Hi Anoop – my PKU example was to illustrate the premise that most (all?) diseases are 100% genetically determined and 100% environmentally determined, rather than it being the best analogy for the gene/environment interaction for fatness. Nevertheless I guess if there was no food around at all – in the pre-garbage can era – then even these extreme leptin deficient cases wouldn't get fat. Also I assume most people with genetic predispositions to fatness have a much weaker hunger signal that in prader-will syndrome (albeit stronger than people without these genes) so I wonder if in fact most fatness genes are indeed sitting silently waiting for the right environment to manifest.

Regards Rod       

From: Anoop Balachandran <[log in to unmask]>
Date: Fri, 6 Jan 2012 17:19:00 +1300
To: Rod Jackson <[log in to unmask]>
Cc: "[log in to unmask]" <[log in to unmask]>
Subject: Re: The Fat Trap

H Rod,


Thanks for the reply. And you make some very good points. 


One question I had is about the comparison of Phenylktone Urea and obesity. We know that PKU, kids are not 'hungry' for phenylalanine. In obesity, the driving force is hunger. They can't help but eat. We know from the leptin deficiency cases studies that the first thing that happens with leptin injections is a tremendous drop in hunger. They lose weight by not eating food because they are not hungry. Another example is the prader-willi syndrome where they eat even from garbage cans. The same happens with bariatric surgery.  So I am not sure if obesity genes are sitting silently for the right environment to manifest.


So is PKU or other diseases and obesity is a fair comparison?


Here are 2 interviews with Katherine Flegal: http://www.psychologicalscience.org/observer/getArticle.cfm?id=2599

http://www.sciencewatch.com/ana/st/obesity2/10sepObes2Fleg/


The interview had a question regarding Friedman's assertion of only a modest weight gain causing the obesity epidemic. And this is what she had to say: 


One of my projects is to write a paper about that. I have all the graphs. There are two effects at work. One, of course, is that if you have a normal distribution and you shift the distribution to the right by a fixed amount, the median is going to increase and the prevalence of obesity is going to increase.

But what you can see in the data is that both the median is moving and the distribution is becoming more skewed. The tails are longer and longer. It's not just a shift of the distribution. It's a shift and a change in the shape of the distribution. The median has gone up by a certain amount and the prevalence of obesity has gone up more than you'd expect from the change in the median.

Thanks

Anoop Balachandran



On Wed, Jan 4, 2012 at 9:52 PM, Rod Jackson <[log in to unmask]> wrote:
I think it is well worth watching the Friedman lecture (http://www.youtube.com/watch?v=kNotqromxjQ). Apart from just a couple of dubious comments  it is an easy to understand and balanced discussion of the genetic mechanisms of obesity.

While Friedman topic is the genetic determinants, so this is what he focusses on, he clearly acknowledges that diseases/conditions are the result of a genetic-environmental interaction.

As an aside, I think Ken Rothman's (author of several great epidemiological texts) comment that all diseases are 100% genetically determined and 100% environmentally determined is a useful way of thinking of the gene-environment interaction. Ken uses the example of phenylketonuria (PKU), which, to quote Wikipedia, 'is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.' This is about as genetic as a disease can get! Nevertheless if there was no phenylalanine in the environment, there would be no PKU, so one could argue it is 100% environmentally determined! What this case study demonstrates is the meaninglessness of statements attributing percentage points (totaling 100%) to genetics and environment for specific conditions. Friedman does not make this surprisingly common mistake. 

To return to the discussion on the list, Friedman makes an important and valid epidemiological observation in his lecture. He shows how the so-called obesity epidemic is exaggerated when it is described using a dichotomous metric of obesity such as a BMI >30 units. Mean BMI has been increasing at about 0.5 –1.0 BMI units per decade in most western countries since 1980 (Lancet2011; 377: 557–67)  which is about a 3-5% relative increase per decade. In contrast the proportion of people with a BMI> 30 has been increasing at a much greater relative rates – closer to 30-50%, simply because the bulk (excuse the pun) of the BMI distribution is below but close to the 30 unit threshold, so a small increase in mean BMI results in a relatively large proportion of people moving past this point. It is questionable whether we should be using this metric in the lay press as it is a very poor measure of the 'obesity problem.' Not only does it exaggerate the speed of the increase in a population's fatness but there is nothing special about a BMI of 30. Risk of death increases from a BMI of about 25 units and each 5 kg/m2 higher BMI is on average associated with about 30% higher overall mortality Lancet 2009; 373: 1083–96. 

