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

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BMC Medical Genetics

, 12:162

Genetic epidemiology and genetic associations


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.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2350-12-162 contains supplementary material, which is available to authorized users.

Shyam Sundar and Jenefer M Blackwell contributed equally to this work.

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Autor: Sanjana Mehrotra - Michaela Fakiola - Joyce Oommen - Sarra E Jamieson - Anshuman Mishra - Medhavi Sudarshan - Puja Tiwary


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