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Sequence Variation in the APOA1 and APOA4 Genes and their Relationship with Plasma HDL-Cholesterol Levels

Hill, Sarah Elizabeth (2009) Sequence Variation in the APOA1 and APOA4 Genes and their Relationship with Plasma HDL-Cholesterol Levels. Master's Thesis, University of Pittsburgh. (Unpublished)

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Heart disease continues to be the leading cause of death in the United States, making it one of the foremost public health concerns. Many factors influence the risk to develop heart disease, including abnormal blood lipid levels. High levels of plasma high-density lipoprotein (HDL)-cholesterol have been shown to have a protective effect. Recent genome-wide association studies (GWAS) and candidate gene studies have identified genes thought to contribute to HDL-cholesterol levels. Two genes, APOA1 and APOA4, have been associated with HDL-cholesterol levels in multiple studies with inconsistent results. The majority of these studies focused on the "common variant-common disease" hypothesis whereas only one study by Cohen et al. (2004) evaluated APOA1 using the "rare variant-common disease" hypothesis. The aim of this study was to further investigate the role of common and rare variation in these two genes by sequencing individuals having extremely low and high HDL-cholesterol levels in two populations, U.S. Non-Hispanic Whites (NHWs), and African Blacks, and then screening the identified variants in the entire sample. In the initial sequence analysis, 54 variants were identified in APOA1 (25 of which were new), and 43 in APOA4 (21 of which were new). According to preliminary analysis of the sequencing data for APOA1 and APOA4, no striking difference was noticed between the distribution of rare variants between high and low HDL groups in either population. To date, screening data was compiled for the entire NHWs and Black samples for a total of seven common variants: 2 for APOA1 (rs5070 and rs5072), and 5 in APOA4 (rs5092, rs5100, rs5104, rs5106, and rs5109). All 7 variants were present in the Black population; five were present in NHWs (rs5070, rs5072, rs5092, rs5100, and rs5104). Modest or marginal significant p-values were observed; however, none would maintain significance after multiple testing correction in either population. Additional variants identified in sequencing remain to be screened in the entire NHWs and Black samples.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Hill, Sarah
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, M Ilyaskamboh@pitt.eduKAMBOH
Committee MemberFinegold, Daviddnf@pitt.eduDNF
Committee MemberDemirci, F Yesimfyd1@pitt.eduFYD1
Date: 29 June 2009
Date Type: Completion
Defense Date: 1 April 2009
Approval Date: 29 June 2009
Submission Date: 8 April 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Genetic Counseling
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Apolipoprotein A-I; Apoliporotien A-IV; Atherosclerosis; HDL-Cholesterol
Other ID:, etd-04082009-141813
Date Deposited: 10 Nov 2011 19:35
Last Modified: 15 Nov 2016 13:39


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