Almeida Lucas, Oliveira Joyce, Guimarães Luiz Henrique, Carvalho Edgar M, Blackwell Jenefer M, Castellucci Léa
National Institute of Science and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.
Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, Australia; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Infect Genet Evol. 2015 Mar;30:225-229. doi: 10.1016/j.meegid.2014.12.034. Epub 2015 Jan 3.
Previous studies have demonstrated a role for wound healing genes in resolution of cutaneous lesions caused by Leishmania spp. in both mice and humans, including the gene FLI1 encoding Friend leukemia virus integration 1. Reduction of Fli1 expression in mice has been shown to result in up-regulation of collagen type I alpha 1 (Col1a1) and alpha 2 (Col1a2) genes and, conversely, in down-regulation of the matrix metalloproteinase 1 (Mmp1) gene, suggesting that Fli1 suppression is involved in activation of the profibrotic gene program. Here we examined single nucleotide polymorphisms (SNPs) in these genes as risk factors for cutaneous (CL) and mucosal leishmaniasis (ML), and leishmaniasis per se, caused by L. braziliensis in humans. SNPs were genotyped in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Family-based association tests (FBAT) showed the strongest association between SNPs rs1061237 (combined P=0.002) and rs2586488 (combined P=0.027) at COL1A1 and CL disease. This contributes to our further understanding of the role of wound healing in the resolution of CL disease, providing potential for therapies modulating COL1A1 via drugs acting on FLI1.
先前的研究已证明伤口愈合基因在小鼠和人类中对利什曼原虫属引起的皮肤病变的消退起作用，包括编码Friend白血病病毒整合1的FLI1基因。已表明小鼠中Fli1表达的降低会导致I型胶原α1（Col1a1）和α2（Col1a2）基因上调，相反，基质金属蛋白酶1（Mmp1）基因下调，这表明Fli1抑制参与了促纤维化基因程序的激活。在此，我们研究了这些基因中的单核苷酸多态性（SNP）作为人类由巴西利什曼原虫引起的皮肤利什曼病（CL）和黏膜利什曼病（ML）以及利什曼病本身的危险因素。对168个核心家庭（250例CL；87例ML病例）中的SNP进行基因分型，并在157个家庭（402例CL；39例ML病例）中进行复制。基于家系的关联测试（FBAT）显示，COL1A1基因座上的SNP rs1061237（合并P = 0.002）和rs2586488（合并P = 0.027）与CL疾病之间的关联最强。这有助于我们进一步了解伤口愈合在CL疾病消退中的作用，为通过作用于FLI1的药物调节COL1A1提供了治疗潜力。
