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Single Nucleotide Polymorphisms Identified in the Cytochrome P450 2B6 Gene among Ugandan and Zimbabwean HIV-1-infected Patients: Potential Implications for Efavirenz Metabolism
Y Jamshidi1, L Tinworth1, S Andrews2, T Nithiyananthan1, S Fredericks1, M Ndoro2, Tariq Sadiq*1,2, and Tariq Sadiq*1,2
1St George's, Univ of London, UK and 2St George's Hlthcare NHS Trust, London, UK
Background:
Polymorphisms in the gene for P4502B6 (CYP2B6), by which efavirenz
(EFV) is primarily metabolized, have been associated with high EFV
concentrations and related central nervous system toxicity. Recent studies
suggest marked ethnic differences in frequencies of single nucleotide
polymorphisms (SNP) of CYP2B6—such as G516T, A785G, and T983C—that may
critically affect EFV metabolism. Generally, Africans exhibit higher levels of
genetic diversity than non-Africans and show higher degrees of population
stratification. Further studies exploring the clinical influence of ethnic
differences in CYP2B6 alleles in
multiple African populations are thus warranted. This study aims to compare
frequencies of allelic variants of CYP2B6
in Ugandan and Zimbabwean HIV-1-infected patients with those in other ethnic
groups reported in the literature.
Methods: Ugandan and Zimbabwean HIV-1-infected patients
routinely attending our clinic were invited to participate irrespective of
stage of disease and ART history. DNA was extracted from whole blood. Nested polymerase
chain reaction (PCR) was used to amplify the exonic
regions of CYP2B6, and sequencing was
carried out using Applied Biosystems BigDye v3.1 and
3100.
Results: To date, we have recruited 34 patients (24
Ugandan and 10 Zimbabwean) of whom 24 are female; median age, 38.0 (IQR 34.2 to
44.5); median CD4 count, 296/mm3, (IQR 203 to 424); median HIV-1 RNA
load ≤50 copies/mL (IQR <50 to 346); and 27
on ART. For the G516T SNP, G/G, G/T, and T/T genotypes were 35%, 44%, and 21%,
respectively; for the A785G SNP, A/A, A/G, and GG genotypes were 35%, 47%, and
18%, respectively; for the T983C SNP T/T, T/C, and C/C genotypes were 86%, 14%,
and 0%, respectively. Historically this compares to a combined prevalence of
both homozygosity and heterozygosity
for G516T, A785G, and T983C of: 48.8%,
47.5%, and 6.6%, respectively, in Ghanaians; 27.8%, 29.8%, and 4.4%,
respectively, in African Americans; 25.5%, 28.7%, and 0%, respectively, in
Caucasians. In 1 patient a nucleic acid change was found in the heterozygous
condition, G1048T, resulting in a switch from glutamic
acid to a stop codon, E350X.
Conclusions:
In this combined group of Ugandans and
Zimbabweans, high rates for key CYP2B6
SNP that may affect metabolism of, and clinical
response to EFV are observed. A novel SNP resulting in premature termination of
CYP2B6 transcription with the
potential to markedly affect EFV metabolism is described and warrants further
investigation.
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