Comprehensive candidate gene analysis 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:10.1111/ahg.12180

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Comprehensive candidate gene analysis for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil

Journal article

Peer reviewed

Comprehensive candidate gene analysis 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

Annals of human genetics, Vol.81(1), pp.41-48

01/2017

DOI: 10.1111/ahg.12180

PMCID: PMC5298939

PMID: 28054334

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Abstract

Genetic risk factors contribute to asymptomatic versus symptomatic visceral leishmaniasis (VL) outcomes following infection with Leishmania infantum. We therefore carried out a family-based (n = 918 post-quality control fully genotyped and phenotyped individuals) candidate gene study for symptomatic VL or asymptomatic delayed-type hypersensitivity (DTH) skin test phenotypes in highly endemic neighborhoods of northeast Brazil. A total of 248 SNPs were genotyped in 42 genes selected as candidates on the basis of prior genetic, immunological, and transcriptional profiling studies. The most significant association with the VL phenotype was with SNP rs6785358 (P = 5.7e-04; p = 0.026) 3.8 kb upstream of TGFBR2, the gene encoding the type 2 receptor for transforming growth factor beta (TGFβ). A second inhibitory member of the TGBβ superfamily signaling pathway, SMAD7, was associated with the DTH phenotype (SNP rs7238442: P = 0.001; p = 0.051). The most significant association for the DTH phenotype was with SNP rs10800309 (P = -8.4e-06; p = 3.9e-04) situated 3.1 kb upstream of FCGR2A, the gene encoding the low-affinity IIa receptor for the Fc fragment of IgG. Overall, our results imply a role for IgG-mediated inflammation in determining DTH associated with asymptomatic infection and contribute to growing evidence that the TGFβ pathway is important in the immunopathogenesis of VL.

Brazil

Genetic Predisposition to Disease

Leishmania infantum

Receptors, Transforming Growth Factor beta - genetics

Genetic Association Studies

Humans

Protein-Serine-Threonine Kinases - genetics

Male

Linkage Disequilibrium

Asymptomatic Infections

Receptors, IgG - genetics

Adolescent

Leishmaniasis, Visceral - genetics

Female

Leishmaniasis, Visceral - parasitology

Polymorphism, Single Nucleotide

Child

Details

Title: Subtitle: Comprehensive candidate gene analysis 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 - Institute of Tropical Medicine of Rio Grande do Norte, 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 - Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil
Michaela Fakiola - Cambridge Institute for Medical Research, University of Cambridge, UK
Jenefer M Blackwell - Telethon Kids Institute, The University of Western Australia, Perth, Australia
Selma M B Jeronimo - Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, RN and the National Institute of Science and Technology of Tropical Diseases, Natal, Rio Grande do Norte, Brazil
Mary E Wilson - Departments of Internal Medicine and Microbiology, University of Iowa and the Iowa City Veterans' Affairs Medical Center, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Annals of human genetics, Vol.81(1), pp.41-48
DOI: 10.1111/ahg.12180
PMID: 28054334
PMCID: PMC5298939
NLM abbreviation: Ann Hum Genet
ISSN: 0003-4800
eISSN: 1469-1809
Publisher: England
Grant note: R01 AI045540 / NIAID NIH HHS T32 GM008629 / NIGMS NIH HHS T32 GM082729 / NIGMS NIH HHS I01 BX000536 / BLRD VA R01 AI067874 / NIAID NIH HHS R03 TW001369 / FIC NIH HHS R01 AI048822 / NIAID NIH HHS R01 AI076233 / NIAID NIH HHS P50 AI030639 / NIAID NIH HHS
Language: English
Date published: 01/2017
Academic Unit: Microbiology and Immunology; International Programs; Epidemiology; Internal Medicine
Record Identifier: 9984001134702771

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