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Variants discovery in the LPL and CETP genes and their associations with plasma lipid and apolipoprotein levels

Pirim, Dilek (2014) Variants discovery in the LPL and CETP genes and their associations with plasma lipid and apolipoprotein levels. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Plasma lipid and lipoprotein levels are known to be under strong genetic control and major risk factors for cardiovascular disease (CVD). Identifying novel genetic variants associated with plasma lipoprotein-lipid concentration are of a considerable public health importance because this knowledge may facilitate the design of genetic markers for risk assessment, diagnosis and prognosis of CVD. In this study, we have comprehensively investigated the associations of both common and uncommon/rare variants in two major lipid genes, lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP), in relation to plasma lipoprotein-lipid levels in U.S. non-Hispanic whites (NHWs) and African blacks. We resequenced the entire LPL and CETP genes plus their flanking regions in 190 individuals presenting extreme high-density lipoprotein cholesterol (HDL-C)/triglyceride (TG) levels selected from two study samples of 623 NHWs and 788 African blacks. We identified a total of 371 and 279 sequence variants in LPL and CETP genes, respectively, including several novel rare and population-specific variants. Following the discovery stage of resequencing, selected common tagSNPs and uncommon/rare variants from each gene were genotyped in the entire samples of 623 NHWs and 788 African blacks. A total of 171 LPL and 184 CETP variants passed the quality control and were analyzed for their associations with plasma lipoprotein-lipid levels by using single-site, haplotype and rare variant association analyses. Multiple common variants in the two genes demonstrated significant effects on plasma lipoprotein-lipids levels in both populations. Two putative functional SNPs, LPL/ rs13702 (P=0.006 in NHWs; P=0.01 in African blacks) and CETP/rs183130 (P=1.91E-04 in NHWs; P=2.25E-06 in African blacks) exhibited strongest associations with HDL-C in both samples. Rare variant analyses indicated that CETP gene harbors rare variants that contribute to plasma lipoprotein-lipid levels in both ethnic groups. However, rare variants in LPL revealed associations with plasma lipoprotein-lipid levels only in African blacks. Our data reaffirm the important role of LPL and CETP genetic variation has in affecting plasma lipoprotein-lipid levels in the general population.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pirim, Dilekdip16@pitt.eduDIP16
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, M Ilyaskamboh@pitt.eduKAMBOH
Committee MemberDemirci, F Yesimfyd1@pitt.eduFYD1
Committee MemberBunker, Clareannbunkerc@pitt.eduBUNKERC
Committee MemberBarmada, M Michaelbarmada@pitt.eduBARMADA
Date: 27 June 2014
Date Type: Publication
Defense Date: 18 November 2013
Approval Date: 27 June 2014
Submission Date: 7 April 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 374
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: LPL, CETP, SNP, genetic association study, lipids, cardiovascular disease genetics, haplotype analyses, rare variants
Date Deposited: 27 Jun 2014 20:23
Last Modified: 01 May 2019 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/20917

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