Genetic Epidemiology of Infectious Diseases

Human Genome Research

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Abstract

This project encompasses the human genetic predisposition to infectious diseases including Visceral leishmaniasis, Amebiasis and HIV/AIDS. Visceral leishmaniasis is a potentially fatal disease caused by the protozoan Leishmania chagasi that is carried by the sandfly. Several studies have documented familial clustering of VL in at risk populations. Recently, we collected complete clinical (eosinophils, neutrophils, hematocrit, etc) and environmental factors (presence of animals, years living in neighborhood) for 1106 members of 216 families living in endemic neighborhoods and compared these clinical characteristics (see below, publication in Scand. Jour Inf Dis). DNA samples have been submitted to the Center for Inherited Disease Research for a whole genome scan and when completed we plan to conduct a genome wide linkage analysis for visceral leishmania and the DTH skin test response. Amebiasis is a large contributor to diarrheal disease in the developing world. Amebiasis is caused by infection of the intestine by the parasite Entamoeba histolytica. Infection with E. histolytica is heterogeneous and it is very likely that genetic predispositions/susceptibility influence acquisition and progression of this parasite in humans. Recently we analyzed the candidate gene, TLR5 (Toll Like Receptor 5) in a case-control study of E. histolytica using this cohort of children. However we failed to find any association with disease susceptibility or severity. We are continuing to analyze the MHC Class I and Class II haplotypes to determine if there is an overall MHC haplotype that confers protection to E. histolytica infection since we previously identified a Class II association (see below, publication in JID). We aim to understand genetic host susceptibility to HIV/AIDS, using a cohort of 3000 injection drug users in Baltimore, Maryland that participate in the AIDS Link to Intravenous Experience (ALIVE). Population based genetic studies including this cohort have identified numerous candidate genes that affect HIV/AIDS disease progression (CCR5, CCR2, RANTES, SDF-1, etc). Recent work has identified a polymorphism in the cytosine deaminase, APOBEC3G, H186R in exon 4 that is strongly associated with a decline in CD4 T cells (CD4 slope on square root scale: -1.86, P=0.009) in African Americans. The 186R allele is also associated with a faster progression to AIDS. This work was published in the Journal of Virology.