TY - JOUR
T1 - Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C
AU - Generation Scotland
AU - Lifelines Cohort Study
AU - CHARGE Lipids Working Group
AU - van Leeuwen, Elisabeth M.
AU - Huffman, Jennifer E.
AU - Bis, Joshua C.
AU - Isaacs, Aaron
AU - Mulder, Monique
AU - Sabo, Aniko
AU - Smith, Albert V.
AU - Demissie, Serkalem
AU - Manichaikul, Ani
AU - Brody, Jennifer A.
AU - Feitosa, Mary F.
AU - Duan, Qing
AU - Schraut, Katharina E.
AU - Navarro, Pau
AU - van Vliet-Ostaptchouk, Jana V.
AU - Zhu, Gu
AU - Mbarek, Hamdi
AU - Trompet, Stella
AU - Verweij, Niek
AU - Lyytikäinen, Leo Pekka
AU - Deelen, Joris
AU - Nolte, Ilja M.
AU - van der Laan, Sander W.
AU - Davies, Gail
AU - Vermeij-Verdoold, Andrea J.M.
AU - van Oosterhout, Andy A.L.J.
AU - Vergeer-Drop, Jeannette M.
AU - Arking, Dan E.
AU - Trochet, Holly
AU - Medina-Gomez, Carolina
AU - Rivadeneira, Fernando
AU - Uitterlinden, Andre G.
AU - Dehghan, Abbas
AU - Franco, Oscar H.
AU - Sijbrands, Eric J.
AU - Hofman, Albert
AU - White, Charles C.
AU - Mychaleckyj, Josyf C.
AU - Peloso, Gina M.
AU - Swertz, Morris A.
AU - Willemsen, Gonneke
AU - de Geus, Eco J.
AU - Milaneschi, Yuri
AU - Penninx, Brenda W.J.H.
AU - Ford, Ian
AU - Buckley, Brendan M.
AU - de Craen, Anton J.M.
AU - Starr, John M.
AU - Deary, Ian J.
AU - Hottenga, Jouke Jan
N1 - Publisher Copyright:
© 2015 Japanese Society of Anti-Aging Medicine/Macmillan Publishers Limited.
PY - 2015/11/12
Y1 - 2015/11/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85056262273
U2 - 10.1038/npjamd.2015.11
DO - 10.1038/npjamd.2015.11
M3 - Article
AN - SCOPUS:85056262273
SN - 2056-3973
VL - 1
JO - npj Aging and Mechanisms of Disease
JF - npj Aging and Mechanisms of Disease
IS - 1
M1 - 15011
ER -