The “thrifty” gene found in Samoa and what it means

SamoaThis (very technical) paper has made a big splash on the internet and in the media, not just in New Zealand but all around the world.

A thrifty variant in CREBRF strongly influences body mass index in Samoans
Ryan L Minster, Nicola L Hawley, Chi-Ting Su, Guangyun Sun, Erin E Kershaw, Hong Cheng, Olive D Buhule, Jerome Lin, Muagututi‘a Sefuiva Reupena, Satupa‘itea Viali, John Tuitele, Take Naseri, Zsolt Urban, Ranjan Deka, Daniel E Weeks, & Stephen T McGarvey
Nat Genet. 2016 Jul 25. doi: 10.1038/ng.3620. [Epub ahead of print]

Samoans are a unique founder population with a high prevalence of obesity, making them well suited for identifying new genetic contributors to obesity. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.

Samoa gene

How the variant gene correlates with BMI in Samoa

This is a big deal because the thrifty gene hypothesis – that some people are prone to obesity because their ancestors evolved to store energy more effectively in times of plenty – had been dead in the water for lack of convincing evidence. Genes are complicated things and previous studies hadn’t turned up anything with this sort of effect size (obesity is common today, yet these “thrifty” genes are normally quite rare). The thinking is that the gene variant (technically a “missense” mutation where a particular amino acid in a protein has been replaced with a different amino acid that reduces its function) was selected for during long sea voyages, where starvation and hypothermia weeded out individuals who had been less effective at storing and/or holding onto fat.

These genes are not destiny

Stephen McGarvey, the senior author, was quick to point out in all his interviews that this genetic evidence doesn’t mean that such genetics destine Pasifika people to be obese independently of environment, that is, diet, lifestyle, and exercise. (Though the study only looked at Samoa, it is almost certain that the gene will be found to be similarly common in other Pasifika populations). It is unlikely that the va’a tele or waka that carried the Polynesian explorers round the Pacific basin carried any obese individuals even when they set out; the stored energy advantage that the gene variant gave in these times was probably a few Kg and barely noticeable. If we look online for historical photographs of Samoa, we find that Samoa has a rich political history – it was the meeting place of the German, British, and U.S. Empires in the late 19th century – which resulted in much photographic documentation. But even as recently as 1930, during the period of the Mau independence movement, there is no evidence of obesity in photos.
These are pupils of Vaipouli school, a Samoan secondary school, ca 1930.


And these (photo at top) are leaders of the Mau movement at the same time.


Regardless of genetics, indigenous populations rarely if ever experience obesity eating their traditional diets, and always experience a high rate of obesity and/or diabetes, as well as the other diseases of Western civilisation (tooth decay, heart disease, cancer, appendicitis), after transitioning to Western processed and refined foods – foods with a high Human Interference (HI) factor. Traditional Samoan staple foods are taro and coconut, breadfruit and banana, turtle, pork and fish; this is never a question of fat vs carbs, or of saturated fat vs unsaturated fat, nor even of fructose vs glucose (the Ti root prepared in much of polynesia is very high in fructose) – it’s a question of natural foods with their fibre, micronutrients, fats and protein intact, vs refined starch, sugar, and refined oils, including the soybean oil used to pack canned fish in the case of Polynesia.[1]

Obesity prevents diabetes? Come again?

A really interesting finding from this study from our point of view is that the “obesity” gene variant is strongly protective against type 2 diabetes.

Higher BMI and adiposity are usually associated with greater insulin resistance (higher fasting insulin levels and homeostatic model assessment–insulin resistance (HOMA-IR)), an atherogenic lipid profile (especially higher serum triglyceride and lower HDL cholesterol levels), and lower adiponectin levels. We therefore expected the BMI-increasing A allele of rs373863828 to also be associated with these metabolic variables. However, even though the A allele was consistently associated with higher BMI and adiposity in both the discovery and replication cohorts, the expected associations with the above obesity-related comorbidities were not observed and, in some cases, were even in the opposite direction to that expected (Table 2 and Supplementary Table 2).
Notably, when considering all subjects, the risk of diabetes was actually lower (OR = 0.586 for the discovery cohort, P = 6.68 × 10−9) or trended lower (0.742 for the replication cohorts, P = 0.029) in carriers of the A allele. Likewise, even in non-diabetic subjects, the variant was associated with moderately but significantly lower fasting glucose levels in both the discovery and replication cohorts (1.65 mg/dl (P = 9.5 × 10−5) and 1.54 mg/dl (P = 8.8 × 10−4) lower for each copy of the A allele, respectively). These effects became even more significant after adjusting for BMI (2.25 mg/dl, P = 6.9 × 10−8 and 2.09 mg/dl, P = 7.6 × 10−6), suggesting an independent effect of the variant on glucose homeostasis and diabetes risk.

