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

van Leeuwen, E. M. et al. (2015) Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C. npj Aging and Mechanisms of Disease, 1, 15011. (doi:10.1038/npjamd.2015.11) (PMID:28721259) (PMCID:PMC5514988)

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Abstract

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. 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. 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. 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian and Padmanabhan, Professor Sandosh
Authors: 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., Lyytikäinen, L.-P., Deelen, J., Nolte, I. M., van der Laan, S. W., Davies, G., Vermeij-Verdoold, A. J., van Oosterhout, A. A., Vergeer-Drop, J. M., Arking, D. E., Trochet, H., Medina-Gomez, C., Rivadeneira, F., Uitterlinden, A. G., Dehghan, A., Franco, O. H., Sijbrands, E. J., Hofman, A., White, C. C., Mychaleckyj, J. C., Peloso, G. M., Swertz, M. A., Willemsen, G., de Geus, E. J., Milaneschi, Y., Penninx, B. W., Ford, I., Buckley, B. M., de Craen, A. J., Starr, J. M., Deary, I. J., Pasterkamp, G., Oldehinkel, A. J., Snieder, H., Slagboom, P. E., Nikus, K., Kähönen, M., Lehtimäki, T., Viikari, J. S., Raitakari, O. T., van der Harst, P., Jukema, J. W., Hottenga, J.-J., Boomsma, D. I., Whitfield, J. B., Montgomery, G., Martin, N. G., Polasek, O., Vitart, V., Hayward, C., Kolcic, I., Wright, A. F., Rudan, I., Joshi, P. K., Wilson, J. F., Lange, L. A., Wilson, J. G., Gudnason, V., Harris, T. B., Morrison, A. C., Borecki, I. B., Rich, S. S., Padmanabhan, S., Psaty, B. M., Rotter, J. I., Smith, B. H., Boerwinkle, E., Cupples, L. A., and van Duijn, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:npj Aging and Mechanisms of Disease
Publisher:Nature Publishing Group
ISSN:2056-3973
ISSN (Online):2056-3973
Copyright Holders:Copyright © 2015 Japanese Society of Anti-Aging Medicine/Macmillan Publishers Limited
First Published:First published in npj Aging and Mechanisms of Disease 1: 15011
Publisher Policy:Reproduced under a Creative Commons license

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