Drink, drank, drunk

Dr John Whitfield is a biochemist by training who knows an awful lot about liver metabolism and the application of biochemistry in diagnostic testing.

He won't be talking much about this to a gathering of neuroscientists at the upcoming IBRO World Congress in Melbourne in July, but he will be discussing what he has learned about the detection of harmful alcohol use and the genetic factors underlying it.

Whitfield is based at the Royal Prince Alfred (RPA) Hospital in Sydney but spends a quarter of his time at the Queensland Institute of Medical Research, where he works with the wonderful resource built up over the last 25 years by Professor Nick Martin's extensive program of twin studies.

This resource has been extremely useful for a number of research areas, including the genetics of alcohol use and abuse. For the IBRO conference, Whitfield will talk about why genetic susceptibility is important in alcohol dependence and the ways in which researchers are trying to track down the particular genes implicated and their actions.

"The research has gone through necessary phases of demonstrating that there was a familial component to risk and then showing through adoption studies and twin studies by many groups that this was largely, mainly entirely, genetic," he says.

"You can put a figure on how much variation in susceptibility to alcohol dependence is genetic - it is around 50 per cent. Similarly, although I can't put a figure on it myself, you could put a figure on nicotine dependence, although there is less work done on that [field].

"And because there is less work done, it can be a bit vague on cannabis or opiate dependence but these things are starting to come out.

"However, genetic researchers don't necessarily buy into genetic determinism. It's pretty clear from our results and the results others are getting that genes are only a part of it."

Whitfiled says there are many monozygotic or identical twin pairs in which one has experienced alcohol dependence and the other has not, "so either environmental effects or just random chance has got a pretty strong role as well".

In addition to gene association research, Whitfield will discuss current understanding about a neuron-receptor system - the gamma-aminobutyric acid (GABA) A receptors - which has been shown to affect alcohol dependence risk and other related psychological characteristics.

"There has been work from an American consortium on the genetics of alcoholism that has identified a receptor called GABA A2, where variations seem to be associated with differences in alcohol dependence risk," he says.

"We have done some work testing to see whether this is mediated by difference in sensitivity to alcohol's effects. One way that a receptor could affect outcomes is if some people with some forms of the receptor feel drunker after they drink alcohol than others.

"We've done studies on samples from the twins who were tested some time ago. One of the difficulties is that the number of people we can test is comparatively limited so although we have some positive results it's a little difficult to say whether they are positive just by chance or positive because there is some important physiological thing there. I think this an issue that confronts a lot of gene association research.

"However, variation in this gene also seems to have consequences for other characteristics, such as Conduct Disorder, things which are personality characteristics that may overlap to some extent with addictions. So this puts it more into the area of brain science as a whole rather than just about addictions."

Whitfield has also spent much time studying the two enzymes linked with alcohol dependence and its effects, alcohol dehydrogenase and aldehyde dehydrogenase.

The discovery of variations in aldehyde dehydrogenase, which primarily affects people from China, Japan and Korea and renders almost of half of the population alcohol intolerant, was hugely important as it was the first concrete example of an enzyme defect that had a role in alcohol use behaviour and alcohol dependence.

"It really set a paradigm that encouraged people to do biological research on the addictions," he says.

As a biochemist, Whitfield is also personally interested in the effects of heavy drinking on the liver and its metabolism.

"One of the projects I have ongoing does look at variation in susceptibility to liver damage of drinking heavily, but that's not so much for the neuroscientists," he says.

"They're more interested in the bit of fat between the ears."