Dilek Pirim1, Xingbin Wang2, Vipavee Niemsiri1, Zaheda H Radwan1, Clareann H Bunker3, John E Hokanson4, Richard F Hamman4, M Michael Barmada1, F Yesim Demirci5, M Ilyas Kamboh6. 1. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 2. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 3. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. 4. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA. 5. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: fyd1@pitt.edu. 6. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: kamboh@pitt.edu.
Abstract
BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a crucial role in lipid metabolism. Associations of common CETP variants with variation in plasma lipid levels, and/or CETP mass/activity have been extensively studied and well-documented; however, the effects of uncommon/rare CETP variants on plasma lipid profile remain undefined. Hence, resequencing of the gene in extreme phenotypes and follow-up rare-variant association analyses are essential to fill this gap. OBJECTIVE: To identify common and uncommon/rare variants in the CETP gene by resequencing the entire gene and test the effects of both common and uncommon/rare CETP variants on plasma lipid traits in two genetically distinct populations. METHODS AND RESULTS: The entire CETP gene plus flanking regions were resequenced in 190 individuals comprising 95 non-Hispanic whites (NHWs) and 95 African blacks with extreme HDL-C levels. A total of 279 sequence variants were identified, of which 25 were novel. Selected variants were genotyped in the entire samples of 623 NHWs and 788 African blacks and 184 QC-passed variants were tested in relation to plasma lipid traits by using gene-based, single-site, haplotype and rare variant association analyses (SKAT-O). Two novel and independent associations of rs1968905 and rs289740 with HDL-C were identified in African blacks. Using SKAT-O analysis, we also identified rare variants with minor allele frequency <0.01 to be associated with HDL-C in both NHWs (P=0.024) and African blacks (P=0.009). CONCLUSIONS: Our results point out that in addition to the common CETP variants, rare genetic variants in the CETP gene also contribute to the phenotypic variation of HDL-C in the general population.
BACKGROUND:Cholesteryl ester transfer protein (CETP) plays a crucial role in lipid metabolism. Associations of common CETP variants with variation in plasma lipid levels, and/or CETP mass/activity have been extensively studied and well-documented; however, the effects of uncommon/rare CETP variants on plasma lipid profile remain undefined. Hence, resequencing of the gene in extreme phenotypes and follow-up rare-variant association analyses are essential to fill this gap. OBJECTIVE: To identify common and uncommon/rare variants in the CETP gene by resequencing the entire gene and test the effects of both common and uncommon/rare CETP variants on plasma lipid traits in two genetically distinct populations. METHODS AND RESULTS: The entire CETP gene plus flanking regions were resequenced in 190 individuals comprising 95 non-Hispanic whites (NHWs) and 95 African blacks with extreme HDL-C levels. A total of 279 sequence variants were identified, of which 25 were novel. Selected variants were genotyped in the entire samples of 623 NHWs and 788 African blacks and 184 QC-passed variants were tested in relation to plasma lipid traits by using gene-based, single-site, haplotype and rare variant association analyses (SKAT-O). Two novel and independent associations of rs1968905 and rs289740 with HDL-C were identified in African blacks. Using SKAT-O analysis, we also identified rare variants with minor allele frequency <0.01 to be associated with HDL-C in both NHWs (P=0.024) and African blacks (P=0.009). CONCLUSIONS: Our results point out that in addition to the common CETP variants, rare genetic variants in the CETP gene also contribute to the phenotypic variation of HDL-C in the general population.
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