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Sequence variation in the APOA2 gene and its relationship with plasma HDL-cholesterol levels

Hollister, Sally Marie (2008) Sequence variation in the APOA2 gene and its relationship with plasma HDL-cholesterol levels. Master's Thesis, University of Pittsburgh. (Unpublished)

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Coronary heart disease (CHD) is a major public health concern, affecting almost 16 million people in the U.S. and leading to 452,300 deaths in 2004 alone. Low levels of high density lipoprotein (HDL) cholesterol have been shown to increase the risk for cardiovascular disease (CVD). The role of genetics in affecting total cholesterol, HDL-cholesterol, and triglycerides levels is significant, with heritability estimates exceeding 50%. Recent studies have identified major loci associated with HDL-cholesterol through genome-wide association studies, which investigated influences of common variants on common traits. Relatively few studies have investigated the impact of rare variants (or common variants with a modest affect) on common disease. The aim of our study was to evaluate the genetic variation in APOA2 (a biological candidate gene involved in HDL metabolism) in relation to HDL-cholesterol levels in epidemiological samples of African Blacks and U.S. Non-Hispanic Whites (NHWs). We resequenced APOA2 in individuals with HDL-cholesterol levels in the upper 5th percentile (47 NHWs and 48 Blacks) and lower 5th percentile (48 NHWs and 47 Blacks), allowing us to identify both rare and common variants. Common tagSNPs and all rare variants have been screened in the larger NHW and Black samples for associations with HDL-cholesterol levels. We detected a total of 26 variants (25 single nucleotide substitutions and 1 microsatellite); 12 of which were previously unreported. Of the 12 new variants, 6 were present in NHWs and 6 in Blacks. We observed an increased number of minor alleles of APOA2 variants (either increased heterozygosity for rare variants or increased homozygosity for common variants) in subjects with low HDL levels, more pronounced in NHWs. We performed a preliminary analysis using a total of 9 variants that were screened in NHWs (n=624, 8 variants) and Blacks (n=788, 5 variants) with TaqMan SNP genotyping assays to date. For the 8 variants that were screened in NHWs, we found significant association in only females for variants 2233C>T/rs6413453 (p=0.028) and 3251A>G (p=0.023). Completing genotyping for remaining variants will allow us to determine the extent to which APOA2 variants influence HDL levels.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Hollister, Sally
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, M
Committee CoChairDemirci, F Yesimyesim.demirci@mail.hgen.pitt.eduFYD1
Committee MemberFinegold, David Ndnf@pitt.eduDNF
Date: 26 June 2008
Date Type: Completion
Defense Date: 9 April 2008
Approval Date: 26 June 2008
Submission Date: 11 April 2008
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: APOA2; HDL-cholesterol; polymorphism; sequencing
Other ID:, etd-04112008-112445
Date Deposited: 10 Nov 2011 19:35
Last Modified: 15 Nov 2016 13:39


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