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A Comprehensive Association Study of Apolipoprotein E-C1-C4-C2 Gene Cluster Variation with Plasma Lipoprotein Traits

Radwan, Zaheda (2014) A Comprehensive Association Study of Apolipoprotein E-C1-C4-C2 Gene Cluster Variation with Plasma Lipoprotein Traits. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Apolipoproteins are major determinants of plasma lipoprotein-lipid distribution. Dyslipidemia with elevated level of low-density lipoprotein cholesterol (LDL-C) and decreased level of high-density lipoprotein cholesterol (HDL-C) is associated with increased risk of cardiovascular disease (CVD), which is a major public health problem worldwide. Therefore, unraveling the genetic basis of plasma lipoprotein-lipid traits would provide insight into risk prediction and contribute to the developing of new therapeutic and intervention measures to reduce the CVD burden, which has a public health importance. The objective of this study was to characterize genetic variation in the APOE-C1-C4-C2 gene cluster on chromosome 19q13.32 by resequencing selected individuals from non-Hispanic White (NHW) and African Black populations with extreme lipid profile and then genotyping the identified sequence variants (common tagSNPs and rare variants) along with the HapMap tagSNPs covering the intergenic regions in the entire datasets (623 NHWs, and 788 Blacks) to evaluate their association with major lipid traits. Sequencing of the four apolipoprotein genes along with their hepatic control regions in subjects falling in the upper (47 NHWs, 48 Blacks), and lower (48 NHWs, 47 Blacks) 10th percentile distribution of HDL-C/triglycerides (TG) revealed 230 variants (215 substitution, 15 indels), of which 63 were shared in both populations, 52 were NHW-specific and 115 were Black-specific. A total of 70 variants (65 sequencing-identified, 5 HapMap tagSNPs) in NHWs and 108 variants (103 sequencing-identified, 5 HapMap tagSNPs) in Blacks were successfully genotyped in the entire datasets and were considered for the association analyses. Twenty variants in NHWs and twenty-four variants in Blacks (MAF>1%) showed nominally significant association (P<0.05) with at least one lipid trait. Although the major contribution of the APOE-C1-C4-C2 gene cluster was on LDL-C and apolipoprotein (apo) B, we observed multiple associations with other lipid traits, including TG, HDL-C, and apoA1. In addition to the significant contribution of common variants, rare/less common variants showed significant association with lipid traits. Our findings confirm the significant contribution of APOE-C1-C4-C2 genetic variation in affecting plasma lipid profile in the general population and consequently the CVD risk.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Radwan, ZahedaZhadwan@hotmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, Ilyas M.kamboh@pitt.eduKAMBOH
Committee CoChairDemirci, Yesim F.fyd1@pitt.eduFYD1
Committee MemberBarmada, Michael M.barmada@pitt.eduBARMADA
Committee MemberBunker, Clareann H.bunkerc@pitt.eduBUNKERC
Date: 29 January 2014
Date Type: Publication
Defense Date: 29 July 2013
Approval Date: 29 January 2014
Submission Date: 20 November 2013
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 259
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: Complex Disease, Candidate genes sequencing study, Association study, Genetic of lipid traits. Apolipoproteins, APOE-C1-C4-C2 gene cluster.
Date Deposited: 29 Jan 2014 17:19
Last Modified: 01 Jan 2019 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/20220

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