Tuberculosis (TB) is a major public health burden worldwide, and more effective treatment is sorely needed. Consequently, uncovering causes of resistance to Mycobacterium tuberculosis (Mtb) infection is of special importance for vaccine design. Resistance to Mtb infection can be defined by a persistently negative tuberculin skin test (PTST–) despite living in close and sustained exposure to an active TB case. While susceptibility to Mtb is, in part, genetically determined, relatively little work has been done to uncover genetic factors underlying resistance to Mtb infection. We examined a region on chromosome 2q previously implicated in our genomewide linkage scan by a targeted, high-density association scan for genetic variants enhancing PTST– in two independent Ugandan TB household cohorts (n = 747 and 471). We found association with SNPs in neighboring genes ZEB2 and GTDC1 (peak meta p = 1.9 × 10–5) supported by both samples. Bioinformatic analysis suggests these variants may affect PTST– by regulating the histone deacetylase (HDAC) pathway, supporting previous results from transcriptomic analyses. An apparent protective effect of PTST– against body-mass wasting suggests a link between resistance to Mtb infection and healthy body composition. Our results provide insight into how humans may escape latent Mtb infection despite heavy exposure.
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World Health Organization. Global tuberculosis report. Geneva, Switzerland: WHO Press; 2016.
Comstock GW. Epidemiology of tuberculosis. Am Rev Respir Dis. 1982;125:8–15.
Stein CM, Sausville L, Wejse C, Sobota RS, Zetola NM, Hill PC, et al. Genomics of human pulmonary tuberculosis: from genes to pathways. Curr Genet Med Rep. 2017;5:149–66.
Möller M, Hoal EG. Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis (Edinburgh). 2010;90:71–83.
Cooke GS, Campbell SJ, Bennett S, Lienhardt C, McAdam KP, Sirugo G, et al. Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. Am J Respir Crit Care Med. 2008;178:203–7.
Bellamy R. Genetics and pulmonary medicine: 3. Genetic susceptibility to tuberculosis in human populations. Thorax. 1998;53:588–93.
Stein CM, Zalwango S, Malone LL, Won S, Mayanja-Kizza H, Mugerwa RD, et al. Genome scan of M. tuberculosis infection and disease in Ugandans. PLoS ONE. 2008;3:e4094.
Mahasirimongkol S, Yanai H, Nishida N, Ridruechai C, Matsushita I, Ohashi J, et al. Genome-wide SNP-based linkage analysis of tuberculosis in Thais. Genes Immun. 2009;10:77–83.
Miller EN, Jamieson SE, Joberty C, Fakiola M, Hudson D, Peacock CS, et al. Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians. Genes Immun. 2004;5:63–67.
Thye T, Vannberg FO, Wong SH, Owusu-Dabo E, Osei I, Gyapong J, et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat Genet. 2010;42:739–41.
Thye T, Owusu-Dabo E, Vannberg FO, van Crevel R, Curtis J, Sahiratmadja E, et al. Common variants at 11p13 are associated with susceptibility to tuberculosis. Nat Genet. 2012;44:257–9.
Chimusa ER, Zaitlen N, Daya M, Möller M, van Helden PD, Mulder NJ, et al. Genome-wide association study of ancestry-specific TB risk in the South African coloured population. Hum Mol Genet. 2014;23:796–809.
Curtis J, Luo Y, Zenner HL, Cuchet-Lourenço D, Wu C, Lo K, et al. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet. 2015;47:523–7.
Mahasirimongkol S, Yanai H, Mushiroda T, Promphittayart W, Wattanapokayakit S, Phromjai J, et al. Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis. J Hum Genet. 2012;57:363–7.
Png E, Alisjahbana B, Sahiratmadja E, Marzuki S, Nelwan R, Balabanova Y, et al. A genomewide association study of pulmonary tuberculosis susceptibility in Indonesians. BMC Med Genet. 2012;13:5.
Sobota RS, Stein CM, Kodaman N, Scheinfeldt LB, Maro I, Wieland-Alter W, et al. A locus at 5q33.3 confers resistance to tuberculosis in highly susceptible individuals. Am J Hum Genet. 2016;98:514–24.
Cobat A, Poirier C, Hoal E, Boland-Auge A, de La Rocque F, Corrard F, et al. Tuberculin skin test negativity is under tight genetic control of chromosomal region 11p14-15 in settings with different tuberculosis endemicities. J Inf Dis. 2015;211:317–21.
Stein CM. Genetic epidemiology of tuberculosis susceptibility: impact of study design. PLoS Pathog. 2011;7:e1001189.
Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K, Hughes J, et al. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med. 2009;206:2583–91.
Cobat A, Barrera LF, Henao H, Arbeláez P, Abel L, García LF, et al. Tuberculin skin test reactivity is dependent on host genetic background in Colombian truberculosis household contacts. Clin Infect Dis. 2012;54:968–71.
Sobota RS, Stein CM, Kodaman N, Maro I, