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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 ( β  unadjusted =3.179 mg/dl ( P  value=5.25×10 −509 ),  β  adjusted =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.

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