Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

Abstract

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 leukaemia 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.

A genome-wide association study highlights a regulatory role forIFNG-AS1contributing to cutaneous leishmaniasis in Brazil

“…No genes/regions achieved genome-wide significance (commonly accepted as P<5x10 -8 [27][28][29]) in a combined analysis. Support was found for the prior hypothesis [14,21] that variants at wound-healing genes are risk factors for CL, including at SMAD2, SMAD3 and SMAD 7 studied previously and novel associations at SMAD1, SMAD4, SMAD6, SMAD9, TGFBR3, COL11A1 and COL24A1. Top novel GWAS hits at P<5x10 -5 that provide plausible candidate genetic risk factors for CL included variants at SERPINB10, CRLF3, STX7, LAMP3, KRT80 and IFNG-AS1.…”

“…As noted above, previous candidate gene studies attempting to identify genetic risk factors for CL caused by L. braziliensis have typically been small, underpowered family-based or casecontrol studies [13][14][15][16][17][18][19][20][21]. We therefore interrogated the GWAS data to determine whether evidence could be found to support the candidacy of these genes.…”

“…This suggested that major genetic risk factors might readily be found for CL. To date, candidate gene studies [13][14][15][16][17][18][19][20][21] undertaken in L. braziliensis endemic regions have demonstrated putative roles for polymorphisms at multiple genes associated with pro-and anti-inflammatory responses (TNFA, SLC11A1, CXCR1, IL6, IL10, CCL2/MCP1) and with wound healing (FLI1, CTGF, TGFBR2, SMAD2, SMAD3, SMAD7, COL1A1) in determining susceptibility to CL or ML disease. This includes susceptibility genes identified from murine studies of leishmaniasis (SLC11A1, FLI1) [15,16].…”

Platelet-Released Growth Factors and Platelet-Rich Fibrin Induce Expression of Factors Involved in Extracellular Matrix Organization in Human Keratinocytes

“…Collagens are the most abundant proteins in the ECM. Collagen type I alpha 1 chain (COL1A1) is involved in the formation of type I collagen fibers [ 66 , 67 ] and is therefore involved in the profibrotic gene induction program [ 68 ]. Although mainly expressed by fibroblasts COL1A1 is also expressed in keratinocytes as confirmed by our study.…”

Human genetics of leishmania infections

“…For CL, candidate gene studies (Almeida et al 2015;Cabrera et al 1995;Castellucci et al 2006Castellucci et al , 2010Castellucci et al , 2011Castellucci et al , 2012Castellucci et al , 2014Ramasawmy et al 2010;Salhi et al 2008) undertaken in L. braziliensis endemic regions had demonstrated associations with polymorphisms at multiple genes associated with pro-and anti-inflammatory responses (TNFA,SLC11A1,CXCR1,IL6,IL10,CCL2/MCP1) and/or with wound healing (FLI1,CTGF,TGFBR2,SMAD2,SMAD3,SMAD7,COL1A1) in determining susceptibility to CL or ML disease. This included susceptibility genes identified from murine studies of leishmaniasis (SLC11A1, FLI1) (Castellucci et al 2010(Castellucci et al , 2011.…”