Genome scan of M. tuberculosis infection and disease in Ugandans.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of...
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Public Library of Science (PLoS)
2008-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0004094&type=printable |
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| author | Catherine M Stein Sarah Zalwango LaShaunda L Malone Sungho Won Harriet Mayanja-Kizza Roy D Mugerwa Dmitry V Leontiev Cheryl L Thompson Kevin C Cartier Robert C Elston Sudha K Iyengar W Henry Boom Christopher C Whalen |
| author_facet | Catherine M Stein Sarah Zalwango LaShaunda L Malone Sungho Won Harriet Mayanja-Kizza Roy D Mugerwa Dmitry V Leontiev Cheryl L Thompson Kevin C Cartier Robert C Elston Sudha K Iyengar W Henry Boom Christopher C Whalen |
| author_sort | Catherine M Stein |
| collection | DOAJ |
| description | Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFalpha) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10(-3)) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal alpha = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFalpha p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFalpha p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system. |
| format | Article |
| id | doaj-art-d2e4e435bac74916a4dac69ae6249f32 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2008-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-d2e4e435bac74916a4dac69ae6249f322025-08-20T02:17:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-01-01312e409410.1371/journal.pone.0004094Genome scan of M. tuberculosis infection and disease in Ugandans.Catherine M SteinSarah ZalwangoLaShaunda L MaloneSungho WonHarriet Mayanja-KizzaRoy D MugerwaDmitry V LeontievCheryl L ThompsonKevin C CartierRobert C ElstonSudha K IyengarW Henry BoomChristopher C WhalenTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFalpha) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10(-3)) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal alpha = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFalpha p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFalpha p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0004094&type=printable |
| spellingShingle | Catherine M Stein Sarah Zalwango LaShaunda L Malone Sungho Won Harriet Mayanja-Kizza Roy D Mugerwa Dmitry V Leontiev Cheryl L Thompson Kevin C Cartier Robert C Elston Sudha K Iyengar W Henry Boom Christopher C Whalen Genome scan of M. tuberculosis infection and disease in Ugandans. PLoS ONE |
| title | Genome scan of M. tuberculosis infection and disease in Ugandans. |
| title_full | Genome scan of M. tuberculosis infection and disease in Ugandans. |
| title_fullStr | Genome scan of M. tuberculosis infection and disease in Ugandans. |
| title_full_unstemmed | Genome scan of M. tuberculosis infection and disease in Ugandans. |
| title_short | Genome scan of M. tuberculosis infection and disease in Ugandans. |
| title_sort | genome scan of m tuberculosis infection and disease in ugandans |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0004094&type=printable |
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