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New study provides clues to genetic causes of high cholesterol

The research found strong evidence that the BTNL9 protein helps cells maintain healthy cholesterol levels.

The finding shows the importance of ensuring diversity in genetic databases.

According to a recent study conducted by geneticists at the University of Pittsburgh School of Public Health in partnership with several other organizations including the University of Otago and the Samoan health research community, the discovery of a genetic variant that is relatively common in individuals of Polynesian descent, but very rare in most other populations, provides clues to the genetic underpinnings of high cholesterol in all humans.

Jenna Carson

Jenna Carlson, Ph.D. Credits: Jenna Carlson

The unexpected finding underscores the value of ensuring diversity in genetic databases and was recently published in the journal Advances in human genetics and genomics.

“If we had only looked at populations with European ancestry, we might have missed this finding altogether,” said lead author Jenna Carlson, Ph.D., assistant professor of human genetics and biostatistics at Pitt Public Health. “It was through the generosity of thousands of Polynesian people that we were able to find this variant, a smoking gun that will spur new research into the underlying biology of cholesterol.”

According to the World Health Organization, high cholesterol is a major source of disease burden in countries of all economic levels, is a risk factor for heart disease and stroke, and is estimated to cause 2.6 million deaths worldwide each year.

Carlson and her team built their study to investigate a signal that showed up in a large genome-wide study of genes related to lipids, or fats, in the body. It suggested that a gene variant on chromosome 5 might be associated with cholesterol. The team sought to “finely 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 verify the finding, the team looked for the association in 3,276 other Polynesian people from Samoa, American Samoa and Aotearoa New Zealand, and the same association between the variant and cholesterol was seen in them.

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 directs production of the BTNL9 protein. Proteins typically signal cells to perform actions, although scientists have still not characterized the precise role of the BTNL9 protein.

It turned out that Polynesian people with low levels of HDL “good” cholesterol and high levels of triglycerides had a “stop-gain” variant in BTNL9, meaning the gene was directed to stop its protein production, a strong hint that it BTNL9 protein is involved in helping cells maintain healthy cholesterol levels.

“We don’t know much about this variant because it’s not seen in published genome references, that individuals of European ancestry are over-represented — it’s virtually non-existent in populations of European ancestry, has a very low frequency in South Asians, and doesn’t even occur particularly often for.” in East Polynesian people, such as Māori who live in Aotearoa, New Zealand,” Carlson said. “But the way it’s linked to lipid panels in Samoan people tells us that this gene is important for cholesterol, something we didn’t know before. By further exploring BTNL9, we may one day discover new ways to help everyone have a maintain healthy cholesterol levels.”

Reference: “A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles” By Jenna C. Carlson, Mohanraj Krishnan, Samantha L. Rosenthal, Emily M. Russell, Jerry Z. Zhang, Nicola L. Hawley, Jaye Moors, Hong Cheng, Nicola Dalbeth, Janak R. de Zoysa, Huti Watson, Muhammad Qasim, Rinki Murphy, Take Naseri, Muagututi’a Sefuiva Reupena, Satupa’itea Viali, Lisa K. Stamp, John Tuitele, Erin E. Kershaw, Ranjan Deka, and Ryan L. Minster, October 12, 2022, Advances in human genetics and genomics.
DOI: 10.1016/j.xhgg.2022.100155

The study was funded by the National Institutes of Health and the New Zealand Health Research Council.

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