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Diet and lifestyle

High-fat marine diet has altered Greenlanders’ genes

For thousands of years, Greenlanders have lived in isolation and have eaten a diet high in fat and low in carbohydrate. Researchers have discovered a gene variant carried by every person with solely Greenlandic ancestors. This gene variant has helped them to metabolize the fat from their diet.

Most people in modern high-income societies are surrounded by plentiful food and copious carbohydrate. When people eat excessive carbohydrate, the body stores it as fat that can be metabolized when food is scarce. The indigenous Greenlanders had a marine diet that was low in carbohydrates and rich in fat and protein. This has strongly affected their genes over time and presumably still strongly influences their health. Blood tests from 1570 people in seven towns in Greenland have provided a unique perspective on this.

“We have identified a genetic variant in the population of Greenland that influences the composition of fatty acids in the blood. The remarkable thing about this is that the variant is only found in indigenous Inuit populations that have traditionally lived in Greenland, Alaska, Canada and around the Bering Strait – and nowhere else. This means that it probably would have been advantageous to possess this genetic variant at some time in the population’s history. This is therefore an example of the human genome adapting to a specific diet and specific environment,” explains the lead author, Line Skotte, Statens Serum Institut, Copenhagen.

Easier to thrive on a very high-fat

The researchers, from Denmark, Greenland and elsewhere, examined blood samples through genotyping: comparing the combination of nearly 1 million common variants in the complete genome of each participant. The researchers also measured more than 200 metabolic parameters, including the concentrations of various fatty acids in the blood.

“One gene variant recurred, and this turned out to strongly affect the concentration of the fatty acids in the blood. This variant presumably made it easier to thrive on a very high-fat and high-protein diet that the waters around Greenland have generally provided.”

The CPT1A gene encodes for an enzyme called carnitine palmitoyltransferase 1A, which regulates the transport of fatty acids within mitochondria, the energy-producing centres in the cells. The rs80356779 variant in the indigenous Greenlanders changes only one of the 773 amino acids in the enzyme, but this still strongly influences metabolism.

“People usually metabolize carbohydrate first and store fat for later use. But when food is scarce, the liver converts fat and this enables the body and especially the brain to function. When food becomes available again, the body can rapidly switch back to metabolizing carbohydrate. However, the bodies of the people with this gene variant do not stop metabolizing fatty acids just because carbohydrate is available.”

Powerful evolutionary forces

The rs80356779 gene variant seems to enable the body to metabolize fatty acids better and to save the scarce carbohydrate. This would have made sense given the traditional high-fat and low-carbohydrate diet consumed by the indigenous people in Greenland.

“This diet was extreme compared with that consumed elsewhere. It included marine mammals such as seals and whales and large quantities of fish. The diet was fat and protein rich – with scarcely any carbohydrate. These people had to adapt to this type of diet and survive the extremely tough climate conditions,” explains Bjarke Feenstra, project leader and Senior Scientist at Statens Serum Institut.

The results are very striking because the gene variant was present in all the participants who solely had Greenlandic ancestors. The researchers did not find this gene variant in other population groups from Europe and China. A comparison of the frequency of the adjacent genetic variants in Greenlandic, European and Chinese populations confirmed that positive selection caused the variant.

“The Greenlanders Inuit ancestors have lived for thousands of years with a very special diet and climate. In addition, the population of Greenland has been very small, and this means that the evolutionary forces that affect the genome may have a much greater influence on the Greenlandic population.”

4.2 cm shorter

The study confirmed several known adaptations of the human genome to diet and the environment. People living in Tibet have adapted to living at altitude, and genetic variants have been discovered in populations exposed to infectious diseases such as malaria.

The Greenlandic genetic profile was striking in another and possibly more surprising way. Even when the researchers compensated for the possible effects of other genes, the rs80356779 gene variant was associated with not being as tall as people without the variant. In fact, those who had inherited the rs80356779 variant of CPT1A from both parents were 4.2 cm shorter than people who had not.

