Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis. Cobat, A., Hoal, E. G., Gallant, C. J., Simkin, L., Black, G. F., Stanley, K., Jaïs, J., Yu, T., Boland-Auge, A., Grange, G., Delacourt, C., van Helden, P., Casanova, J., Abel, L., Alcaïs, A., & Schurr, E. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 57(7):963–970, October, 2013. 00006 doi abstract bibtex BACKGROUND: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy. METHODS: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis. RESULTS: Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P \textless 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ. CONCLUSIONS: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.
@article{cobat_identification_2013,
title = {Identification of a major locus, {TNF1}, that controls {BCG}-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis},
volume = {57},
issn = {1537-6591},
doi = {10.1093/cid/cit438},
abstract = {BACKGROUND: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy.
METHODS: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis.
RESULTS: Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P {\textless} 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ.
CONCLUSIONS: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.},
language = {eng},
number = {7},
journal = {Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America},
author = {Cobat, Aurelie and Hoal, Eileen G. and Gallant, Caroline J. and Simkin, Leah and Black, Gillian F. and Stanley, Kim and Jaïs, Jean-Philippe and Yu, Ting-Heng and Boland-Auge, Anne and Grange, Ghislain and Delacourt, Christophe and van Helden, Paul and Casanova, Jean-Laurent and Abel, Laurent and Alcaïs, Alexandre and Schurr, Erwin},
month = oct,
year = {2013},
pmid = {23800941},
pmcid = {PMC3765013},
note = {00006 },
keywords = {Adult, Analysis of Variance, BCG Vaccine, Chi-Square Distribution, Child, Chromosomes, Human, Pair 11, Endemic Diseases, Family, Genetic Pleiotropy, Humans, Interferon-gamma, Interferon-gamma Release Tests, Leukocytes, Linkage Disequilibrium, Mycobacterium bovis, Phenotype, Quantitative Trait Loci, South Africa, Tuberculosis, Tumor Necrosis Factor-alpha},
pages = {963--970},
}
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{"_id":"39h788LckrkAFBr5J","bibbaseid":"cobat-hoal-gallant-simkin-black-stanley-jas-yu-etal-identificationofamajorlocustnf1thatcontrolsbcgtriggeredtumornecrosisfactorproductionbyleukocytesinanareahyperendemicfortuberculosis-2013","author_short":["Cobat, A.","Hoal, E. G.","Gallant, C. J.","Simkin, L.","Black, G. F.","Stanley, K.","Jaïs, J.","Yu, T.","Boland-Auge, A.","Grange, G.","Delacourt, C.","van Helden, P.","Casanova, J.","Abel, L.","Alcaïs, A.","Schurr, E."],"bibdata":{"bibtype":"article","type":"article","title":"Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis","volume":"57","issn":"1537-6591","doi":"10.1093/cid/cit438","abstract":"BACKGROUND: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy. METHODS: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis. RESULTS: Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P \\textless 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ. CONCLUSIONS: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.","language":"eng","number":"7","journal":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","author":[{"propositions":[],"lastnames":["Cobat"],"firstnames":["Aurelie"],"suffixes":[]},{"propositions":[],"lastnames":["Hoal"],"firstnames":["Eileen","G."],"suffixes":[]},{"propositions":[],"lastnames":["Gallant"],"firstnames":["Caroline","J."],"suffixes":[]},{"propositions":[],"lastnames":["Simkin"],"firstnames":["Leah"],"suffixes":[]},{"propositions":[],"lastnames":["Black"],"firstnames":["Gillian","F."],"suffixes":[]},{"propositions":[],"lastnames":["Stanley"],"firstnames":["Kim"],"suffixes":[]},{"propositions":[],"lastnames":["Jaïs"],"firstnames":["Jean-Philippe"],"suffixes":[]},{"propositions":[],"lastnames":["Yu"],"firstnames":["Ting-Heng"],"suffixes":[]},{"propositions":[],"lastnames":["Boland-Auge"],"firstnames