Abstract
BackgroundIL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). Variants at CXCR1 and CXCR2 have been associated with susceptibility to cutaneous and mucocutaneous leishmaniasis in Brazil. Here we investigate the role of CXCR1/CXCR2 in visceral leishmaniasis (VL) in India.MethodsThree single nucleotide polymorphisms (SNPs) (rs4674259, rs2234671, rs3138060) that tag linkage disequilibrium blocks across CXCR1/CXCR2 were genotyped in primary family-based (313 cases; 176 nuclear families; 836 individuals) and replication (941 cases; 992 controls) samples. Family- and population-based analyses were performed to look for association between CXCR1/CXCR2 variants and VL. Quantitative RT/PCR was used to compare CXCR1/CXCR2 expression in mRNA from paired splenic aspirates taken before and after treatment from 19 VL patients.ResultsFamily-based analysis using FBAT showed association between VL and SNPs CXCR1_rs2234671 (Z-score = 2.935, P = 0.003) and CXCR1_rs3138060 (Z-score = 2.22, P = 0.026), but not with CXCR2_rs4674259. Logistic regression analysis of the case-control data under an additive model of inheritance showed association between VL and SNPs CXCR2_rs4674259 (OR = 1.15, 95%CI = 1.01-1.31, P = 0.027) and CXCR1_rs3138060 (OR = 1.25, 95%CI = 1.02-1.53, P = 0.028), but not with CXCR1_rs2234671. The 3-locus haplotype T_G_C across these SNPs was shown to be the risk haplotype in both family- (TRANSMIT; P = 0.014) and population- (OR = 1.16, P = 0.028) samples (combined P = 0.002). CXCR2, but not CXCR1, expression was down regulated in pre-treatment compared to post-treatment splenic aspirates (P = 0.021).ConclusionsThis well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India.
Highlights
IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN)
[16] we examined the role of polymorphisms at CXCR1 and CXCR2, which act as receptors for CXC chemokines that attract PMN to inflammatory sites, in determining susceptibility to cutaneous forms of leishmaniasis caused by infection with L. braziliensis
We use genetic and functional approaches to evaluate the role of PMN in visceral leishmaniasis (VL) caused by L. donovani in humans through analysis of the receptors CXCR1, which is a specific receptor for IL-8 (= CXCL8), and CXCR2, which is promiscuous in binding a variety of CXC chemokines (CXCL-1, 2, 3, 5, 6, 7) in addition to CXCL8
Summary
IL8RA and IL8RB, encoded by CXCR1 and CXCR2, are receptors for interleukin (IL)-8 and other CXC chemokines involved in chemotaxis and activation of polymorphonuclear neutrophils (PMN). The arrival and maintenance of infiltrating cells at bite sites is thought to be mediated by sand fly-derived factors that mimic a tissue damage signal and/or activate chemokine/chemokine receptor pathways [13,14,15]. [16] we examined the role of polymorphisms at CXCR1 and CXCR2, which act as receptors for CXC chemokines that attract PMN to inflammatory sites, in determining susceptibility to cutaneous forms of leishmaniasis caused by infection with L. braziliensis. We use genetic and functional approaches to evaluate the role of PMN in VL caused by L. donovani in humans through analysis of the receptors CXCR1, which is a specific receptor for IL-8 (= CXCL8), and CXCR2, which is promiscuous in binding a variety of CXC chemokines (CXCL-1, 2, 3, 5, 6, 7) in addition to CXCL8
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