Surprising discovery in people of Polynesian descent offers clues to the genetic basis of high cholesterol

Surprising discovery in people of Polynesian descent offers clues to the genetic basis of high cholesterol

The discovery of a genetic variant that is relatively common in people of Polynesian descent but incredibly rare in most other populations provides clues to the genetic basis of high cholesterol in all people, according to a new study by the University of Pittsburgh School of Public Health geneticists in collaboration with several other groups, including the University of Otago and the Samoan Health Research Community.

The surprising finding, published this week in the journal Human Genetics and Genomics Advances, shows the importance of ensuring diversity in genetic databases.

If we had only examined populations with European ancestry, we might have missed this finding entirely. Thanks to the generosity of thousands of Polynesians, we were able to find this variant, which is crucial evidence for new research into the biology behind cholesterol.”

Jenna Carlson, Ph.D., lead author, assistant professor of human genetics and biostatistics, Pitt Public Health

High cholesterol is a leading cause of disease burden in countries of all income levels, a risk factor for heart disease and stroke, and causes an estimated 2.6 million deaths worldwide annually, according to the World Health Organization.

Carlson and her team designed their study to examine a signal that emerged in a large genome-wide survey looking for genes associated with lipids, or fats, in the body. It has been suggested that a gene variant on chromosome 5 may be linked to cholesterol. The team set out to "fine map" the region using genetic data from 2,851 Samoan adults from the Obesity, Lifestyle, And Genetic Adaptations (OLAGA, meaning "life" in Samoan) study group, who had also provided health information, including lipid panels. To double-check the finding, the team looked for the link in 3,276 other Polynesians from Samoa, American Samoa and Aotearoa, New Zealand, and they found the same link between the variant and cholesterol.

Using data from the Western Polynesian-Samoan participants, the team was able to fill in the missing information around the region they were interested in on chromosome 5. This led them to BTNL9 – a gene that controls the production of the BTNL9 protein. Normally, proteins signal cells to perform actions, although scientists have not yet characterized the exact role of the BTNL9 protein.

It turned out that Polynesian people with low HDL "good" cholesterol and high triglyceride levels had a "stop-gain" variant in BTNL9, meaning the gene was instructed to stop its protein production task, a strong indication that the BTNL9 protein is involved in helping cells maintain healthy to support cholesterol levels.

"We don't know much about this variant because it does not appear in published genome references, which overrepresent individuals of European ancestry - it is virtually absent in populations of European ancestry, is very rare in South Asians, and is not even particularly common in East Asia." “Polynesian people like the Māori who live in Aotearoa, New Zealand,” Carlson said. "But the way it is linked to the lipid panels of the Samoan population tells us that this gene is important for cholesterol levels, which we didn't know before. By further researching BTNL9, we may one day discover new ways to help everyone maintain healthy cholesterol levels."

Source:

University of Pittsburgh

Reference:

Carlson, J.C., et al. (2022) A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles. Advances in human genetics and genomics. doi.org/10.1016/j.xhgg.2022.100155.

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