Strong effects of parasite genotype on drug susceptibility in the Indian subcontinent

Abstract

Intracellular parasites of the Leishmania donovani species complex cause visceral leishmaniasis (VL). For parasitic diseases, VL has a mortality rate second only to malaria, and is associated with poverty-stricken areas of the world: primarily Brazil, East Africa and the Indian subcontinent (ISC). Miltefosine (MIL) and the antimonal sodium stibogluconate (SSG) are drugs used in the treatment of leishmaniasis. However, treatment efficacy is variable, and the numbers of reports of parasite resistance to both drugs have risen since their introductions, particularly in the ISC. To assess the level of parasite genotype contribution to drug resistance, we utilised the sequencing and associated drug susceptibility data from Imamura et al. (2016) to estimate heritability and GWAS using LDAK. We obtained strong heritability results, with mainly SNP/indel variations associated with SSG and copy number variants associated with MIL resistance, respectively. However, GWAS results were inconclusive, suggesting that, although the parasite genotype directly influences drug resistance, the effect might be multifactorial.