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 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.

Keywords: COL1A1; Cutaneous leishmaniasis; Gene analysis; Wound healing.

Figure 1

LD patterns for D’ (A) and r² (B) were determined in Haploview software v4.2 (Barrett et al., 2005) for the 3 COL1A1 SNPs used in the association analyses. D' values and confidence levels (LOD) are represented as red for D'=1, LOD>2 (none present); shades of pink for varying D’, LOD<0.2; white for D'<1, LOD<2 (none present). r² values are represented white for r² = 0, with intermediate values for 0<r² < 1 indicated by shades of grey. The numbers within the squares represent the D' or r² scores for pairwise LD.