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

Abstract

Summary 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 (TGF-β). A second inhibitory member of the TGB-β 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. (196 words; 200 words allowed)

Premature deaths by visceral leishmaniasis in Brazil investigated through a cohort study: A challenging opportunity?

“…For example, a population genetics study provided evidence for the link between TGF beta pathway and progression of L . infantum infection [36]. Recently it was shown that clinical severity of VL is associated with changes in the profile of IgG Fc N-Glycopepetide and that this is restored after treatment [37].…”

Associations of TGFBR1 and TGFBR2 gene polymorphisms with the risk of hypospadias: a case–control study in a Chinese population

“…Further analysis of the association amongst three genotypes (GA, AA, and GG) of TGFBR2 rs6785358 and the pathological type of hypospadias revealed statistical differences in the frequencies of GA or AA genotype, but not in the GG genotype, between the case and control groups. TGFBR2 rs6785358 polymorphism was reported to be correlated to the visceral leishmaniasis phenotype [ 27 ], which meant that TGFBR2 rs6785358 polymorphism was associated with the development of disease. The results of the present study also revealed that patients carrying a G allele of TGFBR2 rs6785358 might exhibit an increased risk of hypospadias.…”

Macrophages as host, effector and immunoregulatory cells in leishmaniasis: Impact of tissue micro-environment and metabolism

“…In addition to IL-10, other cytokines might facilitate Leishmania persistence in macrophages. Several studies with L. tropica -, L. infantum - or L. donovani -infected mice and with humans from Leishmania -endemic areas suggested a pathogenic role for TGF- β [16] , [221] , [222] , [223] , a known suppressor of macrophage functions and Th1 differentiation [93] , [224] , [225] . For type I IFNs (IFN- α/β ) , at least five different categories of mechanisms of action have been described that could support parasite survival in vivo .…”