A genome-wide association study highlights a regulatory role for IFNG-AS1 contributing to cutaneous leishmaniasis in Brazil
Year: 2020
Type: preprint
Study design: Observational Study
Abstract: Background Cutaneous 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. Methods Genome-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. Results Combined analysis across cohorts found no associations that achieved genome-wide significance, commonly accepted as P <5×10 -8 . Support for variants at wound-healing genes previously studied as candidate genes for CL included SMAD2 (rs115582038/rs75753347; P imputed_1000G =1.47×10 -4 ). Top novel GWAS hits at P<5×10 -5 in plausible candidate genes for CL included SERPINB10 (rs62097497; P imputed_1000G =2.67×10 -6 ), CRLF3 (rs75270613; P imputed_1000G =5.12×10 -6 ), STX7 (rs144488134; P imputed_1000G =6.06×10 -6 ), KRT80 (rs10783496 P imputed_1000G =6.58×10 -6 ), LAMP3 (rs74285558; P imputed_1000G =6.54×10 -6 ) and IFNG-AS1 (rs4913269; P imputed_1000G =1.32×10 -5 ). Of these, LAMP3 (P adjusted =9.25×10 -12 ; +6-fold), STX7 (P adjusted =7.62×10 -3 ; +1.3-fold) and CRLF3 (P adjusted =9.19×10 -9 ; +1.97-fold) were all expressed more highly in CL biopsies compared to normal skin, whereas expression of KRT80 (P adjusted =3.07×10 -8 ; −3-fold) was lower. Notably, the percent peripheral blood CD3 + T cells making interferon-γ in response to Leishmania antigen differed significantly by IFNG-AS1 genotype. Conclusions In 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-γ responses.
Institutions: Universidade Federal da Bahia, Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais, Newcastle University, Istituto Nazionale Genetica Molecolare, AC Camargo Hospital, Universidade Federal de Minas Gerais, The Kids Research Institute Australia, The University of Western Australia, University of Cambridge
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Conselho Nacional das Fundações Estaduais de Amparo à Pesquisa, National Institutes of Health, Medical Research Council
Awards: G1690248604, G1783637876, Development and application of statistical methodology for the detection and characterisation of genetic factors in complex disease., Development and application of statistical methodology for the detection and characterisation of genetic factors in complex disease., DESCOBRINDO GENES E VIAS FUNCIONAIS ASSOCIADOS COM LEISHMANIOSE TEGUMENTAR AMERICANA (LTA) CAUSADA POR LEISHMANIA BRAZILIENSIS., Discovering genes and functional pathways associated with American cutaneous leishmaniasis (ACL) caused by Leishmania brasiliensis., G7338976372, G8289215479, G9000214106
OpenAlex ID: W3000185809