One of the world's leading population health researchers, Brown University's Professor Stephen McGarvey, is visiting New Zealand this week.
Last month, a team led by McGarvey published landmark research that revealed a rare genetic variant in adult Samoans had a big influence on their obesity risk.
McGarvey, a keynote speaker at the Queenstown Research Week conference, opening today, now suspects there may be similar links in other Polynesian groups - including Maori.
He spoke to Herald science reporter Jamie Morton.


Can you briefly recap your findings?



We identified a new and significant genetic variant on chromosome 5, in the CREBRF gene, that contributes to obesity risk using a genome-wide search of the chromosomes of more than 3000 Samoan adults from the independent nation of Samoa whom we measured in 2010.

We looked at more than 700,000 places, across all the chromosomes to see what genetic variants would be associated with body mass index (BMI), a measure of adiposity or obesity.

We did this because Samoans, like all Polynesians, had been a semi-isolated population until recent times.

And also because Polynesians have very high levels of obesity that are very recent public health phenomena (since the 1960s).

We thought that the changes in nutrition, diet and exercise pattern were largely responsible for the obesity increase, but that there might be some genetic susceptibility that made these changes happen more rapidly or at a higher level.

We replicated this finding in older DNA samples from Samoans that I had collected since the 1990s.

So we knew the association was real.

The frequency of the obesity risk variant is about 27 per cent in Samoans, and about 7 per cent of our Samoan participants had two copies and 38 per cent had one copy of this susceptibility variant.

The identified variant is almost non-existent in other human groups.

The genetic variant had remained undiscovered in other humans because it is so very rare.

While the elevated risk conferred by this genetic variant is much greater than any other known common BMI risk variant, overall it explains only about 2 per cent of the variation in BMI among Samoans.

Other factors such as diet, physical activity and early life nutrition and growth are important and their influences on obesity in the context of this gene variant will be investigated in future studies.

We then sought to understand the biological reasons or mechanisms that are responsible for the obesity association we found.

In fat cell models in the lab, we found that this genetic variant behaved in a thrifty manner, promoting more efficient storage of more fat.

Lastly, we found that the pattern of variation in the genome in the chromosome 5 region encompassing the discovered gene variant is consistent with the variant having been evolutionarily selected for among Samoans.

Q. So what made you focus on this variant? Did you go searching for it, or happen upon it during analysis? Did you always suspect something was there?
A. We did not have any idea that the variant in the CREBRF gene we discovered or identified existed or was important in obesity.

We found it using the genome-wide association methods, and saw that it was very significantly associated with BMI.

In your words, we 'happened upon it'.

Q. As scientists, how tough was it to tease this elusive variant out?
A. We were very careful to do and re-do all analyses using all the statistical genetic methods we could to adjust for potential noise that might cause us to misidentify the variant.

Then we replicated the finding in the older study data from the 1990s and 2000s.

Then when we did not have a good explanation of the possible biology behind the association we used the fat cell model to explore how the genetic variant behaved in this laboratory model.

So, yes, we did a lot so we could be confident of what we found and its meaning.

Q. What impact can we now say that fatty diets have had on Samoan adults; and is it fair to say they've been unfairly maligned for disproportionate obesity rates?
A. I have done much other research besides this genetic work.

Clearly the amount of animal product saturated fat in the diet has increased over the last 50 years.

But so has the amount of simple carbohydrates in the form of bread, rice, flour and sugar in sweetened beverages.

We do not know enough to implicate one specific part of the diet.

The entire Pacific region has experienced a modernisation of their diet and generally to the worse for population health.

This general increase in total calories and in fats and carbohydrates, as well as, a decrease in physical activity have contributed to their remarkable obesity levels.

Q. The findings came out last month: what has been the response since? Are you aware of policy-makers already factoring the study into what they're doing?
A. We had several Samoan co-authors and active collaborators.

This finding is contributing to their understanding that changes in diet, physical activity and weight gain patterns at all ages must be addressed.

Q. How relevant do you think the findings are to New Zealand - and do they apply to those descended from other Polynesian nations?

A. Since the Maori people are Polynesians, and many other Pacific island groups reside in New Zealand.

I think these findings have relevance for those New Zealanders.

I think that New Zealand as a society may be the among the most important high-income nations for trying to determine how to translate these findings, and those to follow, into effective clinical and public health action.

This includes especially drug discoveries.

Q. What are the next big questions you want to answer next and where has this work taken you now?
A. How does this variant interact with the diet and physical activity patterns to increase risk?

How does this variant interact with other genetic risk factors?

What are the precise biological mechanisms in humans that are influenced by this variant?
What are the biological pathways affected by this variant and what pathways influence it?

We have a new research grant from the US NIH that will allow us to look at these questions in fat cells from Samoans and in lab models of fat cells.