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

Media type: E-Article
Title: Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C
Contributor: van Leeuwen, Elisabeth M; Huffman, Jennifer E; Bis, Joshua C; Isaacs, Aaron; Mulder, Monique; Sabo, Aniko; Smith, Albert V; Demissie, Serkalem; Manichaikul, Ani; Brody, Jennifer A; Feitosa, Mary F; Duan, Qing; Schraut, Katharina E; Navarro, Pau; van Vliet-Ostaptchouk, Jana V; Zhu, Gu; Mbarek, Hamdi; Trompet, Stella; Verweij, Niek; Lyytikäinen, Leo-Pekka; Deelen, Joris; Nolte, Ilja M; van der Laan, Sander W; Davies, Gail; [...]
imprint: Springer Science and Business Media LLC, 2015
Published in: npj Aging and Mechanisms of Disease
Language: English
DOI: 10.1038/npjamd.2015.11
ISSN: 2056-3973
Keywords: Geriatrics and Gerontology ; Aging
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background:</jats:title> <jats:p>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 (<jats:italic>CETP)</jats:italic> gene. In this study, we investigate the association of <jats:italic>CETP</jats:italic> and HDL-C further to identify novel, independent <jats:italic>CETP</jats:italic> variants associated with HDL-C in humans.</jats:p> </jats:sec><jats:sec> <jats:title>Methods:</jats:title> <jats:p>We performed a meta-analysis of HDL-C within the <jats:italic>CETP</jats:italic> 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.</jats:p> </jats:sec><jats:sec> <jats:title>Results:</jats:title> <jats:p>The meta-analysis of HDL-C within the <jats:italic>CETP</jats:italic> 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 <jats:italic>CETP</jats:italic> variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (<jats:italic>β</jats:italic><jats:sub>unadjusted</jats:sub>=3.179 mg/dl (<jats:italic>P</jats:italic> value=5.25×10<jats:sup>−509</jats:sup>), <jats:italic>β</jats:italic><jats:sub>adjusted</jats:sub>=0.859 mg/dl (<jats:italic>P</jats:italic> value=9.51×10<jats:sup>−25</jats:sup>)), and this finding suggests that these five novel variants may partly explain the association of <jats:italic>CETP</jats:italic> with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>The causal variants in <jats:italic>CETP</jats:italic> 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 <jats:italic>CETP</jats:italic> 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.</jats:p> </jats:sec>
Access State: Open Access

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