Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Genetic influence of sequence variants in SCARB1 and ABCA1 genes on major lipid traits: a candidate gene association study

Niemsiri, Vipavee (2015) Genetic influence of sequence variants in SCARB1 and ABCA1 genes on major lipid traits: a candidate gene association study. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img]
Preview
PDF (APPENDIX A: Supplemental Material for Chapter 6.0)
Submitted Version

Download (3MB)
[img]
Preview
PDF (APPENDIX B: Supplemental Material for Chapter 7.0)
Submitted Version

Download (3MB)
[img]
Preview
PDF (APPENDIX C: Supplemental Material for Chapter 8.0)
Submitted Version

Download (7MB)
[img]
Preview
PDF (ETD Dissertation)
Submitted Version

Download (18MB)
[img]
Preview
Image (TIFF) (Figure 6.1)
Submitted Version

Download (25MB)
[img]
Preview
Image (TIFF) (Figuue 6.2)
Submitted Version

Download (5MB)
[img]
Preview
Image (JPEG) (Figure A1)
Submitted Version

Download (4MB)
[img]
Preview
Image (JPEG) (Figure A2)
Submitted Version

Download (2MB)
[img]
Preview
Image (JPEG) (Figure A3)
Submitted Version

Download (2MB)
[img]
Preview
Image (TIFF) (Figure 7.2)
Submitted Version

Download (1MB)
[img]
Preview
Image (TIFF) (Figure 7.3)
Submitted Version

Download (3MB)
[img]
Preview
Image (JPEG) (Figure B1)
Submitted Version

Download (2MB)
[img]
Preview
Image (JPEG) (Figure B2)
Submitted Version

Download (1MB)
[img]
Preview
PDF (Figure B3)
Submitted Version

Download (1MB)
[img]
Preview
PDF (Figure B4)
Submitted Version

Download (2MB)
[img]
Preview
Image (JPEG) (Figure 8.1)
Submitted Version

Download (3MB)
[img]
Preview
PDF (Figure 8.2)
Submitted Version

Download (485kB)
[img]
Preview
PDF (Figure 8.3)
Submitted Version

Download (196kB)
[img]
Preview
PDF (Figure 8.4A)
Submitted Version

Download (11MB)
[img]
Preview
PDF (Figure 8.4B)
Submitted Version

Download (4MB)
[img]
Preview
PDF (Figure C1)
Submitted Version

Download (4MB)
[img]
Preview
Image (JPEG) (Figure C3)
Submitted Version

Download (7MB)
[img]
Preview
Image (JPEG) (Figure C4)
Submitted Version

Download (8MB)
[img]
Preview
Image (JPEG) (Figure C5)
Submitted Version

Download (5MB)

Abstract

Background: Abnormal lipid-lipoprotein levels are associated with the risk of coronary heart disease (CHD), a major public health problem worldwide. Scavenger receptor class B type 1 (SCARB1) and ATP-binding cassette transporter A1 (ABCA1) play important roles in the reverse cholesterol transport. We aimed to identify genetic variants in two lipid genes, SCARB1 and ABCA1, and elucidated their contribution to major lipid traits in two populations; Non-Hispanic Whites (NHWs) and African Blacks (ABs).

Methods: We resequenced mainly the exons and exon-intron boundaries of SCARB1 and ABCA1 genes in 190 individuals (95 NHWs; 95 ABs) with extreme high-density lipoprotein cholesterol (HDL-C) levels, followed by genotyping of selected variants in the entire sample (623 NHWs; 788 ABs). Lipid associations were evaluated by multiple analyses.

Results: Initial sequencing identified 105 SCARB1 (44/NHWs; 83/ABs) and 404 ABCA1 variants, including 58 novel ones (21 SCARB1; 37 ABCA1). Among genotyped variants, 159 SCARB1 (69/NHWs; 137/ABs) and 182 ABCA1 variants passed quality controls and were tested for associations. Gene-based tests revealed associations (P <0.05) of SCARB1 with HDL-C and apolipoprotein B (apoB), while ABCA1 demonstrated association with triglycerides (TG). Eleven common SCARB1 variants were nominally associated (P <0.05) with HDL-C or apoB in single-site analyses, and four of them (3/apoB/NHWs; 1/HDL-C/ABs) survived after multiple testing correction. The best signal of SCARB1 was rs4765615 (apoB/P = 0.0059) in NHWs and rs11057851 (HDL-C/P = 0.0043) in ABs. Twenty-one common ABCA1 variants were nominally associated with TG, and 16 remained significant after multiple testing correction. The best signal of ABCA1 with TG was rs2066716 (p.Thr14217Thr; P = 0.0016) in NHWs. A group of rare SCARB1 variants (frequency ≤1%) were associated with apoB (P = 0.0284) in NHWs, and HDL-C (P = 0.0478) in ABs. Several haplotypes and regions of SCARB1 and ABCA1 genes showed associations (global P <0.05) with lipid levels.

Public health relevance: Our findings demonstrate the genetic contribution of common and rare SCARB1 and ABCA1 variants to the regulation of lipoprotein-lipid levels in the general population, supporting the roles of SCARB1 and ABCA1 genes in lipid metabolism. Further investigations of these two genes may lead to the development of potential therapeutic interventions for CHD.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Niemsiri, Vipaveevin4@pitt.eduVIN4
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKamboh, M. Ilyaskamboh@pitt.eduKAMBOH
Committee CoChairDemirci, F. Yesimfyd1@pitt.eduFYD1
Committee MemberBunker, Clareann H.bunkerc@pitt.eduBUNKERC
Committee MemberBarmada, M. Michaelbarmada@pitt.eduBARMADA
Committee MemberKammerer, Candace M.cmk3@pitt.eduCMK3
Date: 30 September 2015
Date Type: Publication
Defense Date: 30 July 2015
Approval Date: 30 September 2015
Submission Date: 22 July 2015
Access Restriction: 4 year -- Restrict access to University of Pittsburgh for a period of 4 years.
Number of Pages: 512
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: ABCA1; candidate gene association study; coronary heart disease; genetic variation; haplotypes; lipids; SCARB1;sequencing, DNA
Date Deposited: 30 Sep 2015 16:00
Last Modified: 01 Sep 2019 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/25673

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item