{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T18:40:27Z","timestamp":1777315227598,"version":"3.51.4"},"reference-count":87,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Autophagy is a crucial host defense mechanism against intracellular pathogens, including\n                      <jats:italic>Mycobacterium leprae<\/jats:italic>\n                      . Genetic variants in autophagy-related genes have been associated with susceptibility to leprosy, but their functional relevance remains incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methodology\/Principal findings<\/jats:title>\n                    <jats:p>\n                      We investigate the association of single nucleotide polymorphisms (SNPs) in three genes involved in autophagy,\n                      <jats:italic>CACNA2D3<\/jats:italic>\n                      ,\n                      <jats:italic>LRRK2<\/jats:italic>\n                      and\n                      <jats:italic>IRGM<\/jats:italic>\n                      . A total of 3,480 individuals from three Brazilian populations were included in a case-control design. We confirmed that the SNP rs1449325 in\n                      <jats:italic>CACNA2D3<\/jats:italic>\n                      was associated with leprosy\n                      <jats:italic>per se<\/jats:italic>\n                      protection in the overdominant model (ORoverdTC\u2009=\u20090.70; p\u2009=\u20090.00443) in Rio de Janeiro, which was then replicated in samples from Manaus and Rondon\u00f3polis. Curiously, CC genotype of rs1449325 was associated with leprosy\n                      <jats:italic>per se<\/jats:italic>\n                      risk in the recessive model in Rio de Janeiro (ORrecCC\u2009=\u20091.51; p\u2009=\u20090.00476), Manaus (ORrecCC\u2009=\u20093.06; p\u2009=\u20091.44E-07) and Rondon\u00f3polis (ORrecCC\u2009=\u20091.50; p\u2009=\u20090.0240). Data from public eQTLs databases and gene expression analysis from whole blood samples suggested increasing\n                      <jats:italic>CACNA2D3<\/jats:italic>\n                      expression levels with TT\u2009&lt;\u2009CT\u2009&lt;\u2009CC genotypes. In the literature,\n                      <jats:italic>CACNA2D3<\/jats:italic>\n                      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\n                      <jats:italic>M. leprae<\/jats:italic>\n                      susceptibility. Associations of SNPs in\n                      <jats:italic>LRRK2<\/jats:italic>\n                      and\n                      <jats:italic>IRGM<\/jats:italic>\n                      genes were also observed in the Rio de janeiro population, although not confirmed in replication cohorts. However, a protective effect of the\n                      <jats:italic>LRRK2<\/jats:italic>\n                      haplotype C\/G\/G\/T\/G (rs7308720\/rs7133914\/rs10878434\/rs3761863\/rs7962370), apparently driven by rs3761863 T allele, was observed in Rio de Janeiro (ORhap\u2009=\u20090.44; p\u2009=\u20090.0121). This allele was associated with lower levels of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      mRNA expression in skin biopsy samples from leprosy patients, as well as in tibial nerve and fibroblast samples of healthy individuals from public databases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions\/Significance<\/jats:title>\n                    <jats:p>\n                      Our results highlight a dual role of calcium signaling and autophagy gene regulation in leprosy susceptibility. Variants in\n                      <jats:italic>CACNA2D3<\/jats:italic>\n                      and\n                      <jats:italic>LRRK2<\/jats:italic>\n                      modulate host response to\n                      <jats:italic>M. leprae<\/jats:italic>\n                      infection and represent potential targets for improved therapeutic and preventive approaches.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0014241","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T17:45:41Z","timestamp":1777311941000},"page":"e0014241","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional single nucleotide polymorphisms in CACNA2D3 and other autophagy-related genes are associated with leprosy among 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Luiz","family":"Leturiondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ohanna Cavalcanti de Lima","family":"Bezerra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta Olmo","family":"Pinheiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Sales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milton Oz\u00f3rio","family":"Moraes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda de Souza Gomes","family":"Kehdy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"key":"pntd.0014241.ref001","first-page":"199","article-title":"Regulation of cell-mediated 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