Open AccessVariants of MIRNA146A rs2910164 and MIRNA499 rs3746444 are associated with the development of cutaneous leishmaniasis caused by Leishmania guyanensis and with plasma chemokine IL-8
Author(s) -
Tirza Gabrielle Ramos de Mesquita,
José do Espírito Santo,
Thaís Carneiro de Lacerda,
Krys Layane Guimarães Duarte Queiroz,
Cláudio Marcello da Silveira Júnior,
José Pereira de Moura Neto,
Lissianne Augusta Matos Gomes,
Mara Lúcia Gomes de Souza,
Marcus Vinítius de Farias Guerra,
Rajendranath Ramasawmy
Publication year - 2021
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0009795
Subject(s) - genotype , biology , leishmaniasis , immunology , odds ratio , allele , leishmania , cutaneous leishmaniasis , genetics , medicine , parasite hosting , gene , world wide web , computer science
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 (ORadj age/sex = 1.3 [95%CI 0.9–1.8]; Padj age/sex 0.14) compared to individuals with the genotype GG (ORadj age/sex = 0.77 [95%CI 0.56–1.0]; Padj age/sex 0.14) if exposed to Lg -infection. Heterozygous GC individuals also showed lower odds of developing CL (ORadj age/sex = 0.77 [95%CI 0.5–1.1]; Padj age/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 (OR adjage = 1.3 [95% CI = 0.9–2.0]; P adjage = 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 (ORadj age = 1.4 [1.1–1.9]). Individuals with the GG genotype have higher odds of developing Lg -CL (ORadj age/sex = 2.0 [95%CI 0.83–5.0]; P adjage = 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.