Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea

Abstract

Objective-Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of artemisinin drugs, a novel series of antimalarials. Our aim was to analyze the prevalence of the most commonly observed CYP2B6 alleles in malaria-endemic populations of West Africa (WA) and Papua New Guinea (PNG).Methods-Using a post-PCR ligation detection reaction-fluorescent microsphere assay, frequencies of CYP2B6*1A, *2, *3, *4, *5, *6, *7, and *9 were determined in WA (n=166) and PNG (n=174). To compare with the results of previous studies, we also determined the allele frequencies in 291 North Americans of various ethnic groups.Results-Significant differences were observed between WA and PNG for the frequencies of alleles CYP2B6*1A (45% vs 33%, P = 0.003), *2 (4% vs. 0%, P<0.001), *6 (42% vs 62%, P<0.001), and *9 (8% vs 1%, P<0.001), and genotypes *1A/*9 (9% vs 0%, P<0.001) and *6/*6 (17% vs 43%, P<0.001). The frequencies of CYP2B6 genotypes in the populations were in HardyWeinberg equilibrium, except for PNG where an overall significant deficit of heterozygosity was observed (H O =0.431, H E =0.505, P=0.004). The allele frequencies in Asian-Americans and Caucasians-Americans were comparable to those documented for Japanese and Caucasian populations.Conclusions-CYP2B6 variants, previously shown to affect metabolism of a variety of drugs, occur in WA and PNG, and there are significant genetic differences at the CYP2B6 locus in these populations. It may be important to determine if these differences alter the efficacy of artemisinin drugs.

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

“…One explanation for these observations may center on the joint contribution of both cytochrome P450 2B6 (CYP2B6)and UGT2B7 polymorphisms. CYP2B6 is involved in the phase I metabolism of artemisinin drugs [27 for references], and CYP2B6 516G>T, associated with reduced CYP2B6 protein expression and activity [54], is the most commonly observed SNP among West Africans (50%) and Papua New Guineans (64%) [27]. We found that 33% of West Africans and 42% of Papua New Guineans carried both CYP2B6 516G>T and UGT2B7 802C>T SNPs.…”

“…Genotyping of UGT1A9 and UGT2B7 SNPs was performed using a high throughput, post-PCR oligonucleotide ligation detection reaction-fluorescent microspheres assay (LDR-FMA) [27]. Our SNP genotyping assay is divided into 3 steps: (1) LDR, (2) FM hybridization, and (3) streptavidin-R-phycoerythrin (SA-PE) signal detection using the Bio-Plex suspension array system, which includes a fluorescence reader and the Bio-Plex Manager analytical software (Bio-Rad Laboratories, Hercules, Calif.).…”

“…Our SNP genotyping assay is divided into 3 steps: (1) LDR, (2) FM hybridization, and (3) streptavidin-R-phycoerythrin (SA-PE) signal detection using the Bio-Plex suspension array system, which includes a fluorescence reader and the Bio-Plex Manager analytical software (Bio-Rad Laboratories, Hercules, Calif.). The basic principle of this assay and buffers/ conditions to perform these steps has been recently described [27]. This multiplex genotyping assay was used for the simultaneous detection of all 6 nonsynonymous SNPs (3 in UGT1A9 and 3 in UGT2B7) in each sample.…”

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

“…This procedure is described in detail elsewhere. 33 Common/conserved and allele-specific probe sequences used in this assay are listed in Supplemental Supplemental Table 2 (available online at www.ajtmh.org ). A multiplex assay was used for simultaneous detection of TLR2 and TLR9 SNPs.…”

“…Conditions for the LDR step of this assay are described elsewhere. 33 Mean fluorescence intensity (MFI) values were used to calculate the allelic ratio for each SNP by dividing the allele-specific MFI value by the sum of the MFI values for that SNP (allele A/A + B = A n and allele B/A + B = B n ), where A and B are the 2 alleles of a SNP. To be homozygous for a particular allele, the allelic ratio must be > 0.75.…”