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Wednesday, May 28, 2008

In Defense of Pharmacogenetics

ResearchBlogging.org

Author: Nils Reinton
Furst Medical Laboratory, Søren Bullsv. 25, N-1051 Oslo, Norway (nreinton_at_furst.no)

Pharmacogenetics is the analysis of specific genetic markers informing you of how efficiently you metabolize a given drug. When it comes to metabolism of drugs used for treating psychiatric disorders (ranging from mild depression to severe psychosis), three genes are commonly analyzed: Cyp2C9, Cyp2C19 and Cyp2D6. Of course, other things than genetics also influence how you respond to a drug, like compliance, diet and smoking, but individual genetic variation have profound stand-alone effects. If your genetic test shows the presence of clinically relevant genetic variants you will be grouped as a Poor Metabolizer (higher risk for unwanted side effects) or Ultrarapid Metabolizer (not responding to medication or in need of very high dosage). For a patient experiencing adverse events or no response at all when taking his medicine, pharmacogenetics can be a tremendous help in choosing more fitting medications (change dosage or use another (sub)class of drugs). Pharmacogenetics is thus, a vital part of personalized medicine.

Recently a commentary - "A Case Study of Personalized Medicine" by
Katsanis et al., was published in Science (subscription may be required), where the use of pharmacogenetics before choosing upon medication was discouraged. The reason for this was the finding that doctors failed to follow up on recommendations based on test-results. I will try to argue against such a negative approach towards pharmacogenetics and attempt to show that pharmacogenetis is in fact a valuable tool, especially for patients on psychoactive drugs who experience adverse events or lack of effect.

Claim 1: Doctors fail to follow medication recommendations based on pharmacogenetic lab-results.


Counter argument: Physicians either not understanding the test-results or ignoring lab results (due to personal conviction of some sort, be it based on clinical experience or not) reflects a general problem not restricted to pharmacogenetics. Health professionals lack of understanding is especially common for genetic tests. One could argue then, that tests that are too difficult for doctors to interpret should not be made available. But, one could easily counter argue that such an approach would be a major obstacle to medical progress. New tests will always need a time-window of learning and enlightenment. To narrow this window, the following message needs to driven home:
A patient that has to try many different drugs to achieve the desired effect without adverse reactions, is mistreated in a costly manner. Pharmacogenetics constitutes a once in a life-time test allowing a targeted approach straight towards the medication most likely to be suitable. When recommendations based on lab-results are implemented in the treatment regime, pharmacogenetic testing is cost effective and in the best interest of the patient.
Claim 2: Physicians seem to be unable to pick the right patients, and pharmacogenetic testing becomes an inefficient (as well as over hyped and expensive) general screening method, also lacking subsequent changes in medication-therapy. That the frequency of mutant alleles in the normal population does not differ from that in a given patient population, supports this notion.

Counter argument: The overall frequency in a population is irrelevant to the patient, as finding his individual response to the drug is what matters. This counter argument however, is an argument favoring screening in any given field of medicine and one may still claim that the overall cost-effectiveness is insufficient. But, in our laboratory, we do not normally get requests for pharmacogenetic testing prior to medication. Physicians using our service send samples from patients already on medication. They have come to their doctor with either adverse events or a lack of clinical effect. In our opinion these are the right patients to test. We have no reason to believe that the physicians resist changing to other medications based on our lab results when the case presented to them is as defined as this. Thus, pharmacogenetics in our hands, is targeted diagnostics rather than general screening.
In addition, we have done a small study (a panel of 12 SNP's and 2D6 copynumber variation on 595 patients) to show that the allele frequency in our patient population is either at the high end of normal variation, or above that seen in a normal population (see figure, European country codes in parentheses):


Similar results (see figure) are obtained when looking at frequency of poor and ultra rapid metabolizers (PM and UM respectively).


Consequently, it seems that physicians are able to pick the right patients. And, our results support the notion that pharmacogenetic testing constitutes targeted diagnostics in the best interest of the patient.

Reinton, N.In Defense of Pharmacogenetics. Sciphu.com

Tuesday, May 27, 2008

The Swedish Chlamydia Mystery

ResearchBlogging.org

Authors: Nils Reinton and Amir Moghaddam
Furst Medical Laboratory, Søren Bullsv. 25, N-1051 Oslo, Norway (nreinton_at_furst.no)

In 2006, Swedish researchers noticed a peculiar trend in the number of positive Chlamydia trachomatis cases. The number of infected patients was down by as much as 25 %. This was unexpected since there had been no public health (or preventive medical) actions to explain such a drastic decrease. Also, the numbers tested for C.trachomatis was similar to previous years. In addition, this trend had not been observed anywhere else. Something strange was happening to sexually active individuals in Sweden in particular.

The reason they found, was not due to calculation error or changes in sexual habits, but in molecular diagnostics, or more precisely, the genetic flexibility of
C.trachomatis (1). A genetic change had appeared creating a novel strain that was given the name "nvC.trachomatis.". This strain had a deletion in its "cryptic plasmid". The deletion was situated in the middle of the target sequence used by diagnostic kits from Abbott and Roche. Consequently, labs using kits from these suppliers (almost everyone in Sweden were using Roche) would misdiagnose any patient infected with the variant as negative for C.trachomatis infection. As a consequence of a diagnostics driven selection pressure, nvC.trachomatis may have reached almost 40 % of total C.trachomatis infections in Sweden (2). Numbers as high as 78 % were reported in some Swedish counties (3). Rapidly then, new tests were introduced to detect the strain and subsequent changes of laboratory routines in Sweden restored normal C.trachomatis detection specificities. Thus, the problem was fixed and everyone thought the mystery was solved.

Not so it seems. The real mystery started when neighboring countries started looking for the variant. Since there is extensive traveling and exchange of labor between the Nordic countries it would seem only natural that the variant C.trachomatis should spread rapidly to other countries as well. Curiously, that did not happen. By now, there have been studies in Norway (4), Denmark (5), England and Wales (6), Ireland (7) and the Netherlands (8). The only other countries nvC.trachomatis was detected was Norway where two out of 47 positives had the variant (one of these was a Swedish citizen) and Denmark which had only two cases out of a total of 383 positives. The conclusion from S Hoffmann and JS Jensen (reference 5) summed it up nicely:
"Sexually transmitted infections are unlikely to respect national borders, especially in an extended period of time. It was therefore an unexpected finding that only one case of the new CT variant was detected among 3,770 specimens tested during a five-month period. The samples were submitted from the whole of Denmark, although the majority came from the Copenhagen area. Considering the intense daily traffic between the Copenhagen area in Denmark and southern parts of Sweden, it is surprising that the spread occurred so late."
The spread is still limited. So far (April 2008) other labs in Norway have failed to find any cases at all, while our laboratory (in Oslo Norway, doing more than 20 000 C.trachomatis analyses a year) only rarely have cases of nvC.trachomatis infection. Consequently, by large the nvC.trachomatis strain remains Sweden-specific. A bug that is specific for only one given nationality is surely a novelty in epidemiology.

Finding the reason seems be far off at the moment. Because: is it likely that Swedes have strong sexual preferences towards other Swedes only ? Or are there biological differences that makes Swedes more prone to nv
C.trachomatis infection ? Sexual behavior and biological signature-attributes either in the infectious agent or in the host, are usually the starting points for STD epidemiology. But in this case either scenario is unlikely. So far then, the mystery remains unsolved.

The lesson learned in diagnostics however, was probably useful for future development of diagnostic tests as pointed out by Björn Hermann (reference
3):
"What can we learn from the emergence of this new variant of chlamydia? This thrilling story provides several lessons. Firstly, how to design a diagnostic test. The new variant is a striking example of diagnostics driven evolution that must be considered when new methods are designed. Since routine diagnostics for chlamydia uses high volume testing based on nucleic acid detection, it is important that the targets used are not only conserved genetic elements but also essential for the organism."
Also, comfort can be taken in knowing that the variant C.trachomatis has lost its evolutionary advantage since due to these events, diagnostics manufacturers have changed their kits to be able to detect all known variants of C.trachomatis. And, in addition, one can hope that through this curious epidemiology event, awareness of STDs have been raised further.

Constant awareness is surely needed given the continuous rise in positive
C.trachomatis cases (regardless of variant strains). Unfortunately, a growing number of C.trachomatis-cases raises the probability of other new strains emerging through natural selection. This time it was easy to adapt to the new situation by changing the diagnostic method. The next time a variant bug appears it may not be this easy to find a fix. Treating the bug and stopping its spread (to achieve eradication) is what we should aim for. This story is just another one of the many wake-up calls given to us in the fight against disease-causing microorganisms over the recent years.

Reinton, N., Moghaddam, A.The Swedish Chlamydia Mystery. Sciphu.com