Transporters in erythrocytes

Here's something to think about.

The erythrocyte is unique among cells because it lacks a nucleus. At some point in its development, it jetisons the nucleus and and other organelles including mitochondria and lives out the rest of its lifespan circulating as a membrane enclosed sac of haemoglobin and various enzymes.

It is an interesting situation because the erythrocyte, despite having no nucleus survives for an estimated 120 days fulfilling some of most important functions in the body. In the course of its work, as it circulates around the body, it is exposed to a wide variety of endogenous and exogenous chemicals.

The question is 'How does the erythrocyte membrane deal with these chemicals?'. More specifically, what transporters are expressed on the erythrocyte membranes, and what role(s) do they play in health, disease and therapeutics?

Genes vs environment

Not an easy topic, but here is an interesting recent guest column by Sandra Aamodt and Sam Wang, in the New York Times discussing the complex interactions between genes and the environment. Although they discuss this from a largely neuropsychiatric perspective the lessons are widely applicable to therapeutics. We have far too many champions of the genetic approach who push ideas that genetic variability underlie everything that determines drug efficacy and toxicity. The underfunded environmental approaches go largely ignored because they use rather unexciting mundane technology, and produce results that tend not to generate patents.

IMO the gene only approach is clearly not valid. The challenge is how to tease out the various gene-environment interactions and to define them clearly so that they can eventually help us optimize our therapeutic regiments.

Boyanese (Baweanese) in Singapore

Here's an interesting aside following from our previous discussions on ear wax and ethnicities.

A casual discussion with a Boyanese lady revealed that she had wet ear wax. Just an interesting association despite n= 1.

The other interesting nugget of information was that apparently the Boyanese do not classify themselves as Malays on their NRIC (National Registration Identify Card). They are either listed as 'Boyanese' or 'Others'. This is of interest because when we are collecting ethnicity/race information for purposes of medical case studies etc, any 'Malay' data may be under-represented.

The Boyanese originate from a small island off the north coast of East Java. It is of interest to us because many Singaporean Malays trace their heritage back to the original Boyanese settlers. Ethnically they are austronesians like the other Malays. If hospital records use NRIC classifications for ethnicity, and if the Boyanese do not classify themselves on the NRIC as Malays, it may be expected the the Malay data from hospital records will not be very representative.

Aldehyde Dehydrogenase polymorphism

We had previously discussed the alcohol dehydrogenase genetic polymorphism, and had pointed out that among the Han Chinese, there is a high frequency of a genetic variant of alcohol dehydrogenase that allowed a faster conversion of ethanol to acetaldehyde. Acetaldehyde is the chemical that is thought to be responsible for not only the unpleasant effects of alcohol consumption (headaches, flushing etc) but is also thought to be the cause of tissue damage.

There is another enzyme that is responsible for the conversion of aldehyde dehydrogenase to acetic acid. This is called aldehyde dehydrogenase (ALDH). ALDH itself is subject to a genetic polymorphism where the genetic variant ALDH2*2 produces a slower enzyme. Among Han Chinese, the frequency of the ALDH2*2 variant is about 30%.

Among Han Chinese therefore, there is a significant number of individuals who will convert alcohol very quickly to acetaldehyde, and then have a slower removal of acetaldehyde. These individuals build up acetaldehyde concentrations in the blood very rapidly after consumption of alcohol. These individuals are the ones we recognize at drinking parties, who turn red very quickly after low consumption of alcohol.

A recent editorial in Human Genomics 3(2) 2009 highlights the risk this polymorphism poses with respect to the development of esophageal cancers.

So, who are the Thais anyway?

I was thinking about this when I was in Khon Kaen.

It is not an easy question to resolve, as despite the Thais now being numerically so much larger than the Khmers, the Khmers were so much more dominant historically because of the Angkorean civilization. The earliest recognition of a Thai entity only surfaced when the Angkor civilization started to decline.

In early prehistory the region was populated by a Mon language speaking people. Who were they? Most likely people of a Sino-Tibetan stock. On top of this was a distinct amount of 'indianization' as evidenced by civilizations like the Dvararati (pre-angkorean). What 'indianization' really means is not clear, and it is not certain if this was a cultural thing or there was actually an influx of Indian genes as had happened in Cambodia (through the Kambujas from India). In any case, during the Angkor period, the region was 'Khmer-ized', so I am sure there was a substantial of genetic admixture. (See 'So, who are the Khmers anyway?')

As the Khmer civilization ebbed, the Thai people emerged as a distinct entity through the Lavo and Sukhothai kingdoms. A large part of this may have resulted from an influx of Southern Chinese people from Yunnan, fleeing the Mongol invasions.