“It is too early to determine precisely why this variant affects height, but discovering a genetic variant that affects height based on a sample of only 1570 participants is unique. In Europe and Asia, researchers need to study 100 times as many people to discover new variants that influence height. Variants with strong effects may be common in Greenland because the total population is small and has been isolated.”

When the diet becomes low fat

People in northern Europe have also adapted genetically to a specific traditional diet: they can digest lactose from dairy products, which many people in more southerly regions cannot. The study also raises new questions about public health.

“This genetic variant has been incredibly beneficial given a diet mostly based on fat and protein. In modern Greenland, most people eat much more carbohydrate, and investigating how this gene variant may influence the future population health and burden of disease is therefore important,” explains Anders Koch, Senior Researcher and Head of the Section for Greenland Research, Statens Serum Institut.

It is too early to determine to what extent this genetic variant increases the risk of lifestyle-related diseases such as obesity, cardiovascular disease or type 2 diabetes, but the researchers say that this new knowledge on the genetic profile of Greenlanders may strongly influence future treatment.

“One focus of much work is personalized medicine, in which the medicine recommended and prescribed for various diseases is increasingly tailored to exactly fit an individual’s genes. Certain groups of people may need slightly different medicines or slightly smaller or larger doses based on their individual genetic profile.”

The researchers are already closely following the associations between the burden of disease and hospitalization and the ongoing changes in diet in Greenland. This includes the numbers of people with various cardiovascular diseases and the changes in the overall burden of disease in a population that is undergoing such major changes to their living conditions.

“We know that the standard diets of most people in most high-income countries have disadvantages, but even more attention might need to be focused on the diets of specific groups of people who have such a genetic profile.”

CPT1A missense mutation associated with fatty acid metabolism and reduced height in Greenlanders” has been published in Circulation: Cardiovascular Genetics. The study was funded by grants from the Danish Council for Independent Research, Greenland’s Ministry of Education, Culture, Research and Church and others. The Danish National Biobank, which is supported by grants from the Novo Nordisk Foundation, contributed to the research project by processing and storing the blood tests from the 1570 study participants.

Line Skotte
Post.doc
Line Skotte's research is focused on developing and applying statistical and computational methods for genomic and transcriptomic data in medical genetics.
Anders Koch
Senior researcher
The primary research field is infectious disease epidemiology in Greenland based on field studies, national registries, and biobanks. This includes both infectious diseases that are frequent in Greenland and cause a high burden of disease, and diseases particular to Greenland. Besides this the work function includes supervision of PhD- and other students, besides scientific collaboration with partners in Greenland and in other circumpolar areas.
Bjarke Feenstra
Senior Scientist
Bjarke Feenstra is a senior research scientist in the Department of Epidemiology Research at Statens Serum Institut. He has an academic background in both biology and statistics, a Ph.D. in statistical genetics, and several years of international experience from USA and Iceland. He pursues research questions in genetic epidemiology, primarily with a focus on childhood traits and diseases. One example is a serious digestive system disease in newborns, known as pyloric stenosis. Dr. Feenstra led the two first genome-wide association studies (GWAS) of the disease followed up by functional work that suggests possible future strategies for prevention. Another recent example concerns febrile seizures after Measles, Mumps, and Rubella (MMR) vaccination. Although generally well-tolerated, MMR vaccination almost triples the risk of febrile seizures in the second week following vaccination. In a series of GWAS analyses, Dr. Feenstra and colleagues were able to identify genetic loci associated with febrile seizures in general and specifically as adverse events of MMR vaccination. Other examples includes studies of preterm delivery, birth weight, childhood eczema, age at menarche, childhood dental health and hypospadias. In addition to the aforementioned projects, Dr. Feenstra pursues research interests in theoretical questions, such as the possibility of detecting sample mix-ups using known SNP-phenotype associations. The combination of detailed phenotype information from Danish health registers and large collections of biospecimens in the Danish National Biobank at SSI provide unique opportunities for genetic epidemiology research.