Single-nucleotide polymorphisms in genes associated with the vitamin D pathway related to clinical and therapeutic outcomes of American tegumentary leishmaniasis

Front Cell Infect Microbiol. 2025 Jan 8:14:1487255. doi: 10.3389/fcimb.2024.1487255. eCollection 2024.

Abstract

Background: The vitamin D pathway contributes to the microbicidal activity of macrophages against Leishmania infection. In addition to induction of this pathway, interferon-gamma (IFNγ), interleukin (IL)-15, and IL32γ are part of a network of pro-inflammatory cytokines. The aim of this study was to evaluate single-nucleotide polymorphisms (SNPs) in the components of the vitamin D pathway and associated cytokine genes that could be related to resistance or susceptibility to American tegumentary leishmaniasis (ATL).

Methods: The expressions of IFNG, IL15, IL32, CYP27B1, VDR, and other pro-inflammatory cytokines TNF, IL6, and IL17 genes were evaluated using real-time polymerase chain reaction (qPCR) in lesions of patients with localized cutaneous leishmaniasis (LCL) or mucosal leishmaniasis (ML). SNP genotypes/alleles (in IL15, IL32, CYP27B1, and VDR) were evaluated by TaqMan PCR assays using DNA from the blood of patients and healthy individuals. Serum vitamin D levels were determined by chemiluminescence.

Results: Vitamin D pathway-associated genes were expressed in cutaneous as well as mucosal lesions. IFNG, IL6, and IL17 were more highly expressed in ML than in LCL. In contrast, IL32γ/CYP27B1/VDR mRNAs were mainly correlated in LCL, and IL32γ in ML makes strong connections with all cytokines. The SNP IL32 rs1555001 was less frequent in patients with ML. In addition, some SNPs appear to influence the VDR and CYP27B1 (IL15 rs10519613 and IL15 rs3775597) and IL6 (VDR rs7975232) expressions in LCL and the IL17 expression in ML (IL15 rs3775597). Gene expression was also correlated with clinical parameters, such as number of lesions (CYP27B1 mRNA) and treatment failure (VDR mRNA). In addition, one SNP was associated with treatment failure in ML (VDR rs7975232).

Conclusions: Our findings suggested that some SNPs in the vitamin D pathway-associated genes can be related to resistance and therapeutic outcomes of ATL. They are promising candidates that need to be further evaluated to understand their biological effects in the control or immunopathogenesis of ATL.

Keywords: CYP27B1; Leishmania (Viannia); interleukin-15; interleukin-32; single nucleotide polymorphism; vitamin D receptor.

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase* / genetics
  • Adolescent
  • Adult
  • Alleles
  • Cytokines* / genetics
  • Cytokines* / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Interferon-gamma / genetics
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Interleukins / genetics
  • Leishmaniasis, Cutaneous* / drug therapy
  • Leishmaniasis, Cutaneous* / genetics
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Receptors, Calcitriol* / genetics
  • Treatment Outcome
  • Vitamin D* / blood
  • Young Adult

Substances

  • Receptors, Calcitriol
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Vitamin D
  • Cytokines
  • CYP27B1 protein, human
  • VDR protein, human
  • Interferon-gamma
  • Interleukins
  • IL32 protein, human
  • IFNG protein, human
  • Interleukin-17

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. RG received PPSUS/FAPEG (n. 202110267000280), and FR-D received PRONEM/FAPEG (CH 07-2016; n. 2017-10267000516) grants from Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG), Brazil. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil/Finance Code 001 plus FAPEG–fellow support to IO. FR-D is fellow researcher of the National Council for Scientific and Technological Development (CNPq)/Brazil. INCT-IPH National Institute of Science and Technology for the strategies in host–pathogen interaction, FAPEG’s grant n. 465771/2014-9.