Thailand now does not recognize differnt ethnicities within the country and everyone is regarded as Thai, although unofficially different ethnic groups are apparent. In a very broad sense, indigenous Thais are generally a sino-tibetan people with a variable amount of Indian admixture. There may be some degree of contribution from the austronesian gene pool, especially in Southern Thailand. On top of these are more recent contributions from Southern China.

So how do we regard pharmacogenetic data from Thailand? I think it becomes important for us to evaluate the source of the data. If it is generated in large urban centres, the contribution of Chinese genes is quite substantial. Indigenous Thai data is best seen in studies conducted in rural communities. In Southern Thailand, one must expect a significant amount of similarity to 'Malay' genetics. In the southern provinces, there still remain pockets of negrito peoples.

This is so far my limited understanding of the situation. I may be wrong. But this is how the current understanding appear to leading us. Perhaps there may be others with a better understanding of Thai ethnicity who can share their experiences and understanding with us?

Hardy & Weinberg

The Hardy Weinberg Equilibrium (HWE) is such a fundamental 'law' in Mendellian genetics. Wikipedia has done a fairly good job summarizing so I am just going to shamelessly copy-paste from there. :) Essentially the principle is based on the random pairing of genetic material during mating. In a system where there is true randomness, at 'steady state' the genotypic frequencies are in 'equilibrium' and will remain relatively stable year after year. In pharmacogenetics, when we are looking at population frequencies of genetic variants, it is always useful to establish if the observed frequencies are consistent with the HWE.

From Wikipedia:
In the simplest case of a single locus with two alleles: the dominant allele is denoted A and the recessive a and their frequencies are denoted by p and q; freq(A) = p; freq(a) = q; p + q = 1. If the population is in equilibrium, then we will have freq(AA) = p² for the AA homozygotes in the population, freq(aa) = q² for the aa homozygotes, and freq(Aa) = 2pq for the heterozygotes.


The HWE is named after G. H. Hardy and Wilhelm Weinberg.

From Wikipedia:

Mendelian genetics were rediscovered in 1900. However, it remained somewhat controversial for several years as it was not then known how it could cause continuous characteristics. Udny Yule (1902) argued against Mendelism because he thought that dominant alleles would increase in the population. The American William E. Castle (1903) showed that without selection, the genotype frequencies would remain stable. Karl Pearson (1903) found one equilibrium position with values of p = q = 0.5. Reginald Punnett, unable to counter Yule's point, introduced the problem to G. H. Hardy, a British mathematician, with whom he played cricket. Hardy was a pure mathematician and held applied mathematics in some contempt; his view of biologists' use of mathematics comes across in his 1908 paper where he describes this as "very simple".

To the Editor of Science: I am reluctant to intrude in a discussion concerning matters of which I have no expert knowledge, and I should have expected the very simple point which I wish to make to have been familiar to biologists. However, some remarks of Mr. Udny Yule, to which Mr. R. C. Punnett has called my attention, suggest that it may still be worth making...

Suppose that Aa is a pair of Mendelian characters, A being dominant, and that in any given generation the number of pure dominants (AA), heterozygotes (Aa), and pure recessives (aa) are as p:2q:r. Finally, suppose that the numbers are fairly large, so that mating may be regarded as random, that the sexes are evenly distributed among the three varieties, and that all are equally fertile. A little mathematics of the multiplication-table type is enough to show that in the next generation the numbers will be as (p+q)²:2(p+q)(q+r):(q+r)², or as p₁:2q₁:r₁, say.

The interesting question is — in what circumstances will this distribution be the same as that in the generation before? It is easy to see that the condition for this is q² = pr. And since q₁² = p₁r₁, whatever the values of p, q, and r may be, the distribution will in any case continue unchanged after the second generation

The principle was thus known as Hardy's law in the English-speaking world until Curt Stern (1943) pointed out that it had first been formulated independently in 1908 by the German physician Wilhelm Weinberg (see Crow 1999). Others have tried to associate Castle's name with the Law because of his work in 1903, but it is only rarely seen as the Hardy–Weinberg–Castle Law.

The Great Ear Wax Poll outcome

We don't know the ethnicity of the pollsters (n=47), nor their country of origin, but with the eye of faith, the outcome shows a nice histogram that is consistent with the Hardy-Weinberg Equilibrium (A=0.73, a=0.27). This is assuming the the three categories represents the three genotypes. This assumption may not be true. Nevertheless the outcome is interesting.