Saturday, March 26, 2011

Personalized medicine ; Genetic variants associated with HCV treatment response

Personalized medicine ; Genetic variants associated with HCV treatment response

What Is Personalized Medicine?

Defined By Duke;
Personalized medicine is a concept in which a patient’s genetic information is used to identify the best courses of treatment, as well as to identify diseases the patient is more predisposed toward and to work toward preventing those diseases...Read the basics on personalized medicine

Today this blog has compiled a few links from Duke University, EASL, New England Journal Of Medicine , the journal Nature and including other sources related to the science of personalized medicine, in particular the genetic research pertaining to HCV therapy. Research has determined that variations in the IL28B gene have been linked to better treatment response among people with chronic hepatitis C virus. In 2009 we began hearing about a genetic test which could predict such a response when a study from Duke was published in the peer-reviewed journal Nature and followed in the media.

Excerpted from the New York Times 2009 article;

"A Duke University team has now uncovered the principal reason for the disparity between the races. It lies not in differing compliance to the treatment or access to health care, as some have assumed, but in genetics.

Using a genetic test called a genome-wide association study, the Duke team, led by David B. Goldstein and John McHutchison, found that the coding at a single site on the DNA, out of the three billion sites in the human genome, made all the difference in people’s response to the treatment.

The site is close to the gene for a special kind of interferon, known as interferon-lambda-3, and may help control the gene’s activity. Some people have the DNA unit T at this site, and others have C. Since a person inherits two copies of the genome, one from each parent, individuals may have T’s on both copies, C’s on both, or one T and one C.

People with the CC version, or allele, respond much better to the standard hepatitis treatment than do those with the TT allele. The C versions are more common in Europeans than in Africans, and this explains half of the difference in the response between the two races, the Duke team said in a report released Sunday on the Web site of the journal Nature.
The C versions are even more common among East Asians, about 75 percent of whom respond well to the standard treatment, compared with 55 percent of European-Americans and 25 percent of African-Americans.

People with the CC versions may produce more interferons, which are virus-fighting substances produced by cells, than those with TT, though the exact mechanism has yet to be worked out.
Dr. Goldstein, a population geneticist, said the different frequencies of the T and C versions were the result of natural selection, which is particularly effective in the case of disease resistance.
“We have clearly had very strong selection in the human population for resistance to different infectious agents, which have been of different importance in different parts of the world,” he said.

People who have a lower chance of benefiting from the grueling treatment because they have the TT allele might decide to wait until better drugs become available, especially if their liver damage is not severe. On the other hand, African-Americans with the CC allele might be more confident in accepting the treatment, Dr. McHutchison said." Continue reading...


What Are Alleles?

Alleles are corresponding pairs of genes located at specific positions in the chromosomes. Together, alleles determine the genotype of their host organism.
For example, the alleles for eye color are found on chromosomes 15 and 19, and depending on which alleles someone has, he or she may have blue, brown, green, gray, or hazel eyes, and sometimes a mixture of these traits is present.

What Are "C" and "T" Alleles ?

As mentioned above a person inherits two copies of each gene; one from each parent to make up each allele. The IL28B rs12979860 SNP has two alleles or variations which are regonized as "C" and "T".
Then What Is C/C or "CC" ?
In Hepatitis C patients who have the C/C pattern simply means that they have two copies of the "C" allele.
Then What Is T/T or "TT" ?
The same is true in Hepatitis C Patients who have the T/T pattern or two "T" alleles .
What Does This Mean To The Hepatitis C Patient?
Hepatitis C Patients With The C/C pattern or two "C" alleles have the best response to HCV therapy.
As for the T/T pattern or two "T" alleles they have the least response to therapy.
What If A Person Has The C/T pattern?
The C/T pattern would mean the person has one copy of each allele. These people would fall somewhere in between.
Summarize All Of This Please
TT - Poorest response to Hepatitis C treatment
CC - Best response to Hepatitis C treatment.
CT- Somewhere in between TT and CC alleles.
For an easy to understand article see the 2010 issue of HCV Advocates Newsletter;
The Gene that Predicts— By Alan Franciscus, Editor-in-Chief.

Poster Sessions To Be Presented At This Months EASL

The data presented at the EASL should be considered preliminary until it has been reviewed and published in a peer-reviewed publication.

EASL Site Links;
Upcoming Oral Presentations
Abstracts/Poster Sessions

P3.14: Category 14: IL28b Polymorphism

Category 14: IL28b Polymorphism:


Nature Reviews Genetics

12, 266-275 (April 2011)
Focus on: Stem cells

Investigating monogenic and complex diseases with pluripotent stem cells

Hao Zhu1,2, M. William Lensch2, Patrick Cahan2 & George Q. Daley2

Hepatogenesis and liver disease.

To better understand conditions that affect the liver, Rashid et al. established a protocol to differentiate human iPSCs into hepatocytes that recapitulate the adult phenotypes of three distinct liver diseases in vitro15. These iPSC-derived hepatocytes shared marker-expression, morphological and physiological features of normal human hepatocytes. The iPSC-derived hepatocytes made from cells taken from patients with α1-antitrypsin deficiency showed the characteristic accumulation of α1-antitrypsin polymers. Of importance, the authors noted little variability in polymer accumulation among multiple iPSC lines derived from the same patient but greater variability among iPSC lines derived from different patients, indicating reproducibility of the phenotype within individual genotypes. In addition, proteosome inhibitor treatment of the cells exacerbated the phenotype, possibly permitting the detection of small but relevant functional differences in genotype; similarly, the assay might detect the impact of environmental modifiers and potentially be used in toxicity studies for the analysis of primary and/or secondary metabolites. This report opens the door to studying more subtle genetic disorders of the liver in vitro. More generally, testing drug–genotype interactions in specific cell types will expedite the efforts of personalized medicine and pharmacogenomics, especially for common variants....Continue reading....

