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MCP1 haplotypes associated with protection from pulmonary tuberculosis
BACKGROUND: 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 MCP1 -362C and the MCP1 -2581G al...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107163/ https://www.ncbi.nlm.nih.gov/pubmed/21504590 http://dx.doi.org/10.1186/1471-2156-12-34 |
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author | Intemann, Christopher D Thye, Thorsten Förster, Birgit Owusu-Dabo, Ellis Gyapong, John Horstmann, Rolf D Meyer, Christian G |
author_facet | Intemann, Christopher D Thye, Thorsten Förster, Birgit Owusu-Dabo, Ellis Gyapong, John Horstmann, Rolf D Meyer, Christian G |
author_sort | Intemann, Christopher D |
collection | PubMed |
description | BACKGROUND: 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 MCP1 -362C and the MCP1 -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 MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. RESULTS: A 14 base-pair deletion in the first MCP1 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 MCP1 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. CONCLUSIONS: 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 MCP1 -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. |
format | Online Article Text |
id | pubmed-3107163 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-31071632011-06-03 MCP1 haplotypes associated with protection from pulmonary tuberculosis Intemann, Christopher D Thye, Thorsten Förster, Birgit Owusu-Dabo, Ellis Gyapong, John Horstmann, Rolf D Meyer, Christian G BMC Genet Research Article BACKGROUND: 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 MCP1 -362C and the MCP1 -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 MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. RESULTS: A 14 base-pair deletion in the first MCP1 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 MCP1 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. CONCLUSIONS: 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 MCP1 -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. BioMed Central 2011-04-19 /pmc/articles/PMC3107163/ /pubmed/21504590 http://dx.doi.org/10.1186/1471-2156-12-34 Text en Copyright ©2011 Intemann et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Intemann, Christopher D Thye, Thorsten Förster, Birgit Owusu-Dabo, Ellis Gyapong, John Horstmann, Rolf D Meyer, Christian G MCP1 haplotypes associated with protection from pulmonary tuberculosis |
title | MCP1 haplotypes associated with protection from pulmonary tuberculosis |
title_full | MCP1 haplotypes associated with protection from pulmonary tuberculosis |
title_fullStr | MCP1 haplotypes associated with protection from pulmonary tuberculosis |
title_full_unstemmed | MCP1 haplotypes associated with protection from pulmonary tuberculosis |
title_short | MCP1 haplotypes associated with protection from pulmonary tuberculosis |
title_sort | mcp1 haplotypes associated with protection from pulmonary tuberculosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107163/ https://www.ncbi.nlm.nih.gov/pubmed/21504590 http://dx.doi.org/10.1186/1471-2156-12-34 |
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