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https://www.arca.fiocruz.br/handle/icict/51437
A GENOME-WIDE ASSOCIATION STUDY IDENTIFIES SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, AND KRT80 AS RISK LOCI CONTRIBUTING TO CUTANEOUS LEISHMANIASIS IN BRAZIL
Author
Castellucci, Léa Cristina de Carvalho
Almeida, Lucas
Cherlin, Svetlana
Fakiola, Michaela
Francis, Richard W
Carvalho, Edgar M
Hora, Anadílton Santos da
Lago, Tainã Souza do
Figueiredo, Amanda Braga de
Cavalcanti, Clara Maciel
Alves, Natalia Silva
Morais, Katia Luciano Pereira
Carvalho, Andréa Teixeira de
Dutra, Walderez Ornelas
Gollob, Kenneth J
Cordell, Heather J
Blackwell, Jenefer M
Almeida, Lucas
Cherlin, Svetlana
Fakiola, Michaela
Francis, Richard W
Carvalho, Edgar M
Hora, Anadílton Santos da
Lago, Tainã Souza do
Figueiredo, Amanda Braga de
Cavalcanti, Clara Maciel
Alves, Natalia Silva
Morais, Katia Luciano Pereira
Carvalho, Andréa Teixeira de
Dutra, Walderez Ornelas
Gollob, Kenneth J
Cordell, Heather J
Blackwell, Jenefer M
Affilliation
National Institute of Science and Technology in Tropical Diseases. Brazil/Federal University of Bahia. Salvador, BA, Brazil.
National Institute of Science and Technology in Tropical Diseases. Brazil/Federal University of Bahia. Salvador, BA, Brazil.
Population Health Sciences Institute. Newcastle University. Newcastle-Upon-Tyne, United Kingdom.
National Institute of Molecular Genetics Romeo ed Enrica Invernizzi. Milan, Italy.
Telethon Kids Institute. University of Western Australia. Nedlands, Australia.
National Institute of Science and Technology in Tropical Diseases. Brazil.
Federal University of Bahia. Salvador, BA, Brazil.
Federal University of Bahia. Salvador, BA, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
National Institute of Science and Technology in Tropical Diseases. Brazil/Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Belo Horizonte, MG, Brazil.
National Institute of Science and Technology in Tropical Diseases. Brazil/International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil/Instituto Mario Penna. Núcleo de Ensino e Pesquisa. Belo Horizonte, MG, Brazil.
Population Health Sciences Institute. Newcastle University. Newcastle-Upon-Tyne, United Kingdom.
Telethon Kids Institute. University of Western Australia. Nedlands, Australia/Department of Pathology. University of Cambridge. Cambridge, United Kingdom.
National Institute of Science and Technology in Tropical Diseases. Brazil/Federal University of Bahia. Salvador, BA, Brazil.
Population Health Sciences Institute. Newcastle University. Newcastle-Upon-Tyne, United Kingdom.
National Institute of Molecular Genetics Romeo ed Enrica Invernizzi. Milan, Italy.
Telethon Kids Institute. University of Western Australia. Nedlands, Australia.
National Institute of Science and Technology in Tropical Diseases. Brazil.
Federal University of Bahia. Salvador, BA, Brazil.
Federal University of Bahia. Salvador, BA, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil.
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil.
National Institute of Science and Technology in Tropical Diseases. Brazil/Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Belo Horizonte, MG, Brazil.
National Institute of Science and Technology in Tropical Diseases. Brazil/International Center for Research. AC Camargo Cancer Center. São Paulo, SP, Brazil/Instituto Mario Penna. Núcleo de Ensino e Pesquisa. Belo Horizonte, MG, Brazil.
Population Health Sciences Institute. Newcastle University. Newcastle-Upon-Tyne, United Kingdom.
Telethon Kids Institute. University of Western Australia. Nedlands, Australia/Department of Pathology. University of Cambridge. Cambridge, United Kingdom.
Abstract
Background: Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis.
Methods: Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4 498 586 imputed single-nucleotide variants (SNVs). A genome-wide association study (GWAS) using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL) and chromatin interaction mapping was performed in Functional Mapping and Annotation (FUMA). Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay.
Results: Positional mapping identified 32 genomic loci associated with CL, none achieving genome-wide significance (P < 5 × 10-8). Lead SNVs at 23 loci occurred at protein coding or noncoding RNA genes, 15 with eQTLs for functionally relevant cells/tissues and/or showing differential expression in lesions. Of these, the 6 most plausible genetic risk loci were SERPINB10 (Pimputed_1000G = 2.67 × 10-6), CRLF3 (Pimputed_1000G = 5.12 × 10-6), STX7 (Pimputed_1000G = 6.06 × 10-6), KRT80 (Pimputed_1000G = 6.58 × 10-6), LAMP3 (Pimputed_1000G = 6.54 × 10-6), and IFNG-AS1 (Pimputed_1000G = 1.32 × 10-5). LAMP3 (Padjusted = 9.25 × 10-12; +6-fold), STX7 (Padjusted = 7.62 × 10-3; +1.3-fold), and CRLF3 (Padjusted = 9.19 × 10-9; +1.97-fold) were expressed more highly in CL biopsies compared to normal skin; KRT80 (Padjusted = 3.07 × 10-8; -3-fold) was lower. Multiple cis-eQTLs across SERPINB10 mapped to chromatin interaction regions of transcriptional/enhancer activity in neutrophils, monocytes, B cells, and hematopoietic stem cells. Those at IFNG-AS1 mapped to transcriptional/enhancer regions in T, natural killer, and B cells. The percentage of peripheral blood CD3+ T cells making antigen-specific interferon-γ differed significantly by IFNG-AS1 genotype.
Conclusions: This first GWAS for CL identified multiple genetic risk loci including a novel lead to understanding CL pathogenesis through regulation of interferon-γ by IFNG antisense RNA 1.
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