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Open Access Research article

Genetic and functional evaluation of the role of CXCR1 and CXCR2 in susceptibility to visceral leishmaniasis in north-east India

Sanjana Mehrotra12, Michaela Fakiola23, Joyce Oommen2, Sarra E Jamieson2, Anshuman Mishra1, Medhavi Sudarshan1, Puja Tiwary1, Deepa Selvi Rani4, Kumarasamy Thangaraj4, Madhukar Rai1, Shyam Sundar1 and Jenefer M Blackwell23*

  • * Corresponding author: Jenefer M Blackwell jmb37@cam.ac.uk

  • † Equal contributors

Author Affiliations

1 Institute of Medical Sciences, Banaras Hindu University, Varanasi, OS 221 005, India

2 Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia

3 Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK

4 Centre for Cellular and Molecular Biology, Hyderabad, India

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BMC Medical Genetics 2011, 12:162  doi:10.1186/1471-2350-12-162

Published: 15 December 2011

Abstract

Background

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). 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.

Methods

Three 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.

Results

Family-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).

Conclusions

This well-powered primary and replication genetic study, together with functional analysis of gene expression, implicate CXCR2 in determining outcome of VL in India.