National Institute of Science and Technology in Tropical Diseases, Brazil and Federal University of Bahia, Salvador, Brazil.
Infect Genet Evol. 2012 Jul;12(5):1102-10. doi: 10.1016/j.meegid.2012.03.017. Epub 2012 Mar 28.
Leishmania braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. In the mouse, Fli1 was identified as a gene influencing enhanced wound healing and resistance to CL caused by Leishmania major. Polymorphism at FLI1 is associated with CL caused by L. braziliensis in humans, with an inverse association observed for ML disease. Here we extend the analysis to look at other wound healing genes, including CTGF, TGFB1, TGFBR1/2, SMADS 2/3/4/7 and FLII, all functionally linked along with FLI1 in the TGF beta pathway. Haplotype tagging single nucleotide polymorphisms (tag-SNPs) were genotyped using Taqman technology in 325 nuclear families (652 CL cases; 126 ML cases) from Brazil. Robust case-pseudocontrol (CPC) conditional logistic regression analysis showed associations between CL and SNPs at CTGF (SNP rs6918698; CC genotype; OR 1.67; 95%CI 1.10-2.54; P=0.016), TGFBR2 (rs1962859; OR 1.50; 95%CI 1.12-1.99; P=0.005), SMAD2 (rs1792658; OR 1.57; 95%CI 1.04-2.38; P=0.03), SMAD7 (rs4464148; AA genotype; OR 2.80; 95%CI 1.00-7.87; P=0.05) and FLII (rs2071242; OR 1.60; 95%CI 1.14-2.24; P=0.005), and between ML and SNPs at SMAD3 (rs1465841; OR 2.15; 95%CI 1.13-4.07; P=0.018) and SMAD7 (rs2337107; TT genotype; OR 3.70; 95%CI 1.27-10.7; P=0.016). Stepwise logistic regression analysis showed that all SNPs associated with CL at FLI1, CTGF, TGFBR2, and FLII showed independent effects from each other, but SNPs at SMAD2 and SMAD7 did not add independent effects to SNPs from other genes. These results suggest that TGFβ signalling via SMAD2 is important in directing events that contribute to CL, whereas signalling via SMAD3 is important in ML. Both are modulated by the inhibitory SMAD7 that acts upstream of SMAD2 and SMAD3 in this signalling pathway. Along with the published FLI1 association, these data further contribute to the hypothesis that wound healing processes are important determinants of pathology associated with cutaneous forms of leishmaniasis.
巴西利什曼原虫可引起皮肤（CL）和黏膜（ML）利什曼病。在小鼠中，Fli1 被鉴定为影响主要利什曼原虫引起的伤口愈合增强和对 CL 抵抗力的基因。FLI1 多态性与巴西利什曼原虫引起的人类 CL 有关，与 ML 疾病呈负相关。在这里，我们扩展分析以研究其他伤口愈合基因，包括 CTGF、TGFB1、TGFBR1/2、SMADS 2/3/4/7 和 FLII，所有这些基因都与 TGFβ 通路中的 FLI1 一起在 TGFβ 途径中具有功能联系。使用 Taqman 技术对来自巴西的 325 个核家族（652 例 CL 病例；126 例 ML 病例）中的 CTGF、TGFBR2、SMAD2、SMAD7 和 FLII 的功能相关单核苷酸多态性（tag-SNPs）进行了基因分型。稳健的病例-假性对照（CPC）条件逻辑回归分析显示，CL 与 CTGF（SNP rs6918698；CC 基因型；OR 1.67；95%CI 1.10-2.54；P=0.016）、TGFBR2（rs1962859；OR 1.50；95%CI 1.12-1.99；P=0.005）、SMAD2（rs1792658；OR 1.57；95%CI 1.04-2.38；P=0.03）、SMAD7（rs4464148；AA 基因型；OR 2.80；95%CI 1.00-7.87；P=0.05）和 FLII（rs2071242；OR 1.60；95%CI 1.14-2.24；P=0.005）之间存在关联，而 ML 与 SMAD3（rs1465841；OR 2.15；95%CI 1.13-4.07；P=0.018）和 SMAD7（rs2337107；TT 基因型；OR 3.70；95%CI 1.27-10.7；P=0.016）之间存在关联。逐步逻辑回归分析表明，与 FLI1、CTGF、TGFBR2 和 FLII 上的 CL 相关的所有 SNP 彼此之间均具有独立作用，但 SNP 位于 SMAD2 和 SMAD7 中，它们对来自其他基因的 SNP 没有独立作用。这些结果表明，TGFβ 通过 SMAD2 信号传导在指导导致 CL 的事件中很重要，而通过 SMAD3 信号传导在 ML 中很重要。这两种信号都被该信号通路中上游的抑制性 SMAD7 调节。结合已发表的 FLI1 关联，这些数据进一步支持这样一种假设，即伤口愈合过程是与皮肤形式的利什曼病相关的病理的重要决定因素。
