The PAGE study fails to replicate CETP rs1864163's HDL-C association across roughly 38,000 diverse-ancestry adults despite adequate power (PLoS Genet 2011)

Original title: Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study

PLoS Genet · 1 June 2011 · 5

Dumitrescu L, Carty CL, Taylor K, Schumacher FR, Hindorff LA, Ambite JL, Anderson G, Best LG, Brown-Gentry K, Bůžková P, Carlson CS, Cochran B et al.

The Population Architecture using Genomics and Epidemiology (PAGE) study genotyped 49 GWAS-identified lipid-associated SNPs, tested across six racial/ethnic groups including roughly 20,000 European American, 9,000 African American, and 6,000 American Indian adults among others, for association with fasting HDL-C, LDL-C, and log-triglycerides. The study replicated 55 of 60 SNP associations (92%) tested in European Americans at P less than 0.05, but despite sufficient statistical power, could not replicate four previously reported associations, including CETP rs1864163 with HDL-C, alongside two ABCA1 variants and one TTC39B variant, indicating this specific CETP-HDL-C association may not generalize as robustly as other established lipid loci.

Original abstract

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.