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P-glycoprotein-like protein, a possible genetic marker for ivermectin resistance selection in Onchocerca volvulus

Bourguinat, Catherine, Ardelli, Bernadette F., Pion, Sébastien D.S., Kamgno, Joseph, Gardon, Jacques, Duke, Brian O.L., Boussinesq, Michel, Prichard, Roger K.
Molecular and biochemical parasitology 2008 v.158 no.2 pp. 101-111
onchocerciasis, ivermectin, alleles, drugs, DNA, males, disease control programs, gastrointestinal nematodes, amino acids, genetic markers, genotype, patients, clinical trials, Onchocerca volvulus, females, ABC transporters, single nucleotide polymorphism, Cameroon
Ivermectin (IVM) is the only safe drug for mass-treatment of onchocerciasis. IVM resistance has been reported in gastrointestinal nematode parasites of animals. A reduction in response to IVM in Onchocerca volvulus could have significant consequences for the onchocerciasis control programs. We have found evidence that, in O. volvulus, repeated IVM treatment selects for specific alleles, of P-glycoprotein-like protein (PLP), a half-sized ABC transporter. In this study, O. volvulus samples were derived from a clinical trial in Cameroon, in which patients were sampled before, and following 3 years (1994-1997) of IVM treatments. There were four treatment groups: 150μg/kg (1xp.a. or 4xp.a.) and 800μg/kg (1xp.a. or 4xp.a.). DNA of O. volvulus macrofilariae was genotyped over a 476bp region of the PLP gene and at two control genes. Of the six polymorphic positions found in the PLP amplicon, three of them showed significant selection after 4xp.a. treatment with IVM (total of 13 IVM treatments) in female worms, and one of the same single nucleotide polymorphisms (SNPs) showed significant selection in the male worms. One of the selected SNPs in the female worms caused an amino acid coding change in the putative protein sequence. We found a clear selection of some genotypes, a high SNPs association and a loss of polymorphism following 4xp.a. treatment with IVM. These PLP SNPs and genotypes could be useful markers to follow selection for IVM resistance in the field.