Predictive pharmacogenetics

Many people agonize about the predictivity of the science of pharmacogenetics. Somehow there is an expectation that pharmacogenetics should somehow lead to position where we can stop thinking.

Sounds a bit harsh but true.

Pharmacogenetics began as a science to understand the genetic basis for outlier behaviour. In much earlier experiences, outliers were characterized principally by phenotypic behaviour. As it is now, phenotypes tended to be classified in binary fashion - rapid/slow, fast/slow, extensive/poor. Such binary depictions of reality can only be predictive when the reaction or process in point is singular, critical or both. In some situations drug response can be described binarily as 'at risk for toxicity', or 'not at risk', e.g. G6PD deficiencies or HLA B*1502 for carbamazepine-SJS. For the most part however, pharmacogenetics data only helped explain genetic bases for limited aspects of drug response.

FDA classification: +, for information only; ++, recommended; +++, required

Gervasini et al, Eur J Clin Pharmacol (2010) 66:755–774

In highly controlled experiments, it can be easily shown that genetic variants can result in either loss or gain in function in specific processes related to drug response, e.g. drug metabolism and clearances. However since drug response/metabolism/

pharmacokinetics is seldom the result of a singular process, genotyping a genetic variant almost never provides a clear prediction of what the final drug response would be like.

Unfortunately the market place has misled many to believe that we can somehow construct a genetic testing panel that will predict with some degree of finality, what the patient's drug response and hence his drug dosage requirements will be. Hooray.... and we can therefore stop thinking! This line of thinking is clearly fallacious. The concept of 'personalized medicine' has been hijacked (biotech commercialism?) to refer to a one step genotyping approach to therapeutics when correctly it should refer to the ability to look at the patient in totality, i.e. the entire person - not just from the perspective of his constitutive make-up, but the totality of contributions of his altered physiology and environmental effects.

The more correct and rational approach is that of 'optimization', but the term sadly is far more mundane and less commercially sexy compared to 'personalized medicine'.

Durian lovers vs durian haters

Here's a slight frivolous post inspired by tonight's after dinner conversation.

The durian (Durio zibethinus), reckoned by many as the king of fruits in Asia. Others have less flattering descriptions. It's a fruit that you either love or hate.

Some descriptions of its taste (shamelessly plagiarized from Wikipedia):
Writing in 1856, the British naturalist Alfred Russel Wallace provides a much-quoted description of the flavour of the durian:
“The five cells are silky-white within, and are filled with a mass of firm, cream-coloured pulp, containing about three seeds each. This pulp is the edible part, and its consistence and flavour are indescribable. A rich custard highly flavoured with almonds gives the best general idea of it, but there are occasional wafts of flavour that call to mind cream-cheese, onion-sauce, sherry-wine, and other incongruous dishes. Then there is a rich glutinous smoothness in the pulp which nothing else possesses, but which adds to its delicacy. It is neither acid nor sweet nor juicy; yet it wants neither of these qualities, for it is in itself perfect. It produces no nausea or other bad effect, and the more you eat of it the less you feel inclined to stop. In fact, to eat Durians is a new sensation worth a voyage to the East to experience. ... as producing a food of the most exquisite flavour it is unsurpassed.”

While Wallace cautions that "the smell of the ripe fruit is certainly at first disagreeable", later descriptions by westerners are more graphic. British novelist Anthony Burgess writes that eating durian is "like eating sweet raspberry blancmange in the lavatory." Chef Andrew Zimmern compares the taste to "completely rotten, mushy onions." Anthony Bourdain, while a lover of durian, relates his encounter with the fruit as thus: "Its taste can only be described as...indescribable, something you will either love or despise. ...Your breath will smell as if you'd been French-kissing your dead grandmother." Travel and food writer Richard Sterling says:

“... its odor is best described as pig-shit, turpentine and onions, garnished with a gym sock. It can be smelled from yards away. Despite its great local popularity, the raw fruit is forbidden from some establishments such as hotels, subways and airports, including public transportation in Southeast Asia.

Other comparisons have been made with the civet, sewage, stale vomit, skunk spray and used surgical swabs.

There are clear indications that this is a pharmacogenetic differentiation of durian lovers from haters, though I do not know of any study to this effect.

Go ahead and take the Great Durian Poll!!

Genetics of taste?

Bimodal distribution of PTC sensitivity

Here's a a bit of an update on Arthur Fox's PTC taste blindness story from. Not a whole lot of people interested in this other than the food industry and nutritional scientists.

There is a rather dated review of this here (2001) and here (1995). Apparently the frequency of non-tasters among Caucasians is about 26-30%, but only 6-10% among Asians (whatever that means for the Americans!). Apparently tasters have a lower acceptance for bitter foodstuff such as broccoli/cruciferous vegetables, naringin, green tea and tofu. But this does not seem to be borne out in real life given the high acceptance of green tea and tofu in Asia despite a much lower incidence of non-tasters.

One of these ethnic confounders.

Carbamazepine - Stevens-Johnson Syndrome

In 2004, a Taiwanese group (Chung et al, Nature 2004, 428:486) reported a very strong association between the HLA-B*1502 allele with the development of Stevens-Johnson Syndrome with the anti-epileptic drug carbamazepine.

This is actually a very interesting story about an drug SAE (serious adverse event) associated with a specific HLA genotype. Not only genetics, but also an intriguing tale about ethnicity and populations.

So far all the clinical data verify the association in Han Chinese (Taiwan, Hong Kong) and Thai. No associations have been found for Europeans....and here is what is also interesting...not for Japanese as well. Ferrel and McLeod (2008) have reviewed the data, and there have also been a number of more recent studies reporting on the HLA-B*1502 allele frequencies from different populations.

A Table of these frequencies from Ferrel and McLeod is reproduced here.
There are a couple of more recent data not only showing the same patterns but also showing how the Northern Chinese group pulls apart from the Southern Chinese. Han Chinese from Shaanxi, Koreans and Japanese have a Caucasian type frequency while Southern Chinese in Guangdong cluster with the rest of South East Asia (Philippines, Java). The Indian subcontinent occupies an intermediate position, and depending on the population sampled, with frequencies ranging between Caucasian frequencies to those similar to South East Asians and Southern Chinese. The association between HLA-B*1502 and carbamazepine SJS appears not in doubt, but apparently only for Southern Chinese (Taiwan, Hong Kong, most of Singapore) and people of South East Asian ancestry. It does not seem to apply for Caucasians, and remains doubtful for Northern Chinese, and people of a more northern ancestry such as the Japanese (and possibly the Koreans). There remains a big question mark for people from the Indian subcontinent.

The FDA did us a major injustice when in their haste they recommended that genotyping for HLA-B*1502 be done prior to dosing, for people of an "Asian ancestry". We have no idea what this means. For Singapore, it is probably reasonable for Chinese and Malays (although it may not apply to the more northern Chinese among us), but we are totally in the dark with regards to "Indians" and "Eurasians".