New clues to the cause of high cholesterol genes

A new study by geneticists at the University of Pittsburgh's School of Public Health, in collaboration with other groups such as the University of Otago and the Samoa Health Research Group, shows that a genetic variant is relatively common in people of Polynesian ancestry but extremely rare in most other populations, providing clues
to the genetic basis of high cholesterol in all people.

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

"If we only looked at populations of European ancestry, we might have missed this finding entirely," said
lead author Jenna Carlson, Ph.
D.
, assistant professor of human genetics and biostatistics at the Pitt School of Public Health.
"Thanks to the generosity of thousands of Polynesians, we were able to discover this variant, which is conclusive evidence that will inspire new research
into the underlying biology of cholesterol.
"

According to the World Health Organization, high cholesterol is a major cause of disease burden in countries of all income levels, a risk factor
for heart disease and stroke.
High cholesterol is estimated to kill 2.
6 million people worldwide each year
.

Carlson and her team built their study to explore signals that popped up in a large genome-wide survey that looked for genes
associated with lipids or fats in the body.
This suggests that a gene variant on chromosome 5 may be related to
cholesterol.
The team began to "fine-tune" the region using genetic data from the Obesity, Lifestyle, and Genetic Adaptation (OLAGA, which means "life" in Samoa) research group, who also provided health information, including lipid profiles
.
To test the findings, the team looked for the association in 3,276 Polynesians from Samoa, American Samoa and New Zealand, and found the same link
between the variant and cholesterol in them.

Using data from participants in Samoa, Western Polynesia, the team was able to fill in missing information
in their region of interest on chromosome 5.
This led them to BTNL9, a gene
that directs the production of the BTNL9 protein.
Proteins typically signal cells to perform actions, although scientists have yet to determine exactly what the BTNL9 protein does
.

It was found that Polynesians with low levels of HDL cholesterol and higher triglyceride levels had a "stop gain" variant in the BTNL9 gene, meaning the gene was instructed to stop its work in producing protein, strongly suggesting that the BTNL9 protein was involved in helping cells maintain healthy cholesterol levels
.

"We don't know much about this variant because it doesn't see in published genomic references that overrepresent individuals of European ancestry — it's almost non-existent in people of European ancestry, very low in South Asians, and not particularly common even in East Polynesians, such as the Maori people
who live in Oteroa, New Zealand," Carlson said.
"But the way it is associated with the lipid panel of Samoans tells us that this gene is important for cholesterol, something we didn't know about before
.
" By exploring BTNL9 further, we may one day discover new ways
to help everyone maintain healthy cholesterol levels.
”

Journal Reference:

1. 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, Stephen T.
   McGarvey, Tony R.
   Merriman, Daniel E.
   Weeks, Ryan L.
   Minster.
   A stop-gain variant in BTNL9 is associated with atherogenic lipid profiles.
   Human Genetics and Genomics Advances, 2022; 100155 DOI: 10.
   1016/j.
   xhgg.
   2022.
   100155