Alcohol pharmacogenetics in Singapore

The news about the alcohol related death at the National University of Singapore triggered some thinking about the interesting aspects about how alcohol (ethanol) is handled by the Chinese in Singapore.

Ethanol regardless of the form it comes in, is metabolized fairly efficiently in the body by means of an enzyme, alcohol hydrogenase (ADH). Although there are other enzymes that can also do this (e.g. CYP2E1), the most important pathway for alcohol degradation is really ADH. ADH itself is encoded by 7 genes but the major enzyme in the stomach mucosa and liver is the Class 1 enzyme, encoded by the ADH1B gene.

CH₃CH₂OH + NAD⁺ → CH₃CHO + NADH + H⁺

What is important for us to realize is that there is a common genetic polymorphism affecting the ADHB1 gene in Chinese. An 'atypical' ADH was first described in 1968 by Von Wartburg and Schuerch (Ann. N.Y. Acad. Sci. 151: 936-947, 1968). Subsequently Stamatoyannopoulos in 1975 found the atypical variant in 85% of Japanese. The variant is now identified as ADH1B*47 (previously ADH2*2) and exchanges a histidine for arginine in the protein, resulting in an enzyme with very much enhanced activity (100 fold difference in Vmax). A recent study (Alcohol Clin Exp Res. 2004 Jan;28(1):10-4) in Jewish carriers of this variant showed increased rate of elimination of alcohol from the blood (8.09 vs 7.14 g/hr).

This genetic variant is particularly common in South East and East Asia and is an important genetic 'protector' against alcoholism because it is thought to result in more unpleasant outcomes because of higher levels of aldehyde production . The frequency among Taiwanese Han Chinese is about 75% (Hepatology. 1997 Jan;25(1):112-7 ).

A recent report was able to show this global distribution of ALD1B*47 variant (Am J Hum Genet. 2007 Oct;81(4):842-6. Epub 2007 Aug 24). Note the interesting cluster in West Asia. Also the absence of this variant in the Indian subcontinent. More about this later, and its implications for us in Singapore.

Global contour plot of the ADH1B*47His allele frequency