A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| Outros Autores: | , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/51437 |
Resumo: | National Institute of Science and Technology in Tropical Diseases. Brazil/Federal University of Bahia. Salvador, BA, Brazil. |
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Castellucci, Léa Cristina de CarvalhoAlmeida, LucasCherlin, SvetlanaFakiola, MichaelaFrancis, Richard WCarvalho, Edgar MHora, Anadílton Santos daLago, Tainã Souza doFigueiredo, Amanda Braga deCavalcanti, Clara MacielAlves, Natalia SilvaMorais, Katia Luciano PereiraCarvalho, Andréa Teixeira deDutra, Walderez OrnelasGollob, Kenneth JCordell, Heather JBlackwell, Jenefer M2022-02-23T18:09:55Z2022-02-23T18:09:55Z2021CASTELLUCCI, Léa Cristina de Carvalho et al. A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil. Clin Infect Dis., v. 72, n. 10, e515-e525, 2021. doi: 10.1093/cid/ciaa12301058-4838https://www.arca.fiocruz.br/handle/icict/5143710.1093/cid/ciaa1230engOxford University PressA Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazilinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleNational 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.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.IFNG-AS1LeishmaniaGWASinterferon-γpost-GWAS integrated analysisinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83082https://www.arca.fiocruz.br/bitstream/icict/51437/1/license.txt9193a7c197bc67acd023525e72a03240MD51ORIGINALA follow-up study (2007–2018) on American Tegumentary .pdfA follow-up study (2007–2018) on American Tegumentary .pdfapplication/pdf7365459https://www.arca.fiocruz.br/bitstream/icict/51437/2/A%20follow-up%20study%20%282007%e2%80%932018%29%20on%20American%20Tegumentary%20.pdfe6f04cf37261b0c71ccc86c43a3c24e4MD52icict/514372022-02-23 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| dc.title.pt_BR.fl_str_mv |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil |
| title |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil |
| spellingShingle |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil Castellucci, Léa Cristina de Carvalho IFNG-AS1 Leishmania GWAS interferon-γ post-GWAS integrated analysis |
| title_short |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil |
| title_full |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil |
| title_fullStr |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil |
| title_full_unstemmed |
A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil |
| title_sort |
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 |
| author_facet |
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 |
| author_role |
author |
| author2 |
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 |
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author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
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 |
| dc.subject.en.pt_BR.fl_str_mv |
IFNG-AS1 Leishmania GWAS interferon-γ post-GWAS integrated analysis |
| topic |
IFNG-AS1 Leishmania GWAS interferon-γ post-GWAS integrated analysis |
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National Institute of Science and Technology in Tropical Diseases. Brazil/Federal University of Bahia. Salvador, BA, Brazil. |
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2021 |
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2021 |
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2022-02-23T18:09:55Z |
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2022-02-23T18:09:55Z |
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CASTELLUCCI, Léa Cristina de Carvalho et al. A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil. Clin Infect Dis., v. 72, n. 10, e515-e525, 2021. doi: 10.1093/cid/ciaa1230 |
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https://www.arca.fiocruz.br/handle/icict/51437 |
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1058-4838 |
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10.1093/cid/ciaa1230 |
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CASTELLUCCI, Léa Cristina de Carvalho et al. A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil. Clin Infect Dis., v. 72, n. 10, e515-e525, 2021. doi: 10.1093/cid/ciaa1230 1058-4838 10.1093/cid/ciaa1230 |
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