Startling Discovery: New Study Gives Clues to Genetic Causes of High Cholesterol

Research has found strong evidence that the BTNL9 protein helps cells maintain healthy cholesterol levels.

The finding demonstrates how vital it is to ensure diversity in genetic databases.

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

Jenna Carlson, Ph.D. 1 credit

The unexpected finding highlights 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 for populations of European ancestry, we might have completely missed this finding,” said lead author Jenna Carlson, Ph.D., assistant professor of human genetics and biostatistics at Pitt. Public Health. “It is thanks to the generosity of thousands of Polynesians that we were able to find this variant, which is an irrefutable gun that will spark new research into the biology underlying cholesterol.”

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

Carlson and his team built their study to explore a signal that emerged in a large genome-wide survey looking for genes associated with lipids, or fats, in the body. He suggested that a gene variant on chromosome 5 might be associated with cholesterol. The team set out to ‘finely map’ the region using genetic data from 2,851 Samoan adults from the Obesity, Lifestyle and Genetic Adaptations Study Group (OLAGA, which means ‘life’ in Samoan). ) that had also provided health information, including lipid panels. .

To double-check the finding, the team looked for the association in 3,276 other Polynesians from Samoa, American Samoa and Aotearoa in New Zealand, and the same link between the variant and cholesterol was observed in them.

Using data from the Western Polynesian Samoan participants, the team was able to fill in missing information around the region they were interested in on chromosome 5. This led them to BTNL9 – a gene that directs the production of the protein BTNL9. Proteins typically signal cells to perform actions, although scientists have yet to characterize the precise role of the BTNL9 protein.

It turned out that Polynesians with low levels of “good” HDL cholesterol and high levels of triglycerides had a “stop-gain” variant in BTNL9, meaning the gene had to stop doing its job of producing proteins, a strong index. that the BTNL9 protein helps cells maintain healthy cholesterol levels.

“We don’t know much about this variant because it does not appear in published genomic references, which over-represent individuals of European ancestry – it is virtually non-existent in populations of European ancestry, has a very low frequency in South Asians and isn’t even particularly common among eastern Polynesians, like the Maori living in Aotearoa in New Zealand,” Carlson said. “But the way it’s linked to lipid panels in Samoans 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 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.