title: Comprehensive candidate gene analysis for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil.
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; pcorrected= 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; pcorrected= 0.051). The most significant association for the DTH phenotype was with SNP rs10800309 (P = -8.4e-06; pcorrected= 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.
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Weirather
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.affiliation: Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil.|Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
authors.forename: Eliana L
authors.initials: EL
authors.lastname: Nascimento
authors.affiliation: Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
authors.forename: Gloria R
authors.initials: GR
authors.lastname: Monteiro
authors.affiliation: Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
authors.forename: Daniella R
authors.initials: DR
authors.lastname: Martins
authors.affiliation: Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil.|Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
authors.forename: Henio G
authors.initials: HG
authors.lastname: Lacerda
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fakiola
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, UK.|Telethon Kids Institute, The University of Western Australia, Perth, Australia.
authors.forename: Jenefer M
authors.initials: JM
authors.lastname: Blackwell
authors.affiliation: Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil.|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.
authors.forename: Selma M B
authors.initials: SM
authors.lastname: Jeronimo
authors.affiliation: Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA.|Departments of Internal Medicine and Microbiology, University of Iowa and the Iowa City Veterans' Affairs Medical Center, Iowa City, IA, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Wilson
mesh_terms: D000293:Adolescent; D058345:Asymptomatic Infections; D001938:Brazil; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D018314:Leishmania infantum; D007898:Leishmaniasis, Visceral / Q000235:genetics* / Q000469:parasitology; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D017452:Receptors, IgG / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
chemical_list: C445323:FCGR2A protein, human; D017452:Receptors, IgG; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Fc gamma receptor; Leishmania infantum; asymptomatic infection; candidate gene studies; transforming growth factor-beta; visceral leishmaniasis