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A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil

Lookup NU author(s): Dr Svetlana CherlinORCiD, Professor Heather Cordell



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. 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.

Publication metadata

Author(s): Castellucci LC, Almeida L, Cherlin S, Fakiola M, Francis RW, Carvalho EM, Santos da Hora A, do Lago TS, Figueiredo AB, Cavalcanti CM, Alves NS, Morais KLP, Teixeira-Carvalho A, Dutra WO, Gollob KJ, Cordell HJ, Blackwell JM

Publication type: Article

Publication status: Published

Journal: Clinical Infectious Diseases

Year: 2021

Volume: 72

Issue: 10

Pages: e515-e525

Print publication date: 15/05/2021

Online publication date: 23/08/2020

Acceptance date: 10/08/2020

Date deposited: 26/07/2021

ISSN (print): 1058-4838

ISSN (electronic): 1537-6591

Publisher: Oxford University Press


DOI: 10.1093/cid/ciaa1230

PubMed id: 32830257


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Funder referenceFunder name
MR/N017390/1Medical Research Council (MRC)