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

Elisabeth M. van Leeuwen, Jennifer E. Huffman, Joshua C. Bis, Aaron Isaacs, Monique Mulder, Aniko Sabo, Albert V. Smith, Serkalem Demissie, Ani Manichaikul, Jennifer A. Brody, Mary F. Feitosa, Qing Duan, Katharina E. Schraut, Pau Navarro, Jana V. van Vliet-Ostaptchouk, Gu Zhu, Hamdi Mbarek, Stella Trompet, Niek Verweij, Leo-Pekka LyytikäinenJoris Deelen, Ilja M. Nolte, Sander W. van der Laan, Gail Davies, Andrea Jm Vermeij-Verdoold, Andy Alj van Oosterhout, Jeannette M Vergeer-Drop, Dan E. Arking, Holly Trochet, Carolina Medina-Gomez, Fernando Rivadeneira, Andre G. Uitterlinden, Abbas Dehghan, Oscar H. Franco, Eric J. G. Sijbrands, Albert Hofman, Charles C. White, Josyf C. Mychaleckyj, Gina M. Peloso, Morris A. Swertz, Gonneke Willemsen, Eco J. C. de Geus, Yuri Milaneschi, Brenda Wjh Penninx, Ian Ford, Brendan M. Buckley, Anton Jm de Craen, John M. Starr, Ian J. Deary, Blair H Smith, Generation Scotland

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    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.

    Original languageEnglish
    Article number15011
    Pages (from-to)1-9
    Number of pages9
    JournalNPJ Aging and Mechanisms of Disease
    Volume1
    Early online date12 Nov 2015
    DOIs
    Publication statusPublished - 2015

    Keywords

    • Cardiovascular diseases
    • Epidemiology
    • Genetics

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  • Cite this

    van Leeuwen, E. M., Huffman, J. E., Bis, J. C., Isaacs, A., Mulder, M., Sabo, A., Smith, A. V., Demissie, S., Manichaikul, A., Brody, J. A., Feitosa, M. F., Duan, Q., Schraut, K. E., Navarro, P., van Vliet-Ostaptchouk, J. V., Zhu, G., Mbarek, H., Trompet, S., Verweij, N., ... Generation Scotland (2015). Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C. NPJ Aging and Mechanisms of Disease, 1, 1-9. [15011]. https://doi.org/10.1038/npjamd.2015.11