Fine-mapping of the CETP region identifies five novel variants, including a common intronic insertion, linked to HDL-C (NPJ Aging Mech Dis 2015)

Original title: Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

NPJ Aging Mech Dis · 1 January 2015 · 6

van Leeuwen EM, Huffman JE, Bis JC, Isaacs A, Mulder M, Sabo A, Smith AV, Demissie S, Manichaikul A, Brody JA, Feitosa MF, Duan Q et al.

Because individuals with exceptional longevity and their offspring tend to carry larger HDL particles linked to homozygosity for the CETP I405V variant, researchers fine-mapped the CETP region for additional variants associated with HDL cholesterol (HDL-C). A meta-analysis of 59,432 individuals imputed to the 1000 Genomes reference panel identified five independent variants, including an exonic variant and a common intronic insertion, which were replicated in an independent sample of 47,866 individuals; Sanger sequencing confirmed segregation of the insertion within a single family. After conditioning on these five novel variants, support for the previously strongest CETP-HDL-C association, rs3764261, was greatly reduced (unadjusted beta 3.179 mg/dL, P = 5.25x10-509; adjusted beta 0.859 mg/dL, P = 9.51x10-25), and three of the five novel variants proved independent of rs3764261. The causal variants underlying the CETP-HDL-C association remain unidentified, but these five variants may account for part of it.

Original abstract

Background: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.

Methods: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.

Results: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.

Conclusions: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.