Sunday, September 18, 2016

The 'Thrifty Gene' of Samoa

A recent study conducted a genome-wide association study (GWAS) in 3072 Samoans and found a gene variant of the CREBRF gene that is much more prevalent in Samoans and is strongly associated with higher BMI [1].  The narrative being sold is that this thrifty gene had positive selection in Samoans to help promote storage of fat for periods of food scarcity, like travelling across the Pacific [2]

Unfortunately for the thrifty gene hypothesis (which I’ve previously discussed), the function of CREBRF suggests this gene could scarcely be a worse match for this narrative

The main functions of the endoplasmic reticulum (ER) include Ca2+ homeostasis, the synthesis of proteins and lipids, and ‘folding’ proteins into their tertiary structure.  However, several things (including infection, nutrient stress, oxidative stress, etc) can impair protein folding, leading to an accumulation of unfolded or misfolded proteins and ER stress.  One of the homeostatic responses to ER stress is the unfolded protein response, which attempts to reduce the load on the ER.  If ER stress is prolonged or intense the cell initiates apoptosis [3]

CREBRF stands for ‘cyclic AMP-responsive element-binding protein 3 regulatory factor’ or CREB3 regulatory factor.  CREB3 is part of unfolded protein response [4], while CREBRF is a negative regulator of CREB3, and thus is a negative regulator of the unfolded protein response [5]

This is highly relevant, as endoplasmic reticulum stress is a cause of leptin resistance in diet-induced obesity [6] [7].  Specifically, ER stress increases PTP1B, which mediates the effect of ER stress on leptin resistance [8].  The GWAS paper cites other research showing that knocking out CREBRF lowers body weight in mice and flies [1].  So the chain of mechanisms involved seems to be as follows:

↓ CREBRF > ↑ CREB3 > ↑ homeostatic ER stress response > ↓ ER stress ↓ PTP1B > ↓ leptin resistance > ↓ weight gain

And so for people with the gene variant:

p.Arg457Gln > ↑ CREBRF > ↓ CREB3 > ↓ homeostatic ER stress response > ↑ ER stress ↑ PTP1B > ↑ leptin resistance > ↑ weight gain

The paper provides evidence that the gene variant had positive selection, but that doesn’t explain what outcomes of the gene variant were the source of the positively selection, it doesn’t necessary mean fat storage or that such extreme fat storage as obesity was being selected for.  Going back 100’s of years ago this gene variant doesn’t seem like it would be a problem when ER stress would have been an infrequent transient response to something like infection.  But these days, the average Samoan on a western diet likely has chronic low level ER stress, which leads to higher PTP1B and leptin resistance – and this is being amplified by a weaker homeostatic response

This gene variant fits the certainly fits the outcomes of being thrifty gene, but not the purpose of one.  The thrifty gene hypothesis suggests that overweight/obesity is an evolutionary adaptive physiological condition, whereas this gene variant increases weight by increasing ER stress, a pathological state

Finally, as George Henderson shows below, Samoans were lean and muscular before adopting a western diet.  If you try to explain the leanness by suggesting the picture was taken during a period of scarcity, then why so much muscle mass?  People promoting the thrifty gene hypothesis need to show evidence that ethnic groups who are susceptible to obesity have been overweight during periods of abundance (before adopting a western diet).  Such periods wouldn’t have been uncommon, as we’re talking about tropical Pacific islands, not northern Europe

It’s time for evolutionary medicine to stop looking for reasons why chronic disease may been evolutionary adaptive, and then focus on sources of mismatch

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