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The Genetic Contributions to HAART-Associated Dyslipidemia

Nicholaou, Matthew James (2011) The Genetic Contributions to HAART-Associated Dyslipidemia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Highly active anti-retroviral therapy (HAART) has been successful in delaying the progression to AIDS in HIV infected individuals. Exposure to HAART can result in metabolic side effects such as dyslipidemia and lipodystrophy in a subset of treated patients. We used a custom designed Illumina GoldenGate Genotyping assay to investigate the genetic susceptibility to dyslipidemia attributed to HIV infection and HAART treatment. 1,945 men were selected from the Multicenter AIDS Cohort Study (MACS) for genotyping and phenotypic analysis of serum lipid levels. This population was stratified by biogeographical ancestry and HIV/HAART status. Among men of European ancestry, those who were infected with HIV and receiving HAART had significantly lower serum low-density lipoprotein cholesterol (LDL-C, P = 1.90 x10-4) and high-density lipoprotein cholesterol levels (HDL-C, P < 1.00 x10-7), with significantly higher serum triglyceride (TRIG, P < 1.00 x10-7) levels compared to HIV/HAART (-/-) controls. Among men of mixed African and European ancestry, those who were HIV/HAART (+/+) had significantly lower LDL-C (P = 1.80 x10-4) levels compared to HIV/HAART (-/-) controls. Four SNPs; rs1532624 (P = 1.66 x10-5), rs1532625 (P = 2.36 x10-5), rs711752 (P = 4.48 x10-5), and rs708272 (P = 4.59 x10-5), located in the CETP gene region on chromosome 16 had statistically significant associations with serum HDL-C levels in HIV/HAART (+/+) European men. One SNP, rs261334 (P = 6.53 x10-6), located in the LIPC gene region on chromosome 15 was associated with serum LDL-C levels and another SNP, rs4783961 (P = 9.83 x10-6) located in the CETP gene region, was associated with HDL-C levels in HIV/HAART (+/+) men of mixed African and European ancestry. These results show that dyslipidemia attributed to HAART varies depending on biogeographical ancestry and implicates two genes associated with serum lipid levels in these patients. Understanding the mechanism of HAART-associated dyslipidemia is important to global public health because nearly half of the estimated 30 million individuals infected with HIV are receiving or eligible to receive these drugs and are at risk of these HAART related side effects. Our results can also aid in identifying those individuals at greatest risk of developing HAART-associated dyslipidemia, which could improve monitoring and management of care given to these patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Nicholaou, Matthew Jamesmnicholaou@gmail.commnicholaou@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMartinson, Jeremyjmartins@pitt.edujmartins@pitt.edu
Committee MemberFeingold, Eleanorfeingold@pitt.edufeingold@pitt.edu
Committee MemberKingsley, H, Lawrencekingsley@pitt.edukingsley@pitt.edu
Committee MemberEvans, Rhobertrwe2@pitt.edurwe2@pitt.edu
Date: 23 September 2011
Date Type: Completion
Defense Date: 11 July 2011
Approval Date: 23 September 2011
Submission Date: 26 July 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: DrPH - Doctor of Public Health
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Biogeographical Ancestry; cardiovascular disease; CETP; dyslipidemia; Genetics; Genotyping; HAART; HIV; LIPC; MACS; SNP
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07262011-175247/, etd-07262011-175247
Date Deposited: 10 Nov 2011 19:54
Last Modified: 20 Jan 2012 18:15
URI: http://d-scholarship.pitt.edu/id/eprint/8642

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