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

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). Genome-wide association testing 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 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&5x10 -8). Lead SNVs at 23 loci occurred at protein coding or non-coding RNA genes, 15 with eQTLs for functionally relevant cells/tissues and/or showed differential expression in lesions. Of these, the 6 most plausible genetic risk loci were: SERPINB10 (Pimputed_1000G=2.67x10 -6), CRLF3 (Pimputed_1000G=5.12x10 -6), STX7 (Pimputed_1000G=6.06x10 -6), KRT80 (Pimputed_1000G=6.58x10 -6), LAMP3 (Pimputed_1000G=6.54x10 -6) and IFNG-AS1 (Pimputed_1000G=1.32x10 -5). 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 expressed more highly in CL biopsies compared to normal skin; KRT80 (Padjusted=3.07x10 -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 haematopoietic stem cells. Those at IFNG-AS1 mapped to transcriptional/enhancer regions in T, natural killer, and B cells. The percent 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.

Cytokine Receptor-Like Factor 3 (CRLF3) Contributes to Early Zebrafish Hematopoiesis

“…There is some evidence from other studies that CRLF3 contributes to blood and immune cell development and/or function throughout the life-course. Human CRLF3 variants have been associated with lymphocyte percentage in the blood ( 50 ) and risk of cutaneous leishmaniasis ( 51 ), while variants in the corresponding chicken gene are associated with an altered antibody response ( 52 ). It also forms part of a rare UTP6-CRLF3 fusion observed in human acute myeloid leukemia ( 53 ).…”

Genetics, Transcriptomics and Meta-Taxonomics in Visceral Leishmaniasis

“…Together our genetic and transcriptional profiling studies have provided important evidence to support the importance of antigen presentation to CD4+ T cells and the role of IFNg in the pathogenesis of L. donovani infection. In a more recent GWAS for cutaneous leishmaniasis in Brazil (Castellucci et al, 2020) we were able to carry out integrated post-GWAS annotation that related genetic risk loci to public domain data on expression quantitative trait loci as well as disease-specific transcriptional data that allowed us to focus in on the most plausible genetic risk loci. Application of this type of integrated analysis might highlight additional genetic risk loci for VL that were not apparent in our meta-analysis of VL caused by L. donovani in India compared to L. chagasi in Brazil.…”

SERPINB10 Contributes to Asthma by Inhibiting the Apoptosis of Allergenic Th2 Cells

“…One genome-wide association study found that many cis-expression quantitative trait loci across SERPINB10 were in the chromatin-interaction regions of transcriptional/enhancer activity in some immune cells. Those ndings indicate that SERPINB10 has central roles in the immune response [14]. A review by Ashton and colleagues showed that several SERPINS in clade B can control the recognition of antigens and effector functions of T lymphocytes by promoting their viability [15].…”