A Polynesian - specific missense CETP variant alters the lipid profile

Abstract

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.

Keywords: Association analyses; CETP; HDL-C; Lipids; Māori; Pacific; equity; genetics.

Figure 1

Association analyses of rs1597000001 T-allele with HDL-C Forest plot of a fixed-effect meta-analysis for the association of rs1597000001 T-allele with HDL-C (mmol/L) (A). Associations were adjusted by age, sex, 10 PCs, and relatedness in the Aotearoa NZ cohort and age, sex, first four PCs, and relatedness in the Samoan I-III cohorts, and age, sex and number of Pacific and Māori grandparents in the PTO cohort. Association of HDL-C at the CETP locus (+/− 500 kb the lead variant rs1597000001) (B) and after conditioning on rs1800775 (C) using variants on the Illumina Infinium CoreExome v24 bead chip platform for genotyped participants from the Aotearoa NZ cohort. The strength of LD, as measured by the r², between each variant and rs1597000001, is represented by the color of each point according to the legend in the top right hand corner. The plot was generated using a custom locus zoom-like R package. HDL-C, high-density lipoprotein cholesterol; NZ Māori, New Zealand Māori; CI Māori, Cook Island Māori; PC, principal component; PTO, Pacific Trust Otago; CETP, cholesteryl ester transfer protein.

Figure 2

The population-specific rs1597000001 variant changes the amino acid sequence of CETP and reduces function (A) The CADD, GERP, and Multiz UCSC track alignment at rs1597000001 for which the substitution creates a non-synonymous amino acid residue change (p.Pro177Leu). (B) 3D schematic of p.Pro177Leu (P160L) in the mature CETP protein structure in the N-terminal barrel domain (left) of CETP. The CETP protein structure was obtained from The Protein Databank and illustrated using PyMOL. (C) Plasma activity of CETP (pmol/h/μL) in 11 participants of the PTO cohort who had the heterozygous rs1597000001 genotype (CT) versus the homozygous rs1597000001 genotype for the major allele (CC). CETP, cholesteryl ester transfer protein. Error bars represent standard error of the mean. A two-sample t test with Welch’s correction was conducted to test for a statistically significant (p = 0.028) difference in mean CETP activity between the two genotypic groups. CETP, cholesteryl ester transfer protein; CADD, Combined Annotation Dependent Depletion scores; GERP, Genomic Evolutionary Rate Profiling.