New clues to genetic causes of high cholesterol

The study demonstrates the importance of ensuring diversity in genetic databases.


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Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels.

Now a discovery of a genetic variant that is relatively common among people of Polynesian ancestry but incredibly rare in most other populations is giving clues to the genetic underpinnings of high cholesterol in all people.

Lead author Dr. Jenna Carlson, assistant professor of human genetics and biostatistics at Pitt Public Health, said, “If we had only been looking in populations with European ancestry, we might have missed this finding entirely. Through the generosity of thousands of Polynesian people, we were able to find this variant, a smoking gun that will spark new research into the biology underlying cholesterol.”

The team developed their research to investigate a signal that surfaced after a thorough genome-wide search for genes related to lipids, or fats, in the body. It was suggested that a chromosome 5 gene variation might be connected to cholesterol.

It was suggested that a chromosome 5 gene variation might be connected to cholesterol. Using genetic information from 2,851 Samoan people from the Obesity, Lifestyle, and Genetic Adaptations (OLAGA) Study Group, who had also submitted health information, including lipid panels, the team set out to “fine map” the area. To double-check the finding, the team looked for the association in 3,276 other Polynesian people from Samoa, American Samoa, and Aotearoa, New Zealand. The same connection between the variant and cholesterol was seen in them.

The team was able to fill in the gaps in knowledge surrounding the region of chromosome 5 they were interested in using information from the western Polynesian Samoan individuals. They discovered BTNL9 as a result, which is a gene that controls the creation of the BTNL9 protein. Proteins normally instruct cells to take certain behaviors, but the specific function of the BTNL9 protein is yet unknown to scientists.

It was discovered that Polynesians with low levels of HDL “good” cholesterol and high levels of triglycerides had a BTNL9 “stop-gain” variant, which implies the gene was being directed to cease producing proteins. This strongly indicates that the BTNL9 protein is essential in assisting cells in maintaining healthy cholesterol levels.

Carlson said“We don’t know a lot about this variant because it’s not seen in published genome references, which overrepresent European ancestry individuals — it’s virtually nonexistent in European ancestry populations, has a shallow frequency in South Asians and isn’t even particularly common in eastern Polynesian people, such as Māori living in Aotearoa New Zealand.”

“But the way it’s linked to lipid panels in Samoan people tells us that this gene is important to cholesterol, something we didn’t know before. By further exploring BTNL9, we might someday discover new ways to help everyone maintain healthy cholesterol levels.”

Journal Reference:

  1. Jenna C.Carlson et al. A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles. Human Genetics and Genomics Advances. DOI: 10.1016/j.xhgg.2022.100155


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