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Monday, November 14, 2011

Fitting into your genes

Fitting into your genes

Some years ago, I was given the honour of delivering the opening plenary lecture to the First World Congress of Public Health Nutrition and I had carte blanche as to the content. I chose to talk about nutrition and genetics and when I finished, I was set upon by the doyens of the subject to whom the idea that genes could play a role in such chronic diseases as obesity was verging on sacrilege. The argument was simple but fundamentally flawed. Obesity rates, they argued, have rocketed over the last 50 years[1] during which time the gene pool has remained constant so how could genes be involved.  Recently, I gave a similar talk to the Polish EU Presidency gig and got the same reaction. So here is how it happens. Imagine you could take 1000 extremely muscular Maasai tribesmen from the utterly non-obesogenic Kenyan plains and re-house them with a decent disposable income in any western city awash with obesogenic facilities. Some would resist weight gain. Some would show modest weight gain of which some would do so quickly and others more slowly. Some would become overweight and obese and do so at different rates. When the experiment is finished, I would predict a pattern of body weight among the Maasai broadly similar to the prevailing local pattern.

The evidence dates back 30 odd years when three seminal papers were published in leading medical journals. The first used identical and non-identical children and from this mix it is possible to say what part of obesity is inherited and what part is due to the environment. The non-identical twins share the same environment but not the same genome. In the case of identical twins, they share the same environment and the same genome. Geneticists have used this model in many areas to separate out the effects of the environment and the genome. The outcome was that 70%+ of the variation in obesity was inherited. The next set of data took identical twins that were overfed for several months and later, underfed for several months. In the overfeeding phase of 1000 extra calories per day over normal, all subjects gained weight but to varying degrees. The big variation was between groups of identical twins. However, among identical twins, here was no variation. If one gained weight rapidly, so did the other. If one resisted weight gain, so did the other. And when 1000 calories a day were deducted from their habitual intake, the same happened. All lost weight but some more than others. And identical twins shed weight at exactly the same rate. The final study looked at adoptees and compared their body weights with those of their adopting parents and those of their biological parents. The correlation was much stronger with their biological parents.

All of this data was then buried and forgotten because it was a most inconvenient truth. Even accepting its truth, those charged with the public health nutrition challenge of obesity had a further problem. If the average punter got word that their weight problem was genetic, they would abandon all personal efforts at weight management, throw their hands in the air and declare “Its not my fault, its my genes” as they wolfed into some stylish nosh. One has to have considerable sympathy for this point of view since the struggle to help manage obesity is a truly hard road. For a while, there was an escape clause in that it was argued that “that was then and this is now and thirty + years ago we didn’t have the ubiquitous obesogenic environment of today”.  And that was fine until Professor Jane Wardle of University College London began publishing data on modern twin cohorts followed up over a long period and with quite detailed lifestyle and diet recorded. Everything shown 30+ years ago was shown to be still true today. Moreover, Professor Wardle also showed that the belief that obesity in children has a huge socio-economic dimension is just not true. Twins of lean parents remained thin from aged 4 to 11 years irrespective of social class. However, when children from overweight children were considered, those of low social background did show accelerated weight gain. Thus social class matters in childhood obesity but only if filtered by the genes they inherited.

Studying twins helps us to quantify the true rate of heritability of obesity. It doesn’t tell us which genes are involved and thus it doesn’t allow us to predict which one of us will put on weight faster and more easily than others. Now, new technology allows us look at many hundreds of thousands of points of variation along the human genome to see where this natural variance is most pronounced in the obese as opposed to those of us lucky to remain lean. Each point of variation along a gene is known as an allele and there are certain alleles, which are much more commonly found among the obese. Thus we are now approaching the point where we can predict that a certain individual has a strong genetic tendency toward obesity and maybe, that knowledge could be used to help children and parents to take preventative measures against obesity. The converse is also true. We can now conduct simple genetic tests that will indicate the best calorie reduced diet for individuals to follow in losing weight. Some will do best by shedding fat calories and other will do best shedding carbohydrate calories. For some, either route will be equally effective.

When one mentions the link between genes and obesity, attention always turns to genetic variation influencing how energy rich substrates are handled (digested, transported stored, retrieved, metabolized and so on) in the body. However, this is simply because the people with the biggest interest in genetic research are usually biologists. But a genetic tendency to become obese may relate to our behaviour, our food choice, our satiety, our will power and any one of the many aspects of our lives that govern food intake. That poses an even greater challenge to the study of diet and obesity.

As to the extension of nutrition and genetics to the wider area of personalised nutrition, take a look at the website of an EU funded project that I am coordinator:

[1] Actually the rocketing started in the 1850s but that’s another story

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