A Polynesian-specific missense CETP variant alters the lipid profile

• Published in: HGG advances Vol. 4; no. 3; p. 100204
• Main Authors: Moors, Jaye, Krishnan, Mohanraj, Sumpter, Nick, Takei, Riku, Bixley, Matt, Cadzow, Murray, Major, Tanya J., Phipps-Green, Amanda, Topless, Ruth, Merriman, Marilyn, Rutledge, Malcolm, Morgan, Ben, Carlson, Jenna C., Zhang, Jerry Z., Russell, Emily M., Sun, Guangyun, Cheng, Hong, Weeks, Daniel E., Naseri, Take, Reupena, Muagututi’a Sefuiva, Viali, Satupa’itea, Tuitele, John, Hawley, Nicola L., Deka, Ranjan, McGarvey, Stephen T., de Zoysa, Janak, Murphy, Rinki, Dalbeth, Nicola, Stamp, Lisa, Taumoepeau, Mele, King, Frances, Wilcox, Phillip, Rapana, Nuku, McCormick, Sally, Minster, Ryan L., Merriman, Tony R., Leask, Megan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-07-2023; Elsevier
• Subjects: Association analyses; CETP; Cholesterol Ester Transfer Proteins - genetics; Cholesterol, HDL - genetics; Cholesterol, LDL; equity; genetics; HDL-C; Humans; Lipids; Maori People; Māori; Pacific; Pacific Island People; Polymorphism, Genetic; HDL-C; CETP; Māori; genetics; Pacific; Lipids; Association analyses; equity
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2023.100204

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Māori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.
Sequencing of CETP identified a common missense variant specific to Polynesian people that associates with higher HDL-C levels and results in CETP deficiency. Given the therapeutic potential of CETP, this study highlights the importance of population-specific genetic analyses of under-represented populations for improving health equity.