Dataset Information

FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil.

ABSTRACT: Mapping murine genes controlling cutaneous leishmaniasis (CL) identified Fli1 as a candidate influencing resistance to L. major and enhanced wound healing. We examine FLI1 as a gene controlling CL and mucosal leishmaniasis (ML) caused by L. braziliensis in humans. Intron 1 single nucleotide polymorphisms tagging promoter and enhancer elements were analysed in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Robust case-pseudocontrol logistic regression analysis showed association between allele C (odds ratio (OR) 1.65; 95% confidence interval 1.18-2.29; P=0.003) of FLI1_rs7930515 and CL in the primary sample that was confirmed (OR 1.60; 95% confidence interval 1.10-2.33; P=0.014) in the replication set (combined P=1.8 × 10(-4)). FLI1_rs7930515 is in linkage disequilibrium with the functional GAn microsatellite in the proximal promoter. Haplotype associations extended across the enhancer, which was not polymorphic. ML associated with inverse haplotypes compared with CL. Wound healing is therefore important in CL, providing potential for therapies modulating FLI1.

SUBMITTER: Castellucci L

PROVIDER: S-EPMC3297968 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil.

Castellucci L L Jamieson S E SE Miller E N EN de Almeida L F LF Oliveira J J Magalhães A A Guimarães L H LH Lessa M M Lago E E de Jesus A R AR Carvalho E M EM Blackwell J M JM

Genes and immunity 20110602 7

Mapping murine genes controlling cutaneous leishmaniasis (CL) identified Fli1 as a candidate influencing resistance to L. major and enhanced wound healing. We examine FLI1 as a gene controlling CL and mucosal leishmaniasis (ML) caused by L. braziliensis in humans. Intron 1 single nucleotide polymorphisms tagging promoter and enhancer elements were analysed in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Robust case-pseudocontrol logistic regres ...[more]

PMID: 21633373

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Project description:BackgroundCutaneous leishmaniasis (CL) is a vector-borne disease classified by the World Health Organization as one of the most neglected tropical diseases. Brazil has the highest incidence of CL in America and is one of the ten countries in the world with the highest number of cases. Understanding the spatiotemporal dynamics of CL is essential to provide guidelines for public health policies in Brazil. In the present study we used a spatial and temporal statistical approach to evaluate the dynamics of CL in Brazil.MethodsWe used data of cutaneous leishmaniasis cases provided by the Ministry of Health of Brazil from 2001 to 2017. We calculated incidence rates and used the Mann-Kendall trend test to evaluate the temporal trend of CL in each municipality. In addition, we used Kuldorff scan method to identify spatiotemporal clusters and emerging hotspots test to evaluate hotspot areas and their temporal trends.ResultsWe found a general decrease in the number of CL cases in Brazil (from 15.3 to 8.4 cases per 100 000 habitants), although 3.2% of municipalities still have an increasing tendency of CL incidence and 72.5% showed no tendency at all. The scan analysis identified a primary cluster in northern and central regions and 21 secondary clusters located mainly in south and southeast regions. The emerging hotspots analysis detected a high spatial and temporal variability of hotspots inside the main cluster area, diminishing hotspots in eastern Amazon and permanent, emerging, and new hotspots in the states of Amapá and parts of Pará, Roraima, Acre and Mato Grosso. The central coast the state of Bahia is one of the most critical areas due to the detection of a cluster of the highest rank in a secondary cluster, and because it is the only area identified as an intensifying hotspot.ConclusionsUsing a combination of statistical methods we were able to detect areas of higher incidence of CL and understand how it changed over time. We suggest that these areas, especially those identified as permanent, new, emerging and intensifying hotspots, should be targeted for future research, surveillance, and implementation of vector control measures.

Project description:L. braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. Wound healing neutrophil (PMN) and macrophage responses made following the bite of the vector sand fly contribute to disease progression in mice. To look at the interplay between PMN and macrophages in disease progression in humans we asked whether polymorphisms at genes that regulate their infiltration or function are associated with different clinical phenotypes. Specifically, CXCR1 (IL8RA) and CXCR2 (IL8RB) are receptors for chemokines that attract PMN to inflammatory sites. They lie 30-260 kb upstream of SLC11A1, a gene known primarily for its role in regulating macrophage activation, resistance to leishmaniasis, and wound healing responses in mice, but also known to be expressed in PMN, macrophages and dendritic cells.Polymorphic variants at CXCR1, CXCR2 and SLC11A1 were analysed using Taqman or ABI fragment separation technologies in cases (60 CL; 60 ML), unrelated controls (n = 120), and multicase families (104 nuclear families; 88 ML, 250 CL cases) from Brazil. Logistic regression analysis, family-based association testing (FBAT) and haplotype analysis (TRANSMIT) were performed.Case-control analysis showed association between the common C allele (OR 2.38; 95% CI 1.23-4.57; P = 0.009) of CXCR1_rs2854386 and CL, supported by family-based (FBAT; Z score 2.002; P = 0.045) analysis (104 nuclear families; 88 ML, 250 CL cases). ML associated with the rarer G allele (Z score 1.999; P = 0.046). CL associated with a 3' insertion/deletion polymorphism at SLC11A1 (Z score 2.549; P = 0.011).The study supports roles for CXCR1 and SLC11A1 in the outcome of L. braziliensis infection in humans. Slc11a1 does not influence cutaneous lesion development following needle injection of Leishmania in mice, suggesting that its role here might relate to the action of PMN, macrophage and/or dendritic cells in the wound healing response to the sand fly bite. Together with the CXCR1 association, the data are consistent with hypotheses relating to the possible role of PMN in initiation of a lesion following the delivery of parasites via the sand fly bite. Association of ML with the rare derived G allele suggests that PMN also have an important positive role to play in preventing this form of the disease.

Dataset Information

FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil.

Publications

FLI1 polymorphism affects susceptibility to cutaneous leishmaniasis in Brazil.

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