@article{103498,
  keywords = {Genes, Single nucleotide polymorphisms, Brazil, leprosy},
  author = {Espasandin I and Cardoso CC and Leal-Calvo T and Mendes MA and Latini ACP and de Castro SHM and Leturiondo AL and Bezerra OCDL and Pinheiro RO and Sales AM and Moraes MO and Kehdy FDSG},
  editor = {Belo VS},
  title = {Functional single nucleotide polymorphisms in CACNA2D3 and other autophagy-related genes are associated with leprosy among Brazilians},
  abstract = {<jats:sec id="sec001">
                    <jats:title>Background</jats:title>
                    <jats:p>
                      Autophagy is a crucial host defense mechanism against intracellular pathogens, including
                      <jats:italic>Mycobacterium leprae</jats:italic>
                      . Genetic variants in autophagy-related genes have been associated with susceptibility to leprosy, but their functional relevance remains incompletely understood.
                    </jats:p>
                  </jats:sec>
                  <jats:sec id="sec002">
                    <jats:title>Methodology/Principal findings</jats:title>
                    <jats:p>
                      We investigate the association of single nucleotide polymorphisms (SNPs) in three genes involved in autophagy,
                      <jats:italic>CACNA2D3</jats:italic>
                      ,
                      <jats:italic>LRRK2</jats:italic>
                      and
                      <jats:italic>IRGM</jats:italic>
                      . A total of 3,480 individuals from three Brazilian populations were included in a case-control design. We confirmed that the SNP rs1449325 in
                      <jats:italic>CACNA2D3</jats:italic>
                      was associated with leprosy
                      <jats:italic>per se</jats:italic>
                      protection in the overdominant model (ORoverdTC = 0.70; p = 0.00443) in Rio de Janeiro, which was then replicated in samples from Manaus and Rondonópolis. Curiously, CC genotype of rs1449325 was associated with leprosy
                      <jats:italic>per se</jats:italic>
                      risk in the recessive model in Rio de Janeiro (ORrecCC = 1.51; p = 0.00476), Manaus (ORrecCC = 3.06; p = 1.44E-07) and Rondonópolis (ORrecCC = 1.50; p = 0.0240). Data from public eQTLs databases and gene expression analysis from whole blood samples suggested increasing
                      <jats:italic>CACNA2D3</jats:italic>
                      expression levels with TT &lt; CT &lt; CC genotypes. In the literature,
                      <jats:italic>CACNA2D3</jats:italic>
                      mRNA levels are positively correlated with calcium influx levels. Taken together, the genetic and expression data support the hypothesis that either low or high levels of calcium leads to
                      <jats:italic>M. leprae</jats:italic>
                      susceptibility. Associations of SNPs in
                      <jats:italic>LRRK2</jats:italic>
                      and
                      <jats:italic>IRGM</jats:italic>
                      genes were also observed in the Rio de janeiro population, although not confirmed in replication cohorts. However, a protective effect of the
                      <jats:italic>LRRK2</jats:italic>
                      haplotype C/G/G/T/G (rs7308720/rs7133914/rs10878434/rs3761863/rs7962370), apparently driven by rs3761863 T allele, was observed in Rio de Janeiro (ORhap = 0.44; p = 0.0121). This allele was associated with lower levels of
                      <jats:italic>LRRK2</jats:italic>
                      mRNA expression in skin biopsy samples from leprosy patients, as well as in tibial nerve and fibroblast samples of healthy individuals from public databases.
                    </jats:p>
                  </jats:sec>
                  <jats:sec id="sec003">
                    <jats:title>Conclusions/Significance</jats:title>
                    <jats:p>
                      Our results highlight a dual role of calcium signaling and autophagy gene regulation in leprosy susceptibility. Variants in
                      <jats:italic>CACNA2D3</jats:italic>
                      and
                      <jats:italic>LRRK2</jats:italic>
                      modulate host response to
                      <jats:italic>M. leprae</jats:italic>
                      infection and represent potential targets for improved therapeutic and preventive approaches.
                    </jats:p>
                  </jats:sec>},
  year = {2026},
  journal = {PLOS Neglected Tropical Diseases},
  volume = {20},
  pages = {1 - 22},
  month = {04/2026},
  publisher = {Public Library of Science (PLoS)},
  issn = {1935-2735},
  url = {https://www.researchgate.net/publication/404228947_Functional_single_nucleotide_polymorphisms_in_CACNA2D3_and_other_autophagy-related_genes_are_associated_with_leprosy_among_Brazilians},
  doi = {10.1371/journal.pntd.0014241},
  language = {ENG},
}