Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil

Jason L Weirather; Priya Duggal; Eliana L Nascimento; Gloria R Monteiro; Daniella R Martins; Henio G Lacerda; Michaela Fakiola; Jenefer M Blackwell; Selma M.B Jeronimo; Mary E Wilson

doi:10.1016/j.meegid.2016.05.005

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Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil

Journal article

Peer reviewed

Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil

Jason L Weirather, Priya Duggal, Eliana L Nascimento, Gloria R Monteiro, Daniella R Martins, Henio G Lacerda, Michaela Fakiola, Jenefer M Blackwell, Selma M.B Jeronimo and Mary E Wilson

Infection, genetics and evolution, Vol.43, pp.1-5

09/2016

DOI: 10.1016/j.meegid.2016.05.005

PMCID: PMC5005107

PMID: 27155051

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Abstract

Infection with the protozoan Leishmania infantum can lead to asymptomatic infection and protective immunity, or to the progressive and potentially fatal disease visceral leishmaniasis (VL). Published studies show host genetic background determines in part whether infected individuals will develop a symptomatic or asymptomatic outcome. The purpose of the current study was to fine map chromosome regions previously linked with risk for symptomatic (chromosome 9) or asymptomatic (chromosomes 15 and 19) manifestations of L. infantum infection. We conducted a family-based genetic study of VL and asymptomatic infection (detected by a DTH skin test) with a final post quality control sample of 961 individuals with full genotype and phenotype information from highly endemic neighborhoods of northeast Brazil. A total of 5485 SNPs under the linkage peaks on chromosomes 9, 15 and 19 were genotyped. No strong SNP associations were observed for the DTH phenotype. The most significant associations with the VL phenotype were with SNP rs1470217 (p=5.9e−05; pcorrected=0.057) on chromosome 9, and with SNP rs8107014 (p=1.4e−05; pcorrected=0.013) on chromosome 19. SNP rs1470217 is situated in a 180kb intergenic region between TMEM215 (Transmembrane protein 215) and APTX (Aprataxin). SNP rs8107014 lies in the intron between exons 26 and 27 of a 34 exon transcript (ENST00000204005) of LTBP4, (Latent transforming growth factor-beta-binding protein 4a). The latter supports growing evidence that the transforming growth factor-beta pathway is important in the immunopathogenesis of VL. •Symptomatic and asymptomatic outcome occur with Leishmania infantum infection.•High density SNP mapping was undertaken on chromosome 9, 15 and 19.•LTBP4 on chromosome 19 was associated with symptomatic disease.•Results confirm regulation of TGF-β as important in disease pathogenesis.

Fine mapping

Linkage regions

Visceral leishmaniasis

Tropical disease

Genetic risk factors

Details

Title: Subtitle: Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil
Creators: Jason L Weirather - Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA
Priya Duggal - Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
Eliana L Nascimento - Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil
Gloria R Monteiro - Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil
Daniella R Martins - Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil
Henio G Lacerda - Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil
Michaela Fakiola - Cambridge Institute for Medical Research, University of Cambridge, UK
Jenefer M Blackwell - Cambridge Institute for Medical Research, University of Cambridge, UK
Selma M.B Jeronimo - Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil
Mary E Wilson - Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Infection, genetics and evolution, Vol.43, pp.1-5
DOI: 10.1016/j.meegid.2016.05.005
PMID: 27155051
PMCID: PMC5005107
NLM abbreviation: Infect Genet Evol
ISSN: 1567-1348
eISSN: 1567-7257
Publisher: Elsevier B.V
Grant note: name: NIH, award: R01 AI076233, AI045540, AI067874, T32 GM008629, T32 GM082729; name: Tropical Medicine Research Center, award: P50 AI-30639; DOI: 10.13039/100000738, name: Department of Veterans' Affairs, award: 1i01BX001983, 5I01BX000536
Language: English
Date published: 09/2016
Academic Unit: Microbiology and Immunology; International Programs; Epidemiology; Internal Medicine
Record Identifier: 9984001219802771

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