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Structural genetic variation and dyslipidemia among men in the multicenter aids cohort study

Marino, Rebecca B (2014) Structural genetic variation and dyslipidemia among men in the multicenter aids cohort study. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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While highly active antiretroviral therapy has resulted in slowing the rate of progression to AIDS among individuals infected with human immunodeficiency virus, it has also resulted in detrimental metabolic lipid changes. As this dyslipidemia is not observed for all individuals receiving antiviral therapy, genetic factors likely influence the increased susceptibility for some. We designed this study to investigate the role of human gene copy number variation (CNV) in therapy associated dyslipidemia and risk assessment as well as investigating mRNA expression levels to identify new genetic variants associated with this lipid dysfunction.

A custom multiplex ligation dependent probe amplification assay was developed to analyze CNV of reverse cholesterol transport pathway (RCT) genes within individuals (n=320) enrolled in the Multicenter AIDS Cohort Study (MACS). The resulting analysis demonstrated that CNV was present in extremely low levels within these genes as the only loss identified and verified was observed for CETP in one individual. To further identify lipid metabolism associated genes, blood-derived RNA from 437 MACS participants was analyzed using the Illumina Human HT-12 microarray. Significant transcripts were present only for variation in HDL-C and Triglyceride levels with 4 differentially expressed transcripts (HDC, CPA3, GATA2 & SLC45A3) repeatedly identified. Finally, to determine if CNV can alter the functionality of single nucleotide polymorphism (SNP) genotyping, we analyzed SNPs in regions with/without CNV by Fluorescence Polarization, TaqMan SNP genotyping assays and Sanger Sequencing. SNPs in regions of no CNV were observed to have 3 distinct genotype groups but in the presence of CNV, this distinction was lost resulting in a continuous spread of allele values.

These results show that CNV is not a major factor in the development of antiviral therapy-associated dyslipidemia. Other genetic variants, such as HDC, may explain some of the variability. Furthermore, when CNV is present it hinders the ability to SNP genotype when using the standard assumption of three genotype groups. As antiretroviral therapy is becoming more available for the over 35 million living with HIV-1, identification of factors leading to antiviral-associated dyslipidemia is important for Public Health. Here, we have identified genes that could serve as markers for lipid level changes helping physicians custom tailor therapy and care for these individuals.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Marino, Rebecca Brsb24@pitt.eduRSB24
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMartinson, Jeremy Jjmartins@pitt.eduJMARTINS
Committee MemberKingsley, Lawrence A.kingsley@pitt.eduKINGSLEY
Committee MemberRinaldo, Charles R.rinaldo@pitt.eduRINALDO
Committee MemberFerrell, Robert E
Date: 29 September 2014
Date Type: Publication
Defense Date: 15 August 2014
Approval Date: 29 September 2014
Submission Date: 1 September 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 163
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Copy Number Variation, HAART, Dyslipidemia, HIV-1, MACS, Transcriptome, SNP
Date Deposited: 29 Sep 2014 21:03
Last Modified: 15 Nov 2016 14:23


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