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Aims: Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. Materials & methods: Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated. Results: All CYP2C19/CYP2C9 alleles obeyed Hardy–Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC0–24) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher Cmax (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071). Conclusion: CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.

As an anti-inflammatory mediator IL10 is beneficial in certain contexts and deleterious in others. As increased production of IL10 favours protection against inflammatory disease, whereas low production promotes elimination of foreign pathogens by the host, we investigated the possible influence of balancing selection at this locus. We began by resequencing 48 European and 48 African chromosomes across 2.2 kb of the IL10 promoter region, and compared this with four neighbouring gene regions: MK2, IL19, IL20 and IL24. Analysis of nucleotide diversity showed a positive Tajima's D-test for IL10 in Europeans, of borderline statistical significance (1.89, P=0.05). Analysis of F(st) values showed significant population divergence at MK2, IL19, IL20 and IL24 (P

Linkage disequilibrium across the human genome is generally lower in West Africans than Europeans. However in the 5q31 region, which is rich in immune genes, we find significantly more examples of apparent nonrecombination between distant marker pairs in West Africans. Much of this effect is due to SNPs that are absent in Europeans, possibly reflecting recent positive selection in the West African population.

We investigated the association between severe malaria and genetic variation of IL10 in Gambian children, as several lines of evidence indicate that IL10 is protective against severe malaria and that IL10 production is genetically determined. We began by identifying five informative SNPs in the Gambian population that were genotyped in a combined case-control and intrafamilial study including 654 cases of severe malaria, 579 sets of parents and 459 ethnically matched controls. No significant associations were identified with individual SNPs. One haplotype of frequency 0.11 was strongly associated with protection against severe malaria in the case-control analysis (odds ratio 0.52, P=0.00002), but the transmission disequilibrium test in families showed no significant effect. These findings raise the question of whether IL10 associations with severe malaria might be confounded by foetal survival rates or other sources of transmission bias.

Background Cytochrome P450 CYP2C19 metabolizes a wide range of pharmacologically active substances and a relatively small number of naturally occurring environmental toxins. Poor activity alleles of CYP2C19 are very frequent worldwide, particularly in Asia, raising the possibility that reduced metabolism could be advantageous in some circumstances. The evolutionary selective forces acting on this gene have not previously been investigated. We analyzed CYP2C19 genetic markers from 127 Gambians and on 120 chromosomes from Yoruba, Europeans and Asians (Japanese + Han Chinese) in the Hapmap database. Haplotype breakdown was explored using bifurcation plots and relative extended haplotype homozygosity (REHH). Allele frequency differentiation across populations was estimated using the fixation index (FST) and haplotype diversity with coalescent models. Results Bifurcation plots suggested conservation of alleles conferring slow metabolism (CYP2C19*2 and *3). REHH was high around CYP2C19*2 in Yoruba (REHH 8.3, at 133.3 kb from the core) and to a lesser extent in Europeans (3.5, at 37.7 kb) and Asians (2.8, at −29.7 kb). FST at the CYP2C19 locus was low overall (0.098). CYP2C19*3 was an FST outlier in Asians (0.293), CYP2C19 haplotype diversity