MCP-1 promoter variant -362C associated with protection from pulmonary tuberculosis in Ghana, West Africa

Abstract

Current endeavour focuses on human genetic factors that contribute to susceptibility to or protection from tuberculosis (TB). Monocytes are crucial in containing Mycobacterium tuberculosis infection, and the monocyte chemoattractant protein-1 (MCP-1) cytokine plays a role in their recruitment to the site of infection. The G allele of the MCP-1 promoter polymorphism at position -2581 relative to the ATG transcription start codon has been described to be associated in Mexican and Korean TB patients with increased susceptibility to TB. We genotyped this and additional MCP-1 variants in sample collections comprising more than 2000 cases with pulmonary TB and more than 2300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and more than 1400 TB patients and more than 1500 controls from Russia. In striking contrast to previous reports, MCP-1 -2581G was significantly associated with resistance to TB in cases versus controls [odds ratio (OR) 0.81, corrected P-value (P(corr)) = 0.0012] and nuclear families (OR 0.72, P(corr) = 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P = 0.86). Our and other results do not support an association of MCP-1 -2581 with TB. In the Ghanaian population, eight additional MCP-1 polymorphisms were genotyped. MCP-1 -362C was associated with resistance to TB in the case-control collection (OR 0.83, P(corr) = 0.00017) and in the affected families (OR 0.7, P(corr) = 0.004). Linkage disequilibrium (LD) and logistic regression analyses indicate that, in Ghanaians, the effect results exclusively from the MCP-1 -362 variant, whereas the effect of -2581 may in part be explained by its LD with -362.

MCP-1 gene polymorphisms in North Chinese patients with pulmonary tuberculosis

“…The results of the study are consistent with those of previous reports regarding the association between MCP-1 -2518A/G polymorphisms and tuberculosis in Mexicans, Koreans, Peruvians, Tunisians, and Zambians (Flores-Villanueva et al, 2005;Buijtels et al, 2008;Ganachari et al, 2010;Ben-Selma et al, 2011). Others have reported different results, such as in South African Coloreds, Indians, and Ghanaians (Alagarasu et al, 2009;Moller et al, 2009;Thye et al, 2009). Different genetic backgrounds may account for these differences.…”

Erratum: Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2

“…Pathogen variation may underlie some of the difficulties in finding loci for a given infectious disease and M. tuberculosis displays substantial geographic variation in genotype frequencies 9 . However, as we have shown previously and also here [9][10][11][12][13] , combined analyses with increased aggregate sample sizes may help in the identification of novel genetic variants, perhaps particularly those less sensitive to pathogen variation. Analyzing African individuals poses specific challenges, and genetic differences between populations, even within West Africa, are large enough to complicate standard imputation procedures.…”

Innate Immune Gene Polymorphisms in Tuberculosis

“…Discrepant results obtained from genotypeand allele-based TB association studies with MCP-1 variants (especially at Ϫ2518) ( Table 1) failed to yield solid evidence for genetic effects of MCP-1. Carriers of the Ϫ2518 GG genotype were reported to produce high levels of MCP-1, which inhibits IL-12 production in response to M. tuberculosis and promotes active pulmonary TB (78), whereas Thye et al (227) initially found association of the Ϫ2518G allele with TB resistance in Ghana, and further genotyping led to the identification of the Ϫ362C allele as the putatively "true" protective variant of MCP-1, reflecting linkage disequilibrium between Ϫ2518 and Ϫ362. This study is a cautionary note for the need to carry out a thorough genetic investigation to search for the actual causative polymorphism.…”