A genome-wide association study highlights a regulatory role for IFNG-AS1 contributing to cutaneous leishmaniasis in Brazil
Castellucci, L. C.; Almeida, L.; Cherlin, S.; Fakiola, M.; Carvalho, E.; Figueiredo, A. B.; Cavalcanti, C. M.; Alves, N. S.; Dutra, W. O.; Gollob, K. J.; Cordell, H. J.; Blackwell, J. M.
Show abstract
BackgroundCutaneous leishmaniasis (CL) caused by Leishmania braziliensis remains an important public health problem in Brazil. The goal of this study was to identify genetic risk factors for CL. MethodsGenome-wide analysis was undertaken using DNAs from 956 CL cases and 868 controls (phase 1) and 1110 CL cases and 1178 controls (phase 2) genotyped using Illumina HumanCoreExome BeadChips. Imputation against 1000G data provided 4,498,586 quality-controlled single nucleotide variants (SNVs) common across phase 1 and phase 2 samples. Linear mixed models in FastLMM were used to take account of genetic diversity/ethnicity/admixture. Cellular cytokines were measured using flow cytometry. ResultsCombined analysis across cohorts found no associations that achieved genome-wide significance, commonly accepted as P<5x10-8. Support for variants at wound-healing genes previously studied as candidate genes for CL included SMAD2 (rs115582038/rs75753347; Pimputed_1000G=1.47x10-4). Top novel GWAS hits at P<5x10-5 in plausible candidate genes for CL included SERPINB10 (rs62097497;Pimputed_1000G=2.67x10-6), CRLF3 (rs75270613; Pimputed_1000G=5.12x10-6), STX7 (rs144488134;Pimputed_1000G=6.06x10-6), KRT80 (rs10783496 Pimputed_1000G=6.58x10-6), LAMP3 (rs74285558;Pimputed_1000G=6.54x10-6) and IFNG-AS1 (rs4913269;Pimputed_1000G=1.32x10-5). Of these, LAMP3 (Padjusted=9.25x10-12; +6-fold), STX7 (Padjusted=7.62x10-3; +1.3-fold) and CRLF3 (Padjusted=9.19x10-9; +1.97-fold) were all expressed more highly in CL biopsies compared to normal skin, whereas expression of KRT80 (Padjusted=3.07x10-8; -3-fold) was lower. Notably, the percent peripheral blood CD3+ T cells making interferon-{gamma} in response to Leishmania antigen differed significantly by IFNG-AS1 genotype. ConclusionsIn addition to supporting variants in wound-healing genes as genetic risk factors for CL, our GWAS results provide important novel leads to understanding pathogenesis of CL including through the regulation of interferon-{gamma} responses.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Interleukin-17 pathway activation in Equus caballus supporting limb laminitis 93%
- Cytokine and phenotypic cell profiles in human cutaneous leishmaniasis caused by Leishmania donovani 92%
- Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis 91%
Similar papers in this journal
- A new paradigm for leprosy diagnosis based on host gene expression 94%
- Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis 92%
- Over-expression and increased copy numbers of a cytochrome P450 and two UDP-glucuronosyltransferase genes in macrocyclic lactone resistant Psoroptes ovis of cattle 92%
Similar papers in this journal
- Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation 94%
- Population-level genome-wide STR typing in Plasmodium species reveals higher resolution population structure and genetic diversity relative to SNP typing 91%
- IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta 90%
Similar papers in this journal
- Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature 95%
- Micronutrient-deficient diets and possible environmental enteric dysfunction in Buruli ulcer endemic communities in Ghana: lower dietary diversity and reduced serum zinc and vitamin C implicate micronutrient status a possible susceptibility factor 92%
- Demographic characteristics and clinical features of patients presenting with different forms of cutaneous leishmaniasis, in Lay Gayint, Northern Ethiopia 92%
Similar papers in this journal
- Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility 92%
- Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control. 91%
- Genetic risk factors and Covid-19 severity in Brazil: results from BRACOVID Study 90%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.