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Variants of MIRNA146A rs2910164 and MIRNA499 rs3746444 are associated with the development of cutaneous leishmaniasis caused by Leishmania guyanensis and with plasma chemokine IL-8
- Source :
- PLoS Neglected Tropical Diseases, PLoS Neglected Tropical Diseases, Vol 15, Iss 9, p e0009795 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science, 2021.
-
Abstract
- Leishmania are intracellular protozoan parasites that cause a wide spectrum of clinical manifestations in genetically susceptible individuals with an insufficient or balanced Th1 immune response to eliminate the parasite. MiRNAs play important regulatory role in numerous biological processes including essential cellular functions. miR146-a acts as an inhibitor of interleukin 1 receptor associated kinase 1 (IRAK1) and tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) present in the toll-like receptors pathway while miR499a modulates TGF-β and TNF signalling pathways. Here, we investigated whether MIRNA146A rs2910164 and MIRNA499 rs3746444 variants are associated with the development of L. guyanensis (Lg)-cutaneous leishmaniasis (CL). The variants MIR146A rs2910164 and MIR499A rs3746444 were assessed in 850 patients with Lg-CL and 891 healthy controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma cytokines were measured using the BioPlex assay. Carriers of rs2910164 CC genotype have 30% higher odds of developing CL (ORadjage/sex = 1.3 [95%CI 0.9–1.8]; Padjage/sex 0.14) compared to individuals with the genotype GG (ORadjage/sex = 0.77 [95%CI 0.56–1.0]; Padjage/sex 0.14) if exposed to Lg-infection. Heterozygous GC individuals also showed lower odds of developing CL (ORadjage/sex = 0.77 [95%CI 0.5–1.1]; Padjage/sex 0.09). Homozygosity for the allele C is suggestive of an association with the development of Lg-CL among exposed individuals to Lg-infection. However, the odds of developing CL associated with the CC genotype was evident only in male individuals (ORadjage = 1.3 [95% CI = 0.9–2.0]; Padjage = 0.06). Individuals homozygous for the G allele tend to have higher plasma IL-8 and CCL5. Similarly, for the MIR499A rs3746444, an association with the G allele was only observed among male individuals (OR = 1.4 [1.0–1.9]; P = 0.009). In a dominant model, individuals with the G allele (GG-GA) when compared to the AA genotype reveals that carriers of the G allele have 40% elevated odds of developing Lg-CL (ORadjage = 1.4 [1.1–1.9]). Individuals with the GG genotype have higher odds of developing Lg-CL (ORadjage/sex = 2.0 [95%CI 0.83–5.0]; Padjage = 0.01. Individuals homozygous for the G allele have higher plasma IL-8. Genetic combinations of both variants revealed that male individuals exposed to Lg bearing three or four susceptible alleles have higher odds of developing Lg-CL (OR = 2.3 [95% CI 1.0–4.7]; p = 0.017). Both MIR146A rs2910164 and MIR499A rs3746444 are associated with the development of Lg-CL and this association is prevalent in male individuals.<br />Author summary Leishmaniasis is caused by infection with Leishmania parasites. In regions with the presence of Leishmania parasites, all people do not develop the disease despite similar exposure. Only a proportion of inhabitants progress to the development of disease. Clinical manifestations depend on the vector and Leishmania species, as well the host genetic background and genetically determined immune responses. miRNAs play important roles in regulating gene expression and many biological processes including immune pathways. miR-146a targets TRAF6 and IRAK1 genes, that encode key adaptor molecules downstream of toll-like receptors (TLRs). TLRs are critical in immune response to Leishmania-infection. miR499-a modulates inflammation-related signalling pathways such as TGFβ, TNFα and TLR pathways. In this study, we showed that MIR146A and MIR499A variants are risk factors to developing cutaneous leishmaniasis caused by L. guyanensis in Amazonas state of Brazil. Individuals with these variants are susceptible to the development of CL.
- Subjects :
- Male
Chemokine
Heredity
Physiology
RC955-962
Biochemistry
Immune Receptors
Homozygosity
Medical Conditions
Arctic medicine. Tropical medicine
Immune Physiology
Zoonoses
Genotype
Medicine and Health Sciences
Receptor
Leishmania guyanensis
Leishmaniasis
Toll-like Receptors
Protozoans
Leishmania
Innate Immune System
Immune System Proteins
Intracellular Signaling Peptides and Proteins
Eukaryota
Middle Aged
Nucleic acids
Genetic Mapping
Infectious Diseases
Interleukin-1 Receptor-Associated Kinases
Cytokines
Female
Public aspects of medicine
RA1-1270
Restriction fragment length polymorphism
Polymorphism, Restriction Fragment Length
Research Article
Neglected Tropical Diseases
Signal Transduction
Adult
Immunology
Leishmaniasis, Cutaneous
Variant Genotypes
Biology
Polymorphism, Single Nucleotide
Cutaneous leishmaniasis
medicine
Genetics
Parasitic Diseases
Humans
Genetic Predisposition to Disease
Interleukin 8
Allele
Non-coding RNA
Alleles
Natural antisense transcripts
Protozoan Infections
Interleukin-8
Public Health, Environmental and Occupational Health
Organisms
Biology and Life Sciences
Proteins
Cell Biology
Molecular Development
medicine.disease
Tropical Diseases
Parasitic Protozoans
Gene regulation
MicroRNAs
Genetic Loci
Immune System
biology.protein
RNA
Gene expression
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 19352735 and 19352727
- Volume :
- 15
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS Neglected Tropical Diseases
- Accession number :
- edsair.doi.dedup.....123edc9a7eec8c100f18d25320a1d0a2