Relationship between polymerase gamma (POLG) polymorphisms and antiretroviral therapy-induced lipodystrophy in HIV-1 infected patients: a case-control study.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used for the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA), which may contribute to severe mitochondrial toxicity including lipodystrophy, through the inhibition of polymerase gamma (POLG). Polymorphisms of POLG could explain the variation in mitochondrial toxicity in HIV-1-infected patients. We explored the relationship between selected polymorphisms of POLG and lipodystrophy related to NRTIs. We studied single nucleotide polymorphisms (SNP) at three amino acid residues (R1142, E1143 and R1146) and the CAG repeats of POLG in a case-control study including HIV-1 treated patients with lipodystrophy (n=69) and 2 controls (without lipodystrophy) per case matched by age, race and sex (n=138). Compared with matched controls, the polymorphisms in E1143 were significantly more frequent in case patients with lipodystrophy (aOR=4.7; p=0.048), and this was associated with a significant decrease of mtDNA in PBMC. In addition, among the parameters tested, the conditional logistic regression showed that the lipodystrophy has a strong link with E1143 polymorphisms, associated with D4T treatment (aOR=9.29, p=0.002). In conclusion, patients harbouring the changes of E1143 in the catalytic site of POLG exhibit a 4-fold increased risk to develop lipodystrophy than HIV-1 treated patients who do not have changes in E1143 and this risk can increase if the patient presenting the SNP received D4T. These could be due to decreased content of mtDNA in PBMC in these patients. Therefore, the toxicity of NRTIs leading to lipodystrophy in some HIV-1 infected patients could be explained in part by the occurrence of POLG polymorphisms.
Chiappini
Franck
F
AP-HP, Hôpital Paul Brousse, Service de Biochimie et de Biologie Moléculaire, Université Paris-11, 12, Avenue Paul Vaillant Couturier, Villejuif Cedex, France. fchiappi@bidmc.harvard.edu
Teicher
Elina
E
Saffroy
Raphaël
R
Debuire
Brigitte
B
Vittecoq
Daniel
D
Lemoine
Antoinette
A
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000032:analysis / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008060:Lipodystrophy / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human