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

 
TitleFine mapping the region reveals a common intronic insertion associated to HDL-C.
Publication TypeJournal Article
Year of Publication2015
Authorsvan Leeuwen, EM, Huffman, JE, Bis, JC, Isaacs, A, Mulder, M, Sabo, A, Smith, AV, Demissie, S, Manichaikul, A, Brody, JA, Feitosa, MF, Duan, Q, Schraut, KE, Navarro, P, Van Vliet-Ostaptchouk, JV, Zhu, G, Mbarek, H, Trompet, S, Verweij, N, Lyytikäinen, L-P, Deelen, J, Nolte, IM, van der Laan, SW, Davies, G, Vermeij-Verdoold, AJm, van Oosterhout, AAlj, Vergeer-Drop, JM, Arking, DE, Trochet, H, Medina-Gomez, C, Rivadeneira, F, Uitterlinden, AG, Dehghan, A, Franco, OH, Sijbrands, EJ, Hofman, A, White, CC, Mychaleckyj, JC, Peloso, GM, Swertz, MA, Willemsen, G, de Geus, EJ, Milaneschi, Y, Penninx, BWjh, Ford, I, Buckley, BM, de Craen, AJm, Starr, JM, Deary, IJ, Pasterkamp, G, Oldehinkel, AJ, Snieder, H, P Slagboom, E, Nikus, K, Kähönen, M, Lehtimäki, T, Viikari, JS, Raitakari, OT, van der Harst, P, J Jukema, W, Hottenga, J-J, Boomsma, DI, Whitfield, JB, Montgomery, G, Martin, NG, Polasek, O, Vitart, V, Hayward, C, Kolcic, I, Wright, AF, Rudan, I, Joshi, PK, Wilson, JF, Lange, LA, Wilson, JG, Gudnason, V, Harris, TB, Morrison, AC, Borecki, IB, Rich, SS, Padmanabhan, S, Psaty, BM, Rotter, JI, Smith, BH, Boerwinkle, E, L Cupples, A, van Duijn, C
Corporate AuthorsGeneration Scotland, LifeLines Cohort Study, CHARGE Lipids Working Group
JournalNPJ Aging Mech Dis
Volume1
Pagination15011
Date Published2015
ISSN2056-3973
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.

DOI10.1038/npjamd.2015.11
Alternate JournalNPJ Aging Mech Dis
PubMed ID28721259
PubMed Central IDPMC5514988
Grant ListCZD/16/6/4 / / Chief Scientist Office / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States