%0 Journal Article %J NPJ Aging Mech Dis %D 2015 %T Fine mapping the region reveals a common intronic insertion associated to HDL-C. %A van Leeuwen, Elisabeth M %A Huffman, Jennifer E %A Bis, Joshua C %A Isaacs, Aaron %A Mulder, Monique %A Aniko Sabo %A Smith, Albert V %A Demissie, Serkalem %A Manichaikul, Ani %A Brody, Jennifer A %A Feitosa, Mary F %A Duan, Qing %A Schraut, Katharina E %A Navarro, Pau %A Van Vliet-Ostaptchouk, Jana V %A Zhu, Gu %A Mbarek, Hamdi %A Trompet, Stella %A Verweij, Niek %A Lyytikäinen, Leo-Pekka %A Deelen, Joris %A Nolte, Ilja M %A van der Laan, Sander W %A Davies, Gail %A Vermeij-Verdoold, Andrea Jm %A van Oosterhout, Andy Alj %A Vergeer-Drop, Jeannette M %A Arking, Dan E %A Trochet, Holly %A Medina-Gomez, Carolina %A Rivadeneira, Fernando %A Uitterlinden, André G %A Dehghan, Abbas %A Franco, Oscar H %A Sijbrands, Eric J %A Hofman, Albert %A White, Charles C %A Mychaleckyj, Josyf C %A Peloso, Gina M %A Swertz, Morris A %A Willemsen, Gonneke %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda Wjh %A Ford, Ian %A Buckley, Brendan M %A de Craen, Anton Jm %A Starr, John M %A Deary, Ian J %A Pasterkamp, Gerard %A Oldehinkel, Albertine J %A Snieder, Harold %A Slagboom, P Eline %A Nikus, Kjell %A Kähönen, Mika %A Lehtimäki, Terho %A Viikari, Jorma S %A Raitakari, Olli T %A van der Harst, Pim %A Jukema, J Wouter %A Hottenga, Jouke-Jan %A Boomsma, Dorret I %A Whitfield, John B %A Montgomery, Grant %A Martin, Nicholas G %A Polasek, Ozren %A Vitart, Veronique %A Hayward, Caroline %A Kolcic, Ivana %A Wright, Alan F %A Rudan, Igor %A Joshi, Peter K %A Wilson, James F %A Lange, Leslie A %A Wilson, James G %A Gudnason, Vilmundur %A Harris, Tamar B %A Morrison, Alanna C %A Borecki, Ingrid B %A Rich, Stephen S %A Padmanabhan, Sandosh %A Psaty, Bruce M %A Rotter, Jerome I %A Smith, Blair H %A Eric Boerwinkle %A Cupples, L Adrienne %A van Duijn, Cornelia %X

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 ( gene. In this study, we investigate the association of and HDL-C further to identify novel, independent variants associated with HDL-C in humans.

METHODS: We performed a meta-analysis of HDL-C within the 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 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 variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (=3.179 mg/dl ( value=5.25×10), =0.859 mg/dl ( value=9.51×10)), and this finding suggests that these five novel variants may partly explain the association of with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.

CONCLUSIONS: The causal variants in 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 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.

%B NPJ Aging Mech Dis %V 1 %P 15011 %8 2015 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28721259?dopt=Abstract %R 10.1038/npjamd.2015.11