Human cytochrome P450 2B6 genetic variability in Botswana: a case of haplotype diversity and convergent phenotypes

Abstract

Identification of inter-individual variability for drug metabolism through cytochrome P450 2B6 (CYP2B6) enzyme is important for understanding the differences in clinical responses to malaria and HIV. This study evaluates the distribution of CYP2B6 alleles, haplotypes and inferred metabolic phenotypes among subjects with different ethnicity in Botswana. A total of 570 subjects were analyzed for CYP2B6 polymorphisms at position 516 G > T (rs3745274), 785 A > G (rs2279343) and 983 T > C (rs28399499). Samples were collected in three districts of Botswana where the population belongs to Bantu (Serowe/Palapye and Chobe) and San-related (Ghanzi) ethnicity. The three districts showed different haplotype composition according to the ethnic background but similar metabolic inferred phenotypes, with 59.12%, 34.56%, 2.10% and 4.21% of the subjects having, respectively, an extensive, intermediate, slow and rapid metabolic profile. The results hint at the possibility of a convergent adaptation of detoxifying metabolic phenotypes despite a different haplotype structure due to the different genetic background. The main implication is that, while there is substantial homogeneity of metabolic inferred phenotypes among the country, the response to drugs metabolized via CYP2B6 could be individually associated to an increased risk of treatment failure and toxicity. These are important facts since Botswana is facing malaria elimination and a very high HIV prevalence.

Past and current biological factors affecting malaria in the low transmission setting of Botswana: A review

“…A recent report on drug resistance markers in P. falciparum demonstrated that the parasite harbors certain variation in several of the genes analyzed. In the study, 95.8% of samples showed N86 polymorphism at Plasmodium falciparum multidrug resistance 1 gene ( pfmdr1 ) ( Tawe et al, 2018a , Tawe et al, 2018b ) known to confer sensitivity to 4-aminoquinolines ( Howes et al, 2015 ) (chloroquine and amodiaquine) but also associated to a reduced sensitivity to lumefantrine ( Wongsrichanalai et al, 2002 ). This suggests that a similar situation to that seen in Malawi ( Kublin et al, 2003 ) has unfolded in Botswana with regards to chloroquine.…”

“…Additionally, the recent imposed sedentarism to the traditionally n omadic hunter-gatherers Khoisan communities of the Kalahari region of Botswana ( Kent, 1995 ; Winters, 2015 ; Ikeya, 2018 ) may also have an impact on malaria acquisition risk. Recent reports have also indicated that this genetic diversity plays a significant role in pharmacogenetics pertaining also to antimalarial drugs used in Botswana ( Tawe et al, 2018a , Tawe et al, 2018b ). In Botswana, the peculiar genetic admixture between these two populations clusters specific genotypes more than other Southern African countries ( Retshabile et al, 2018 ).…”

“…More importantly, P. falciparum may be generally tolerant to lumefantrine, which is one of the compounds utilized in first line treatment together with the highly efficacious artemether. The same study found two synonymous mutations -V555V and R513R -in the propeller domain of the P. falciparum Kelch13 gene (pfk13) (Tawe et al, 2018a(Tawe et al, , 2018b which is implicated in the resistance to artemisinin. It should be noted that neither of these genetic variants were associated with a delayed parasite clearance phenotype.…”

“…Admixture has occurred between the two ethnic groups to various extents (Schuster et al, 2010). As a consequence, there is a wider spectrum of genotypes and phenotypes when considering genetic characteristics such as Duffy antigen, sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD), and detoxifying liver enzymes (Howes et al, 2011;Motshoge et al, 2018;Tawe et al, 2018aTawe et al, , 2018b. These human genetic factors play a pivotal role in susceptibility to malaria infection and associated morbidity (Haldane, 1949;Sirugo et al, 2014), as well as for metabolism of medications currently on the market (Tawe et al, 2018a(Tawe et al, , 2018b.…”

“…In Botswana, the peculiar genetic admixture between these two populations clusters specific genotypes more than other Southern African countries (Retshabile et al, 2018). In particular, this genetic structure has potential implications on susceptibility and resistance to infectious diseases and treatment outcomes (Retshabile et al, 2018;Tawe et al, 2018aTawe et al, , 2018bThami and Chimusa, 2019).…”