There is no doubt we are getting fatter, albeit quite slowly. Our own research in adults aged 35-64 years in Auckland, New Zealand suggests that the whole BMI distribution is moving NZ Med J. 2006;119(1245):/2308 and it has been increasing at a similar rate in both sexes, most age groups and in both low and high socio-economic groups. While a slowly increasing mean BMI in a population is likely to be mainly influenced by multiple small changes in the environment, the shape of the distribution is likely to be primarily influenced by genetic factors. Moreover, as stated by Friedman, a substantial proportion of morbid obesity has strong genetic influences.

It is likely that a better understanding of the genetics and a more valid interpretation of the epidemiology of fatness will help us develop more effective strategies to reverse the current trends in fatness. 

I also thought Friedman's bottom line about how we should respond to the 'epidemic'  - in his final Q & A remarks – was well put.

Rod Jackson
Professor of (CVD) Epidemiology
Section of Epidemiology and Biostatistics
School of Population Health, Tamaki Campus
Faculty of Medical & Health Sciences, University of Auckland
Private Bag 92019
Auckland, New Zealand


From: Klim McPherson <[log in to unmask]>
Reply-To: Klim McPherson <[log in to unmask]>
Date: Mon, 2 Jan 2012 19:39:08 +0000
To: <[log in to unmask]>

Subject: Re: The Fat Trap

Thanks Ash, and Anoop.

I strongly recommend the Foresight report of 2007 (Govt Office of Science)  still available on the web I believe. In principle equating increase in lbs to increases in the prevalence of obesity is essentially algebraic, since the curve just moves along largely, among the whole population. All this is testable now on 2009/10 data in the UK . The assumptions we made in Foresight did not assume that however since we modelled the entire (age,sex etc specific) distributions of BMI forward – given current tends, and everything was very well behaved fortunately.

I am all in favour of finding the predicted obesity epidemic exaggerated, and it is clear from more recent data that the under 40's do appear to be doing better than we had predicted in 2007 – especially the young men. (No such sign among older people).  If this can be demonstrated as a 'permanent' cohort effect (and it is too early now) then clearly the dire predictions may not come about when these people reach an age where the morbid consequences are more common, and they remain even then below current predictions – which the current older cohorts are showing no sign of doing.


All best wishes,

Klim
From: Ash Paul <[log in to unmask]>
Reply-To: Ash Paul <[log in to unmask]>
Date: Mon, 2 Jan 2012 18:05:03 +0000
To: Anoop Balachandran <[log in to unmask]>, "[log in to unmask]" <[log in to unmask]>
Cc: Klim McPherson <[log in to unmask]>
Subject: Re: The Fat Trap

Dear Anoop,
You could ask for more advice on this issue from one of the eminent UK epidemiologists in this group viz Prof Klim McPherson.
Klim is the Chair of the National Heart Forum UK, and he was one of the prinicpal epidemiological experts invited by the IOM, USA to a joint UK-US Workshop on Obesity Prevention in 2009.
The output of that Workshop was published by the IOM in 2010:
Perspectives from United Kingdom and United States Policy Makers on Obesity Prevention. Workshop Summary


I'm copying Klim into this email as well.
Regards,
Ash


 



From: Anoop Balachandran <[log in to unmask]>
To: [log in to unmask]
Sent: Monday, 2 January 2012, 17:10
Subject: Re: The Fat Trap

Thanks Ash. I have seen that video. I had one question though.

Friedman says obesity epidemic is exaggerated! In fact, there has only been a 10-15 lb increase. But this was enough to push a lot of people over the 30BMI mark - hence a 33% increase in obesity in 2000.

I have also read that the increase seems to be mainly in the obese population and not an overall increase for the whole population.

What do you all think? And where can I read more about it.