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Modeling the Influence of Polymorphisms of Several Genes Involved in Lipid Metabolism on the Risk of ART-associated Dyslipidemia
Mireia Arnedo*1, P Taffe2, H Furrer3, B Hirschel4, M Battegay5, R Weber6, P Vernazza7, E Bernasconi8, A Telenti1, P Tarr9, and Swiss HIV Cohort Study
1Inst of Microbiology, Univ of Lausanne, Switzerland; 2Swiss HIV Cohort Study Data Ctr, Lausanne; 3Univ Hosp, Berne, Switzerland; 4Geneva Univ Hosp, Switzerland; 5Univ Hosp, Basel, Switzerland; 6Univ Hosp, Zürich, Switzerland; 7Kantonsspital, St Gallen, Switzerland; 8Hosp Civico, Lugano, Switzerland; and 9Ctr Univ Hosp Vaudois, Lausanne, Switzerland
Background: Dyslipidemia in
HIV-1-infected individuals receiving ART reflects the complex contribution of
treatment-specific effects against a background of genetic predisposition.
Methods: We evaluated the contribution of polymorphisms
to dyslipidemia in APOE, APOC3, APOA5,
LPL, LIPC, LIPG, ABCA1, ADRB2, SCARB1,
TNF, and CETP. We used longitudinal modeling of 3300 lipid
determinations in 307 ART-treated patients (testing cohort) during a median
follow-up period of 4.6 years. Polymorphisms with a significant effect in the
testing cohort were reevaluated in an independent validation cohort of 88
patients that contributed 757 lipid determinations during the same duration of
ART exposure. Genotyping methods included Taqman
allelic discrimination, restriction fragment length polymorphism analysis and
direct sequencing.
Results: The effects of variant alleles APOE e2/e4, APOC3 –482C>T/
–455T>C/ 3238C>G, APOA5 64G>C, CETP 279G>A on triglyceride (TG) levels were comparable to those
reported in the general population. In addition, ABCA1 2962 A>G was
found associated with elevated TG levels. The overall contribution of these
variants was confirmed in the validation cohort. The effect of variant allele
of CETP –629C>A on plasma HDL cholesterol
was comparable to that reported in the general population. In addition, APOA5
64G>C and –1131T>C variants were associated with low HDL cholesterol
levels. In patients receiving ritonavir (RTV), the
most unfavorable APOE/APOC3/APOA5/CETP/ABCA1 genotype resulted in median
TG levels of 4.17 mmol/L, while the absence of RTV, and a favorable genetic profile resulted in a median TG
level of 1.64 mmol/L. In patients receiving protease
inhibitor (PI)-sparing ART, the favorable CETP/APOA5 genotype resulted
in median HDL cholesterol levels of 1.40 mmol/L,
while individuals with no ART and an unfavorable genetic profile presented
median HDL levels of 0.90 mmol/L.
Conclusions: The additive effect of multiple genetic
variants influence the net effect of RTV on triglycerides and the beneficial
effect of PI-sparing regimens on HDL-cholesterol. Genetic profiling may
identify patients at risk for ART-associated dyslipidemia.
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