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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.

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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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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairMartinson, Jeremyjmartins@pitt.edu
    Committee MemberFeingold, Eleanorfeingold@pitt.edu
    Committee MemberKingsley, H, Lawrencekingsley@pitt.edu
    Committee MemberEvans, Rhobertrwe2@pitt.edu
    Title: The Genetic Contributions to HAART-Associated Dyslipidemia
    Status: Unpublished
    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.
    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; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: DrPH - Doctor of Public Health
    URN: etd-07262011-175247
    Uncontrolled Keywords: Biogeographical Ancestry; cardiovascular disease; CETP; dyslipidemia; Genetics; Genotyping; HAART; HIV; LIPC; MACS; SNP
    Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
    Date Deposited: 10 Nov 2011 14:54
    Last Modified: 20 Jan 2012 13:15
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-07262011-175247/, etd-07262011-175247

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