Curators' Favorite Papers

The current Curators' Favorite Papers' highlight an article describing a new method in identifying the genetic variation of gene expression using gene sets. To test their novel approach, Abo et al. used KEGG and PharmGKB pathways to define gene sets. In their method, SNPs and mRNA expression were initially grouped as gene sets, then principal components analysis was conducted to collapse the variation and reduce the dimensionality within the gene sets. They proposed that the multiple testing limitations in eQTL studies can be addressed effectively by their method. Many significant associations are found using publicly available data sets. The most significant associations were found between genetic variation and mRNA expression from the same gene sets and provides biological context for SNP-expression associations.

Congratulations, David Botstein!

We extend our hearty congratulations to Dr. David Botstein, winner of one of the initial Breakthrough Prizes in Life Sciences!  Dr. Botstein, the former chairman of genetics at Stanford University, is now Professor of Genomics and molecular biology and Director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University.  He was awarded this prize for his work in linkage mapping of Mendelian disease in humans using DNA polymorphisms.  This research was a major step on the path to the type of clinically relevant work that PharmGKB does today.

FDA to post black box warning on codeine

The FDA has announced they will add a black box warning to the codeine drug label to contraindicate the use of the drug in children after tonsillectomy and/or adenoidectomy (see link).  Codeine is  a pro-drug that is converted to morphine, a reaction that occurs more efficiently in CYP2D6 ultra-rapid metabolizers (UM)- see the Codeine and Morphine Pathway for details of the drug's metabolism. UM of codeine are at greater risk of adverse events due to higher levels of morphine at standard doses.  One of the adverse events associated with morphine is shallow breathing. The CPIC guideline recommends avoidance of codeine in UM due to potential for toxicity PMID: 22205192.

The FDA observed that deaths have occurred post-operatively in children with obstructive sleep apnea who underwent tonsillectomy and/or adenoidectomy and received codeine for pain relief following the procedure. These children may be at greater risk for breathing difficulties that could be exacerbated by high levels of morphine. The black box warning will recommend avoiding codeine in all children undergoing this procedure rather than testing for CYP2D6 UM.

TPMT allele nomenclature update published

Nomenclature for alleles of the Thiopurine Methyltransferase (TPMT) gene has been updated by the TPMT Nomenclature Committee and has been published online in Pharmacogenetics & Genomics. The committee have addressed issues such as previously existing duplication in star allele names, and has provided dbSNP rsIDs when available.

View the updated TPMT allele nomenclature on the PharmGKB haplotype page.

Read the CPIC thiopurine therapeutic dosing guidelines based on TPMT genotype.

Find out about the TPMT nomenclature committee.

Read the article:
Nomenclature for alleles of the thiopurine methyltransferase gene.

Appell ML, Berg J, Duley J, Evans W, Kennedy MA, Lennard L, Marinaki T, McLeod HL, Relling MV, Schaeffeler E, Schwab M, Weinshilboum R, Yeoh AE, McDonagh EM, Hebert JM, Klein TE, Coulthard SA. Pharmacogenet Genomics. 2013 Feb 12. (Epub ahead of print).

How does methylene blue work in the treatment of methemoglobinemia?

Methylene blue is a drug with many clinical applications, including treatment of infectious diseases such as malaria, a cyanide antidote, a dye for diagnostics, and even has the potential as a therapy for Alzheimer Disease and septic shock. It is indicated for the treatment of drug-induced  methemoglobinemia - an increase in the methemoglobin content of red blood cells (RBCs), caused by oxidation of hemoglobin heme iron atoms by reactive oxygen species such as hydrogen peroxide. Various exogenous agents, including therapeutic drugs, can result in oxidative stress in red blood cells and lead to methemoglobinemia.

Three new pathways have been launched on PharmGKB in order to explain some of the mechanisms and the genes involved in the regulation of oxidative stress in red blood cells (RBCs), including the pharmacodynamics of methylene blue:

1. Pentose Phosphate Pathway (Erythrocyte)
2. Oxidative Stress Regulatory Pathway (Erythrocyte)

3. Methylene Blue Pathway, Pharmacodynamics

Methylene blue itself is an oxidizing agent but is reduced to leukomethylene blue by BLVRB. Leukomethylene blue then reduces methemoglobin to hemoglobin, cycling back to methylene blue. This process requires NADPH from the pentose phosphate pathway and thus is dependent on G6PD. NADPH is also required by many other mechanisms that regulate oxidative stress in RBCs and prevent the formation of methemoglobin.

Pharmacogenetics of methylene blue
Methylene blue is contraindicated in the EU in individuals with a deficiency in BLVRB or G6PD, due to their role in the action of the drug. Cases of adverse events including hemolytic anemia in G6PD deficient individuals treated with methylene blue have been reported - these and the safety of methylene blue are discussed in the methylene blue pathway, PD.

SLCO1B1 Haplotypes updated on PharmGKB

The PharmGKB Haplotype table for SLCO1B1 has just been updated and  now contains information for alleles *1-*36.  The literature includes two different alleles which were both named *16 at the time of publication, and we are using the definition for the first *16 allele to be published.  References are listed at the top of the page, above the table.  We appreciate the help of Dr. Laura Ramsey from St. Jude Children's Research Hospital and of  Dr. Kathy Giacomini and the International Transporter Consortium (Polymorphism subgroup) !  Presumably in the future, the duplicate *16 allele will receive a later *allele designation and can then be added to this table.

Curators' Favorite Papers

Russ Altman’s recent commentary in Clinical Pharmacology & Therapeutics highlights the importance of integrating personal genomic information with traditional health information in order to use it for 'personalized medicine' [PMID: 23241835]. PharmGKB’s PI uses a hypothetical example to illustrate how general population-based data can be combined with individual genomic data to create an updated estimate of drug response. In his commentary, Altman concludes that, "We can use Bayesian reasoning to integrate prior knowledge and new sources of data to estimate key clinical probabilities. We then evaluate these in the context of the anticipated value of each outcome to make the best clinical decisions possible... we can make each individual patient a small experiment that contributes to better estimates of these probabilities—a rapid-learning paradigm. We will thus continuously improve our understanding of how to use these powerful new measurements for precise and accurate clinical decisions."