":["Anne"],"suffixes":[]},{"propositions":[],"lastnames":["Grange"],"firstnames":["Ghislain"],"suffixes":[]},{"propositions":[],"lastnames":["Delacourt"],"firstnames":["Christophe"],"suffixes":[]},{"propositions":["van"],"lastnames":["Helden"],"firstnames":["Paul"],"suffixes":[]},{"propositions":[],"lastnames":["Casanova"],"firstnames":["Jean-Laurent"],"suffixes":[]},{"propositions":[],"lastnames":["Abel"],"firstnames":["Laurent"],"suffixes":[]},{"propositions":[],"lastnames":["Alcaïs"],"firstnames":["Alexandre"],"suffixes":[]},{"propositions":[],"lastnames":["Schurr"],"firstnames":["Erwin"],"suffixes":[]}],"month":"October","year":"2013","pmid":"23800941","pmcid":"PMC3765013","note":"00006 ","keywords":"Adult, Analysis of Variance, BCG Vaccine, Chi-Square Distribution, Child, Chromosomes, Human, Pair 11, Endemic Diseases, Family, Genetic Pleiotropy, Humans, Interferon-gamma, Interferon-gamma Release Tests, Leukocytes, Linkage Disequilibrium, Mycobacterium bovis, Phenotype, Quantitative Trait Loci, South Africa, Tuberculosis, Tumor Necrosis Factor-alpha","pages":"963–970","bibtex":"@article{cobat_identification_2013,\n\ttitle = {Identification of a major locus, {TNF1}, that controls {BCG}-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis},\n\tvolume = {57},\n\tissn = {1537-6591},\n\tdoi = {10.1093/cid/cit438},\n\tabstract = {BACKGROUND: Tumor necrosis factor (TNF) is a key immune regulator of tuberculosis resistance, as exemplified by the highly increased risk of tuberculosis disease among individuals receiving TNF-blocker therapy.\nMETHODS: We determined the extent of TNF production after stimulation with BCG or BCG plus interferon gamma (IFN-γ) using a whole blood assay in 392 children belonging to 135 nuclear families from an area hyperendemic for tuberculosis in South Africa. We conducted classical univariate and bivariate genome-wide linkage analysis of TNF production using the data from both stimulation protocols by means of an extension of the maximum-likelihood-binomial method for quantitative trait loci to multivariate analysis.\nRESULTS: Stimulation of whole blood by either BCG or BCG plus IFN-γ resulted in a range of TNF release across subjects. Extent of TNF production following both stimulation protocols was highly correlated (r = 0.81). We failed to identify genetic linkage of TNF release when considering each stimulus separately. However, using a multivariate approach, we detected a major pleiotropic locus (P {\\textless} 10(-5)) on chromosome region 11p15, termed TNF locus 1 (TNF1), that controlled TNF production after stimulation by both BCG alone and BCG plus IFN-γ.\nCONCLUSIONS: The TNF1 locus was mapped in the vicinity of the TST1 locus, previously identified in the same family sample, that controls tuberculin skin test (TST) negativity per se, that is, T-cell-independent resistance to Mycobacterium tuberculosis infection. This suggested that there is a connection between TST negativity per se and TNF production.},\n\tlanguage = {eng},\n\tnumber = {7},\n\tjournal = {Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America},\n\tauthor = {Cobat, Aurelie and Hoal, Eileen G. and Gallant, Caroline J. and Simkin, Leah and Black, Gillian F. and Stanley, Kim and Jaïs, Jean-Philippe and Yu, Ting-Heng and Boland-Auge, Anne and Grange, Ghislain and Delacourt, Christophe and van Helden, Paul and Casanova, Jean-Laurent and Abel, Laurent and Alcaïs, Alexandre and Schurr, Erwin},\n\tmonth = oct,\n\tyear = {2013},\n\tpmid = {23800941},\n\tpmcid = {PMC3765013},\n\tnote = {00006 },\n\tkeywords = {Adult, Analysis of Variance, BCG Vaccine, Chi-Square Distribution, Child, Chromosomes, Human, Pair 11, Endemic Diseases, Family, Genetic Pleiotropy, Humans, Interferon-gamma, Interferon-gamma Release Tests, Leukocytes, Linkage Disequilibrium, Mycobacterium bovis, Phenotype, Quantitative Trait Loci, South Africa, Tuberculosis, Tumor Necrosis Factor-alpha},\n\tpages = {963--970},\n}\n\n\n\n","author_short":["Cobat, A.","Hoal, E. 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