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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04082009-141813 |
| Date | 29 June 2009 |
| Creators | Hill, Sarah Elizabeth |
| Contributors | F. Yesim Demirci, David Finegold, M. Ilyas Kamboh |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04082009-141813/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0026 seconds