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Genome Wide Association Study for visceral leishmaniasis

Jenefer Blackwell

Shyam Sundar, Selma Jeronimo, Muntaser Ibrahim, Mary Wilson.

We wish to undertake a genome-wide association study to identify the genes that control susceptibility to visceral leishmaniasis in India and Brazil, and to determine whether the same genes contribute to susceptibility to disease in Sudan. This will allow us to gain a better understanding of the molecular and cellular basis of disease, with the potential to lead to development of novel therapies. SNP-chip data generated for the control subjects as part of this study can be used for future analysis of other complex diseases in India and Brazil.

500,000 new cases of Kala-azar or clinical visceral leishmaniasis (VL) caused by protozoa of the Leishmania donovani species complex (L. donovani, L. archibaldi, L. infantum/chagasi) occur each year. Clinical VL is fatal unless treated. There are no vaccines in routine use, and current chemotherapeutic regimens are often toxic and expensive. The major foci are in India, Sudan and Brazil. Only around 10% of people infected with the parasite acquire clinical VL. The remainder become skin-test positive for leishmanial antigen and are asymptomatic.

We have been studying genetic susceptibility to clinical visceral leishmaniasis (VL) and to asymptomatic infection in skin-test positive (DTH+) individuals in the three major foci of disease in India, Brazil and Sudan. We have now accumulated DNA samples from a total of 1175 clinical VL cases in multicase families or trios/sibships from India, 526 clinical VL cases and 1160 DTH+/900 DTH- individuals from Brazil, and 235 clinical VL cases from Sudan. From these we can extract >1000 unrelated cases of clinical VL from India and match these with 1000 separately ascertained unrelated controls. Our aim is to use DNA from these unrelated cases and population controls to undertake a GWAS for India, with the full set of cases in families being used to validate regions of association using family-based allelic association tests. For Brazil, a family-based GWAS in which clinical VL will be analyzed as a qualitative trait and DTH as a quantitative trait is proposed. SNPs in positive regions will also be genotyped in cases in families to determine whether any are strongly associated with clinical VL in Sudan. Genotype data will be made available for replication studies in other geographical regions. SNP-chip data for controls will form a resource for future analysis of other complex diseases in India and Brazil.