CCL3L1 copy number, CCR5genotype and susceptibility to tuberculosis

Danielle Carpenter,Jon Goulding,Marie-Anne Shaw,Carmen Taype,John Al Armour,Mike Levin,Suzanne Anderson,Brian Eley

doi:10.1186/1471-2350-15-5

Abstract

BackgroundTuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine MIP-1α and its receptor CCR5 play a role in susceptibility to TB. Thus by measuring copy number variation of CCL3L1, one of the genes that encode MIP-1α, and genotyping a functional promoter polymorphism -2459A > G in CCR5 (rs1799987) we investigate the influence of MIP-1α and CCR5, independently and combined, in susceptibility to clinically active TB in three populations, a Peruvian population (n = 1132), a !Xhosa population (n = 605) and a South African Coloured population (n = 221). The three populations include patients with clinically diagnosed pulmonary TB, as well as other, less prevalent forms of extrapulmonary TB.Methods and resultsCopy number of CCL3L1 was measured using the paralogue ratio test and exhibited ranges between 0–6 copies per diploid genome (pdg) in Peru, between 0–12 pdg in !Xhosa samples and between 0–10 pdg in South African Coloured samples. The CCR5 promoter polymorphism was observed to differ significantly in allele frequency between populations (*A; Peru f = 0.67, !Xhosa f = 0.38, Coloured f = 0.48).ConclusionsThe case–control association studies performed however find, surprisingly, no evidence for an influence of variation in genes coding for MIP-1α or CCR5 individually or together in susceptibility to clinically active TB in these populations.

Highlights

Tuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine macrophage inflammatory protein (MIP)-1α and its receptor chemokine receptor type 5 (CCR5) play a role in susceptibility to TB
The case–control association studies performed find, surprisingly, no evidence for an influence of variation in genes coding for MIP-1α or CCR5 individually or together in susceptibility to clinically active TB in these populations
MIP-1α mRNA expression and protein production has been shown to be upregulated by M. tuberculosis stimulation, and secretion of MIP-1α was detected during the generation of granulomatous lesions [11]

Summary

Introduction

Tuberculosis is a major infectious disease and functional studies have provided evidence that both the chemokine MIP-1α and its receptor CCR5 play a role in susceptibility to TB. A Th1 response, and in particular interferon γ (IFNγ) production, are essential for the activation of macrophages and the Previous studies have demonstrated the central role of MIP-1α in the host’s protective immune response to other intracellular pathogens; MIP-1α is essential for the clearance of Listeria monocytogenes infection [6], and to activate macrophages critical for the eradication of Leishmania [7]. MIP-1α mRNA expression and protein production has been shown to be upregulated by M. tuberculosis stimulation, and secretion of MIP-1α was detected during the generation of granulomatous lesions [11]. MIP-1α production was observed to be higher in HIV patients with pulmonary TB than in controls (patients with HIV but without TB infection) [12]

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