Immunogenetics of Visceral Leishmaniasis

NCT ID: NCT00342823

Last Updated: 2017-07-02

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 7000 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2003-10-20
• Study Completion Date: 2010-06-30

Brief Summary

Visceral leishmaniasis is a potentially fatal disease caused in South America by the protozoan Leishmania chagasi. In neighborhoods with high exposure rates, the outcome of human infection with L. chagasi ranges from asymptomatic to a disseminated wasting disease called visceral leishmaniasis (VL). Several studies document familial clustering of VL in populations at risk. Segregation analyses favor a genetic over an environmental model for susceptibility to L. chagasi infection. A peri-urban outbreak of VL near the Universidade Federal do Rio Grande do Norte (UFRN) in Natal, northeast Brazil, has allowed us to identify endemic neighborhoods with ongoing transmission of L. chagasi infection. Natal is ideal for this study because endemic neighborhoods are easily accessible, people are motivated to cooperate with measures to control VL, and other forms of leishmaniasis are not transmitted in the region. Dr. Jeronimo of the UFRN, and Dr. Mary Wilson at University of Iowa have collected clinical data and DNA from 400 VL families living in these endemic neighborhoods. We have created an unprecedented cohort through which we can identify four distinct phenotypic responses after L. chagasi exposure. We documented familial clustering of L. chagasi infection, and results of both correlation and segregation analyses are consistent with the hypothesis that genetic factors predispose, in part, to the diverse clinical outcomes after infection. Polymorphism in the TNF locus is associated with developing symptomatic as opposed to asymptomatic disease after infection. We recently completed a genome-wide scan of the quantitative immune response (DTH) and identified potential linkage regions on chromosomes 2, 13, 15 and 19. We have also identified a small linkage peak on chromosome 9 for VL. In our ongoing study, we will next perform fine mapping of these regions using dense SNPs to identify genes that may determine susceptibility to L. chagasi infection. Additionally, we will also analyze candidate genes for association/linkage with susceptibility to or protection from L. chagasi disease. We recently identified an association on chromosome 5 with the DTH immune response among two linkage disequilibrium blocks spanning multiple immune related genes.

Detailed Description

Visceral leishmaniasis is a potentially fatal disease caused in South America by the protozoan Leishmania chagasi. In neighborhoods with high exposure rates, the outcome of human infection with L. chagasi ranges from asymptomatic to a disseminated wasting disease called visceral leishmaniasis (VL). Several studies document familial clustering of VL in populations at risk. Segregation analyses favor a genetic over an environmental model for susceptibility to L. chagasi infection. A peri-urban outbreak of VL near the Universidade Federal do Rio Grande do Norte (UFRN) in Natal, northeast Brazil, has allowed us to identify endemic neighborhoods with ongoing transmission of L. chagasi infection. Natal is ideal for this study because endemic neighborhoods are easily accessible, people are motivated to cooperate with measures to control VL, and other forms of leishmaniasis are not transmitted in the region. Dr. Jeronimo of the UFRN, and Dr. Mary Wilson at University of Iowa have collected clinical data and DNA from 400 VL families living in these endemic neighborhoods. We have created an unprecedented cohort through which we can identify four distinct phenotypic responses after L. chagasi exposure. We documented familial clustering of L. chagasi infection, and results of both correlation and segregation analyses are consistent with the hypothesis that genetic factors predispose, in part, to the diverse clinical outcomes after infection. Polymorphism in the TNF locus is associated with developing symptomatic as opposed to asymptomatic disease after infection. We recently completed a genome-wide scan of the quantitative immune response (DTH) and identified potential linkage regions on chromosomes 2, 13, 15 and 19. We have also identified a small linkage peak on chromosome 9 for VL. In our ongoing study, we will next perform fine mapping of these regions using dense SNPs to identify genes that may determine susceptibility to L. chagasi infection. Additionally, we will also analyze candidate genes for association/linkage with susceptibility to or protection from L. chagasi disease. We recently identified an association on chromosome 5 with the DTH immune response among two linkage disequilibrium blocks spanning multiple immune related genes.

Conditions

Visceral Leishmaniasis

Eligibility Criteria

Inclusion Criteria

We used three approaches to identify families in endemic neighborhoods, yielding three populations of families.

Population I: A neighborhood to the northeast of the city was identified through a family with two cases of disease.

Population 2: Individuals with suspected VL are admitted to one of three public hospitals in Natal. Families were interviewed and examined if they wished to participate.

Population 3: The neighboring families living closest to population 2 families were identified.

Exclusion Criteria

Individuals with ongoing illnesses other than VL were excluded from analyses.

Any medical conditions found or suspected based upon history, exam or blood tests were either treated by the investigators or referred to the appropriate medical facility in Natal.

Pregnant women and children less than 1 year were not given any skin test.

No exclusions based on ethnicity were done.

• Minimum Eligible Age: 1 Year
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Human Genome Research Institute (NHGRI)

NIH

Sponsor Role: lead

Locations

Universidade Federal do Rio Grande do Norte

Natal, , Brazil

Countries

Brazil

References

Desjeux P. Leishmaniasis. Public health aspects and control. Clin Dermatol. 1996 Sep-Oct;14(5):417-23. doi: 10.1016/0738-081x(96)00057-0. No abstract available.

Reference Type: BACKGROUND

PMID: 8889319 (View on PubMed)

Wolday D, Berhe N, Akuffo H, Britton S. Leishmania-HIV interaction: immunopathogenic mechanisms. Parasitol Today. 1999 May;15(5):182-7. doi: 10.1016/s0169-4758(99)01431-3.

Reference Type: BACKGROUND

PMID: 10322351 (View on PubMed)

de Gorgolas M, Miles MA. Visceral leishmaniasis and AIDS. Nature. 1994 Dec 22-29;372(6508):734. doi: 10.1038/372734b0. No abstract available.

Reference Type: BACKGROUND

PMID: 7997260 (View on PubMed)

Other Identifiers

04-HG-N024

Identifier Type: -

Identifier Source: secondary_id

999904024

Identifier Type: -

Identifier Source: org_study_id