Read Full Text @ Nature

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Review Article Genomic Medicine

W. Gregory Feero, M.D., Ph.D., Editor, Alan E. Guttmacher, M.D., Editor Genomics and Drug Response Liewei Wang, M.D., Ph.D., Howard L. McLeod, Pharm.D., and Richard M. Weinshilboum, M.D. N Engl J Med 2011; 364:1144-1153

March 24, 2011

Another pharmacogenomic example involving agents used to treat infectious diseases concerns the treatment of chronic infection with hepatitis C virus (HCV), which develops in approximately 80% of patients who are infected with the virus and is a major cause of liver failure.53,54 Successful treatment of chronic HCV infection involves a sustained virologic response, which is defined by an undetectable level of HCV RNA in plasma. Unfortunately, only 40 to 50% of patients who are infected with HCV genotype 1 have a sustained virologic response when receiving the current standard of care for the treatment of chronic HCV infection — injections of pegylated interferon alfa together with oral ribavirin for 48 weeks.53,54 The ability to identify patients with a differential response to pegylated interferon alfa is important in the current era of new anti-HCV drugs because pegylated interferon alfa remains the backbone of therapy, to which many of these new agents are added. Recently, in three independent genomewide association studies55-57 involving patients with chronic HCV infection who were treated with pegylated interferon alfa and ribavirin, there was an association between a variant in IL28B, the gene encoding interleukin-28B, and the drug response. In one of these studies, peripheral-blood mononuclear cells from patients carrying the variant allele that was associated with a poor response had comparatively low levels of IL28B expression.56 IL28B encodes a protein that is thought to be involved in suppressing the replication of a number of viruses, including HCV.55-58 This example shows how pharmacogenomic genomewide association studies not only have identified biomarkers of response to pegylated interferon alfa but also have provided insights that might be used to determine therapeutic approaches to this chronic infection and to select a drug target for therapeutic development...Continue Reading.....

(Read Full Text @ NEJM; New England Journal Of Medicine)


IL28B Gene Predicts Treatment Outcome for Liver Transplantation Patients
ScienceDaily (Mar. 2, 2011) —
German researchers have found a significant association of IL28B genotypes to interferon-based antiviral treatment outcome, and to graft inflammation caused by hepatitis C virus (HCV). The study determined that the presence of G-allele serves as a marker for severe HCV-induced graft inflammation, as well as a predictor for unsuccessful treatment.....Continue Reading...


PDF IL28B & HCV: A step closer to personalized medicine?
File Format: PDF/Adobe Acrobat -
Jan 28, 2011 ...
Under The Presentation Archive See; Journal Club: Liver 1 - "IL28B & Hepatitis C: A Step Closer to Personalized Medicine?" After clicking on the PDF the file will download to your computer.



Genome Medicine: past, present and future

Charles Auffray1*†, Timothy Caulfield2†, Muin J Khoury3†, James R Lupski4,5†, Matthias Schwab6,7† and Timothy Veenstra8

31 January 2011
The field of genomic medicine continues to expand, driven by the efforts of numerous researchers around the world. To celebrate Genome Medicine's 2nd anniversary, we asked our Section Editors what they felt were the most exciting breakthroughs in research in the past 2 years and what the future of genomic medicine might hold. Transformational effect of systems medicineSince we discussed systems medicine as the future of medical genomics and healthcare in the inaugural issue of Genome Medicine [1] , the field has witnessed transformational changes that have brought the prospect and promises of personalized medicine closer to reality. The exponential increase in DNA sequencing capabilities, together with the rapidly declining associated costs, has made whole-genome sequencing accessible to small laboratories, and will soon transform it into a low cost analytical assay. These advances have enabled the emergence of medical systems genetics studies, an approach in which the genetic determinants of diseases are investigated through sequencing of the complete genome of family relatives. For example, sequencing and analysis of the genomes of two siblings and their parents made possible the direct measurement of the inter-generational mutation rate and identified genes potentially associated with two Mendelian disorders [2] ; the gene causing one of these disorders was precisely identified through further exome sequencing in additional diseased patients [3] . Another telling example of both the power and current limitations of the next-generation sequencing approaches is their application to the characterization of the genome, epigenome and transcriptome of monozygotic twins discordant for multiple sclerosis, which failed to uncover significant differences associated with the disease [4] . With several thousand genomes now being completed, and tens of thousands anticipated in the coming year, the limitation is already to a large extent, and will increasingly be, on the side of data analysis, as the collection, storage and analysis of the large datasets generated requires the combined expertise of a wide variety of scientists, engineers and physicians [5] . Fortunately, the software, databases and computing power required for these community efforts are now becoming available through computer grids and cloud computing infrastructures, offering an affordable alternative for genome and translational bioinformatics [6,7] . Combined together, genome sequencing and cloud computing will contribute to bridging the gap between systems biology and medicine by opening the way to the precise and low cost assays that are necessary for systems medicine to become a practical alternative to traditional reactive medicine [8] ... Continue Reading...

(Read Full Text @ Genome Medicine)

Related 2010; Musings on genome medicine: Hepatitis
C David G Nathan, Stuart H Orkin Genome Medicine 2010, 2:4 (27 January 2010)
Abstract Full text PDF PubMed Editor’s summary
Recent advances in our understanding of the genetics of response to interferon treatment are intriguing, but further research is necessary before we can achieve a true cure for hepatitis C.

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