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Ann Hum Genet. 2017 Jan;81(1):41-48. doi: 10.1111/ahg.12180. Epub 2017 Jan 4.

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

Author information

1
Interdisciplinary Program in Genetics, University of Iowa, Iowa City, IA, USA.
2
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
3
Department of Infectious Diseases, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
4
Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal, RN, Brazil.
5
Cambridge Institute for Medical Research, University of Cambridge, UK.
6
Telethon Kids Institute, The University of Western Australia, Perth, Australia.
7
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.
8
Departments of Internal Medicine and Microbiology, University of Iowa and the Iowa City Veterans' Affairs Medical Center, Iowa City, IA, USA.

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.

KEYWORDS:

Fc gamma receptor; Leishmania infantum; asymptomatic infection; candidate gene studies; transforming growth factor-beta; visceral leishmaniasis

PMID:
28054334
PMCID:
PMC5298939
DOI:
10.1111/ahg.12180
[Indexed for MEDLINE]
Free PMC Article

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