Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C.
van 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 AJ., van Oosterhout AA., Vergeer-Drop JM., Arking DE., Trochet H., Generation Scotland None., Medina-Gomez C., Rivadeneira F., Uitterlinden AG., Dehghan A., Franco OH., Sijbrands EJ., Hofman A., White CC., Mychaleckyj JC., Peloso GM., Swertz MA., LifeLines Cohort Study None., Willemsen G., de Geus EJ., Milaneschi Y., Penninx BW., Ford I., Buckley BM., de Craen AJ., Starr JM., Deary IJ., Pasterkamp G., Oldehinkel AJ., Snieder H., Slagboom PE., Nikus K., Kähönen M., Lehtimäki T., Viikari JS., Raitakari OT., van der Harst P., Jukema JW., Hottenga J-J., Boomsma DI., Whitfield JB., Montgomery G., Martin NG., CHARGE Lipids Working Group None., 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., Cupples LA., van Duijn C.
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.