. The molecular basis of variation in drug targets, such as receptors and enzymes, is generally less well understood, although there is consistent evidence that polymorphisms in the genes encoding the beta-adrenergic receptors and the enzyme vitamin K epoxide reductase is of clinical importance. The genetic basis of rare idiosyncratic adverse drug reactions had also been examined. Susceptibility to reactions affecting skin and liver appears to be determined in part by the HLA (human leucocyte antigen) genotype, whereas reactions affecting the heart and muscle may be determined by polymorphisms in genes encoding ion channels and transporters respectively. Genome-wide association studies are increasingly being used to study drug response and susceptibility to adverse drug reactions, resulting in identification of some novel pharmacogenetic associations.

PMID: 20626352 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/20626352?dopt=Abstract