How can this be? Obesity is associated with, and plausibly causal in, diabetes, yet a gene variant that increases obesity halves the rate of diabetes?
This is in fact strongly supportive of the ectopic fat hypothesis of diabetes causation, and the personal fat threshold hypothesis of Professor Roy Taylor of Newcastle Diet fame.

“We hypothesize that each individual has a personal fat threshold (PFT) which, if exceeded, makes likely the development of T2DM. Subsequent weight loss to take the individual below their level of susceptibility should allow return to normal glucose control. Crucially, the hypothesized PFT is independent of BMI.”[2]

“A key reason for the greater increase in diabetes risk per unit increase in BMI in South Asians compared with Europeans may be due to a reduced capacity in South Asians to store fat in the primary superficial subcutaneous adipose tissue compartment, leading to earlier `overflow’ into secondary deep subcutaneous and visceral fat compartments, and potentially the liver.” [3]


(Professor Taylor’s research also pinpoints the pancreas as a target for this “overflow”).
Imagine the body as a house in which rainwater (energy stored as fat) is collected in a tank; if the water is not used, and the tank fills, the water will overflow into the walls and floors of the house; the house will be at risk of rotting and the electrics might short out. The larger the tank, the less risk of damage there will be in a downpour. But no matter how big the tank, the house can still be damaged if it fills to overflowing. This tank is the capacity to store energy (fat, and the fat produced from carbohydrate) subcutaneously (in the folds of fatty tissue under the skin).
So it is not a paradox that while weight gain increases the risk of type 2 diabetes, some of the people who are most prone to obesity for genetic reasons will have a lower risk of type 2 diabetes at a given BMI.

Take-home messages:

1) about 1 in 4 people in Samoa, and possibly similar numbers in other Pacific populations, have a variant gene that makes it easier to store fat and become obese. This strengthens the “thrifty gene” hypothesis of obesity, at least with regard to these populations.

2) This gene is also associated with a significantly reduced risk of diabetes, a fact which strengthens the “ectopic fat” and “personal fat threshold” hypotheses of type 2 diabetes.

3) Variant genes or their lack did not result in obesity or diabetes in Samoan populations living their traditional lifestyles and eating their traditional diets of unrefined, nutritious animal and vegetable foods. Western processed foods and refined high-energy ingredients have been a disaster for these peoples. This strengthens the “gene – environment mismatch” theory of modern diseases, and the Paleolithic diet hypothesis.


[1] Behavioral risk factors for obesity during health transition in Vanuatu, South Pacific.
Kelsey Needham Dancause, Miguel Vilar, Michelle Wilson, Laura E Soloway, Christa DeHuff, Chim Chan, Len Tarivonda, Ralph Regenvanu, Akira Kaneko, J Koji Lum, and Ralph M Garruto. Obesity (Silver Spring). 2013 Jan; 21(1): E98–E104. (full-text link)

[2] Normal weight individuals who develop Type 2 diabetes: the personal fat threshold. Roy Taylor, Rury R. Holman. Clinical Science Apr 01, 2015, 128 (7) 405-410; DOI: 10.1042/CS20140553

[3] Type 2 diabetes as a disease of ectopic fat?
Naveed Sattar and Jason MR Gill. BMC Medicine 2014:12(123) (full-text link)

2 Comments on “The “thrifty” gene found in Samoa and what it means

  1. There’s a good comment on this paper in Pubmed Commons and on pubpeer
    It reads in part:

    Impact on obesity risk

    The authors also investigate the “impact of the gene variant on the risk of obesity” and found that the odds ratio for the gene variant was 1.44 in the replication sample. This value is an odds ratio and indicates the impact on the odds of obesity, not on the risk of obesity. The difference between the two is essential here.

    The value of the odds ratio is similar to the relative risk when the outcome of interest is rare. In this study, the majority of the people were obese, 55.5% and 48.8% in the discovery and replication samples had BMI higher than 32kg/m2. When the prevalence of the outcome is this high, the odds ratio overestimates the relative risk. When the odds ratio is 1.44, the relative risk is 1.43 when the prevalence of obesity in noncarriers is 1%, 1.32 when it is 20%, 1.22 when it is 40%, 1.18 when it is 50%, and 1.16 when 55% of the non-carriers is obese. Regarding the impact on obesity risk, the gene variant might be more ordinary as suggested.

  2. Pingback: PubMed comments & their continuing conversations | PubMed Commons Blog

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