The Han Chinese - fiction or biological reality?

The Chinese people have been called various names. Once we were called Orientals; the word 'orient' referring to the East. The original reference to Orientals by the west was with respect to people from the middle east or asia minor- regions East of Europe. In time, the definition shifted eastwards and became more associated with East Asia. Clearly the term has no meaning today and should be completely dropped from the scientific literature. Another term, 'Asians' was sometimes used, although in the United Kingdom, this has come to refer to people from the Indian subcontinent. The term East Asians attempts to shift the definition towards people from China, Korea and Japan. For the most part, Chinese were just referred to as Chinese.

More recently however, another term 'Han Chinese' has emerged. The implication appears to be that the concept of Chinese was inadequate and that somehow a 'Han' preface was needed to distinguish Han Chinese from non-Han Chinese. I suspect this has arisen as a result of more scientific work from China, where it was necessary to distinguish the main Han ethnic group from the other 56 ethnic groups which were not 'Han'. The following chart shows the increasing use of the term 'Han Chinese' in the literature beginning from about 1980 and rising steeply over the last 10 years.

In Singapore we don't really care to be Han Chinese, other than using the term to be consistent with 1 billion other people who want to use the term. For us, we are just plain and simple Chinese.

The term Han Chinese actually takes reference to a wish to be associated with the legendary 1000 year Han dynasty which ended in 220CE. I think this is more important to the mainland Chinese, more of the northern sorts. Interestingly for many of us more southern type Chinese, of the Min-nan dialects, the term 'Tang people' '唐人' is more frequently used. This is in reference to another wonderful period of Chinese history called the Tang dynasty (618-904).

So there isn't a whole lot of consistency with respect to how Chinese people want to refer to themselves. Tracing an ancestry back to a dynastic period is not an ethnically reasonable proposition since there can be no assumption that people from that dynasty were necessarily ethnically homogeneous.

It is somewhat of a wishful thinking that the Chinese people, whether Han or Tang, are a biologically homogeneous bunch of people. For large stretches of Chinese history, the country had to deal with more belligerent northern neighbours, and had been conquered by Mongols and Manchus from the North. These people, clearly of a different ethnicity from the indigenous Chinese, not only tended to displace the populations southwards and also widely assimilated with the resident Chinese. The more southern Chinese didn't have the benefits of the Great Wall so there was really nothing to keep them from mingling with their more southern non-Han neighbours.

As a result of these admixtures, there is a north-south cline in East Asian populations. In China itself, there would appear at the very least, among the "Han Chinese", to be a distinction between northern and southern Chinese. The watershed for these two groups is not a clear one, but appear to be somewhere in the vicinity of the Yangtze or Chang Jiang river divide.

It is important to be aware of the existence of this cline because it affects the way we look at "East Asian" population data. While for the most part, Chinese data tend to cluster quite closely together (which is not surprising), we need to be careful about too readily extrapolating northern data to a southern Chinese population, and vice versa. In many situations, northern Chinese data seem to be more in alignment with data from Japan and Korea, while southern Chinese data aligns with Hong Kong, Taiwan and Singapore.

Singapore, being the most southern of the major 'Han Chinese' populations, may have some unique features potentially because of some degree of genetic admixtures with the resident austronesian populations in south east Asia.

Does body weight matter?

It would appear, not very much. After all drug doses are seldom adjusted for body weight. Only in situations where the therapeutic index is very low, such as for oncologicals, is the drug dose adjusted for body weight. Clearance as a pharmacokinetic parameter, is seldom denominated by body weight.

Often when discussing differences in PK between populations, you can almost hear the sigh of relief when the differences in AUC can be discounted by body weight. Suddenly it's like the differences should not matter any more.

So should body weight matter?

The answer to my mind is, yes.

Pharmacokinetically, body weight does not matter as much to clearance as it does to distribution. For this reason Vd is often denominated by body weight. But not so clearance. The general reluctance to consider body weight as a major determinant of drug effect related to an older line of reasoning where drug response is seen primarily as a function of AUC, steady state concentrations and consequently clearance, rather than Vd. But as pointed out in previous posts, Vd changes can have considerable effects on drug PK, particularly Cmax and trough concentrations. These are less considered mainly because of their relative instability compared to steady state concentrations. It is however possible that variability in drug responses may in fact be more sensitive to changes in Cmax and troughs rather than steady state concentrations. If so, Vd effects may be potentially more profound than have been previously thought.

Why does this reality bother us?

Principally because one of the immediately noticeable differences between our Asian population and Western population is the difference in body weights. Caucasian males may have an average body weight of 85 kg as compared to age matched Chinese males of 65 kg. Chinese females would have an average of about 55 kg. If one recognizes that drug response may be affected by body weight, it would make us serious reconsider if drug dosage regiments developed from studies involving healthy Caucasian males, may be easily applied to Chinese females without adjustments to the average of 35% lesser body weight.

And this is not yet even considering differences in lean body mass, especially since Chinese/Asians have much less lean body mass for a given body weight, when compared to Caucasians.

Grapefruits and ....Pomelos

Few people in the west will know about pomelos. Apart from being a really yummy fruit, it is as potent as grapefruit in inhibiting CYP3A4, and MDR1 as well.

Here's my interpretation of the family tree of the pomelo and how it relates to the grapefruit.

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.

Who are the Japanese, anyway?

The Japanese ethnic group is deceptively homogeneous.The dominant ethnic group however is recognizable as the Yamato people. These are whom we have come to commonly recognize as 'Japanese'. However, some minor ethnic groups do find their home in Japan. Apart from the obvious transplants such as Koreans, Chinese, Taiwanese etc, these are the Ainus, Ryukyuans and the Nivkhs.

The Yamatos are people who derive originally from the North Chinese mainland, having crossed over through the Korean peninsula. Consequently, there is a genetic thread that runs through and links the Northern Han Chinese and Koreans with the Yamato Japanese. By contrast the Ainu and Ryukyuans are earlier peoples who antedate the arrival of the Yamato people. RIKEN has data that show the genetic similarity between the Ainu and the Ryukuans (Okinawans). It is thought that the arrival of Yamato cleaved the distribution of the original Austronesian population to create a northern Ainu group and a southern Okinawan group. The Nivkhs are a small minority who derive from Siberia.

That said, the Japanese are pretty much of the Yamato group (>98% of toal 130 million). The Ryukuans probably account for about 1% and the Ainu even less (0.3%).

From a practical perspective, when one examines Japanese PGx data we should make mental links with data originating from Northern China and Korea. Accordingly, some caution is necessary when we try and connect the dots between Japanese and essentially Southern Chinese and South East Asian data.

The following excerpted from Wikipedia (Japanese_people):

A recent study for the origins of Japanese people is based on the "dual structure model" proposed by Hanihara in 1991. He concludes that modern Japanese lineages consist of the original Jōmon people and immigrants from the Yayoi period. The Jōmon people originated in southeast Asia, moving to the Japanese Archipelago in the Palaeolithic period. In past several decades, the Japanese people was proposed to relate to Yi, Hani and Dai people based on folk customs or genetic evidences.

Another southeast Asian group moved to northeastern Asia. The population of this group increased in the Neolithic period and some moved to the archipelago during the Yayoi period. The miscegenation prevailed in Kyūshū, Shikoku and Honshū islands but not in Okinawa and Hokkaido, respectively represented by the Ryukyuan and Ainu people. This theory was based on the study of the development of human bones and teeth. The comparison of mitochondrial DNA between Jōmon people and medieval Ainu also supports the theory.