Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders.
BACKGROUND
Single-nucleotide polymorphisms in genes involved in lipoprotein and adipocyte metabolism may explain why dyslipidemia and lipoatrophy occur in some but not all antiretroviral therapy (ART)-treated individuals.


METHODS
We evaluated the contribution of APOC3 -482C-->T, -455T-->C, and 3238C-->G; epsilon 2 and epsilon 4 alleles of APOE; and TNF -238G-->A to dyslipidemia and lipoatrophy by longitudinally modeling >2600 lipid determinations and 2328 lipoatrophy assessments in 329 ART-treated patients during a median follow-up period of 3.4 years.


RESULTS
In human immunodeficiency virus (HIV)-infected individuals, the effects of variant alleles of APOE on plasma cholesterol and triglyceride levels and of APOC3 on plasma triglyceride levels were comparable to those reported in the general population. However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 and [corrected] APOE were at risk of extreme hypertriglyceridemia. They had median plasma triglyceride levels of 7.33 mmol/L, compared with 3.08 mmol/L in the absence of ART. The net effect of the APOE*APOC3*ritonavir interaction was an increase in plasma triglyceride levels of 2.23 mmol/L. No association between TNF -238G-->A and lipoatrophy was observed.


CONCLUSIONS
Variant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV. Interactions between genotypes and ART can lead to severe hyperlipidemia. Genetic analysis may identify patients at high risk for severe ritonavir-associated hypertriglyceridemia.
Tarr
Philip E
PE
Infectious Diseases Service, University Hospital, Lausanne, Switzerland. philip.tarr@chuv.ch
Taffé
Patrick
P
Bleiber
Gabriela
G
Furrer
Hansjakob
H
Rotger
Margalida
M
Martinez
Raquel
R
Hirschel
Bernard
B
Battegay
Manuel
M
Weber
Rainer
R
Vernazza
Pietro
P
Bernasconi
Enos
E
Darioli
Roger
R
Rickenbach
Martin
M
Ledergerber
Bruno
B
Telenti
Amalio
A
D000483:Alleles; D019380:Anti-HIV Agents / Q000009:adverse effects*; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D013557:Switzerland; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D019380:Anti-HIV Agents; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D014409:Tumor Necrosis Factor-alpha