Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C
Authors: 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 , Vermeij-Verdoold Andrea JM , van Oosterhout Andy ALJ , Vergeer-Drop Jeannette M , Arking Dan E , Trochet Holly ,   Generation Scotland, Medina-Gomez Carolina , Rivadeneira Fernando , Uitterlinden Andre G , Dehghan Abbas , Franco Oscar H , Sijbrands Eric J , Hofman Albert , White Charles C , Mychaleckyj Josyf C , Peloso Gina M , Swertz Morris A ,   LifeLines Cohort Study, Willemsen Gonneke , de Geus Eco J , Milaneschi Yuri , Penninx Brenda WJH , Ford Ian , Buckley Brendan M , de Craen Anton JM , Starr John M , Deary Ian J , Pasterkamp Gerard , Oldehinkel Albertine J , Snieder Harold , Slagboom P Eline , Nikus Kjell , Kähönen Mika , Lehtimäki Terho , Viikari Jorma S , Raitakari Olli T , van der Harst Pim , Jukema J Wouter , Hottenga Jouke-Jan , Boomsma Dorret I , Whitfield John B , Montgomery Grant , Martin Nicholas G ,   CHARGE Lipids Working Group, Polasek Ozren , Vitart Veronique , Hayward Caroline , Kolcic Ivana , Wright Alan F , Rudan Igor , Joshi Peter K , Wilson James F , Lange Leslie A , Wilson James G , Gudnason Vilmundur , Harris Tamar B , Morrison Alanna C , Borecki Ingrid B , Rich Stephen S , Padmanabhan Sandosh , Psaty Bruce M , Rotter Jerome I , Smith Blair H , Boerwinkle Eric , Cupples L Adrienne , van Duijn Cornelia 
Published: November 2015

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.