<it>MCP1 </it>haplotypes associated with protection from pulmonary tuberculosis

• Main Authors: Owusu-Dabo Ellis, Förster Birgit, Thye Thorsten, Intemann Christopher D, Gyapong John, Horstmann Rolf D, Meyer Christian G
• Format: Article
• Language: English
• Published: BMC 2011-04-01
• Series: BMC Genetics
• Online Access: http://www.biomedcentral.com/1471-2156/12/34

<p>Abstract</p> <p>Background</p> <p>The monocyte chemoattractant protein 1 (MCP-1) is involved in the recruitment of lymphocytes and monocytes and their migration to sites of injury and cellular immune reactions. In a Ghanaian tuberculosis (TB) case-control study group, associations of the <it>MCP1 </it>-362C and the <it>MCP1 </it>-2581G alleles with resistance to TB were recently described. The latter association was in contrast to genetic effects previously described in study groups originating from Mexico, Korea, Peru and Zambia. This inconsistency prompted us to further investigate the <it>MCP1 </it>gene in order to determine causal variants or haplotypes genetically and functionally.</p> <p>Results</p> <p>A 14 base-pair deletion in the first <it>MCP1 </it>intron, int1del554-567, was strongly associated with protection against pulmonary TB (OR = 0.84, CI 0.77-0.92, P_corrected= 0.00098). Compared to the wildtype combination, a haplotype comprising the -2581G and -362C promoter variants and the intronic deletion conferred an even stronger protection than did the -362C variant alone (OR = 0.78, CI 0.69-0.87, P_nominal= 0.00002; adjusted P_global= 0.0028). In a luciferase reporter gene assay, a significant reduction of luciferase gene expression was observed in the two constructs carrying the <it>MCP1 </it>mutations -2581 A or G plus the combination -362C and int1del554-567 compared to the wildtype haplotype (P = 0.02 and P = 0.006). The associated variants, in particular the haplotypes composed of these latter variants, result in decreased MCP-1 expression and a decreased risk of pulmonary TB.</p> <p>Conclusions</p> <p>In addition to the results of the previous study of the Ghanaian TB case-control sample, we have now identified the haplotype combination -2581G/-362C/int1del554-567 that mediates considerably stronger protection than does the <it>MCP1 </it>-362C allele alone (OR = 0.78, CI 0.69-0.87 vs OR = 0.83, CI 0.76-0.91). Our findings in both the genetic analysis and the reporter gene study further indicate a largely negligible role of the variant at position -2581 in the Ghanaian population studied.</p>