LITERATURE Watch Implications for transplantation
Version of Record online: 29 AUG 2011
© 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 11, Issue 9, page 1763, September 2011
How to Cite
BROMBERG, J. S. (2011), LITERATURE Watch Implications for transplantation. American Journal of Transplantation, 11: 1763. doi: 10.1111/j.1600-6143.2011.03748.x
- Issue online: 29 AUG 2011
- Version of Record online: 29 AUG 2011
GWAS, Gee Whiz
CITATION Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466: 707–713.
SUMMARY AND ANALYSIS
Genome-wide association studies (GWAS) involve large numbers of patients to identify traits, genes and single-nucleotide polymorphisms (SNPs) that are associated with disease. Weaknesses of GWAS include the identification of genetic markers that associate with only a small percentage of phenotypic markers, association rather than causality, failure to validate genetic markers with DNA sequence, failure to validate array platforms with sequencing, failure to validate training sets with test sets, failure to validate findings in other ethnic populations, failure to validate DNA sequence with RNA and protein expression, failure to validate gene expression with mechanistic causality for phenotypic markers, and failure to validate phenotypic markers with disease expression. In other words, simply showing even a strong association of a genetic marker with a phenotypic marker is only the first step of a rigorous proof of molecular activity causing a specifi c disease. In what is likely to set a new standard in GWAS studies, Teslovich and colleagues reported on a massive meta-analysis for the genetics of blood lipids. This analysis comprised 46 prior GWAS involving more than 100,000 patients of European descent from Europe, the United States and Australia, and also involving 207 investigators from 117 institutions. They assessed variations in blood lipids and correlated them with coronary artery disease. They validated sequences, platforms, training sets, test sets, prior known genes, novel genes, other ethnic populations, RNA and protein expression, and even directly validated potential cellular and molecular mechanisms for three novel genes in studies in human cells and mice. The results demonstrate a total of 95 loci associated with lipid traits, of which 59 loci are novel and 36 previously described in prior, smaller studies. The 95 genes account for only 10% to 12% of the total phenotypic variance of lipid blood levels and only 25% to 30% of total genetic variance, so much still remains to be discovered. This report has identifi ed many new potential targets for study and has laid out the validation studies that must be done to ensure quality and veracity of findings and conclusions.
The discovery of new genes is essentially hypothesis generating, and should stimulate basic and translational studies to elucidate the mechanisms of how the genes and gene products influence phenotype and disease. Even if the gene is responsible for only a small percentage of observed phenotype or disease, basic and translational studies have a likelihood of identifying new targets for drug therapy effective in many patients, regardless of genotype.
If markers, phenotypes, or diseases affect a large percentage of a study population, then small numbers (a few hundred) of patients will yield important results. If events are rare and many variables included in the statistical runs, then thousands of patients must be studied, along with additional levels of validation. These numbers are impossible to achieve in transplantation, and thus affect powering and validation. It may be necessary to use the available cohorts of transplant patients only as small test sets for validating discoveries made in much larger studies.
New Treatment for HCV
CITATION Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465: 96–100.
CITATION Murray CL, Rice CM. An unsuspected drug target. Nature 2010; 465: 42–44.
SUMMARY AND ANALYSIS
The failure of chemotherapy to control or cure hepatitis C virus (HCV) infection remains a major challenge. Many studies have zeroed in on well-characterized viral enzymes, in particular the NS3 protease and the RNA-dependent RNA polymerase NS5B. The rapid development of drug resistance due to the high mutation rate of HCV and quasi-species, the need for chronic administration of expensive multidrug cocktails along with costly monitoring and the numerous daunting adverse drug side effects all contribute to the lack of broad, sustained success in the control or cure of HCV infection. The report of an extremely potent compound, identified through a rational drug screen, that inhibits a novel target of the virus comes as welcome news. Gao and colleagues searched for compounds that prevented HCV replicon activity and that did not target the traditional NS3 and NS5B enzymes. They discovered a lead compound, optimized its inhibitory activity through dimerization and developed the small molecule inhibitor BMS-790052. It inhibited both HCV replicons and infectious virus in culture at picomolar concentrations, making it the most potent anti-HCV compound ever discovered. It inhibited a broad range of viral genotypes, including 1a and 1b, which are difficult to treat. A major surprise is that it seemed to inhibit NS5A, a dimeric protein of unknown function that has no known enzymatic activities, but may be involved in viral RNA processing and transport. A phase 1 study showed that it was well tolerated, that a single dose could decrease viral titers by more than 3 orders of magnitude within 24 hours and that the effect was sustained. Much more information is needed to confirm potency, safety, reliability and the other end points that are key to the success of a new antiviral. Nonetheless, the success of the viral screening strategy, the discovery of a new compound, the identifi cation of a new target and dramatic clinical effects have created a great deal of optimism.