TY - JOUR
T1 - Comprehensive candidate gene analysis for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil
AU - Weirather, Jason L.
AU - Duggal, Priya
AU - Nascimento, Eliana L.
AU - Monteiro, Gloria R.
AU - Martins, Daniella R.
AU - Lacerda, Henio G.
AU - Fakiola, Michaela
AU - Blackwell, Jenefer M.
AU - Jeronimo, Selma M.B.
AU - Wilson, Mary E.
N1 - Funding Information:
This work was supported by NIH grant R01 AI076233 (JMB and MEW), AI045540 (MEW) and AI067874 (MEW, JMB). Data were collected under the Tropical Medicine Research Center grant P50 AI-30639 (SMBJ, MEW, JMB). Partial support was received from Merit Review grants from the Department of Veterans’ Affairs (1i01BX001983 and 5I01BX000536; MEW). The work was performed in part during the tenure of J.L.W. on NIH training grants T32 GM008629 and T32 GM082729. The authors are grateful to Anne Kwitek, Ph.D. and to Jeffrey Murray, M.D. for their helpful advice and discussions regarding genetic data analysis.
Publisher Copyright:
© 2017 John Wiley & Sons Ltd/University College London
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Fc gamma receptor
KW - Leishmania infantum
KW - asymptomatic infection
KW - candidate gene studies
KW - transforming growth factor-beta
KW - visceral leishmaniasis
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U2 - 10.1111/ahg.12180
DO - 10.1111/ahg.12180
M3 - Article
C2 - 28054334
AN - SCOPUS:85008153096
VL - 81
SP - 41
EP - 48
JO - Annals of Human Genetics
JF - Annals of Human Genetics
SN - 0003-4800
IS - 1
ER -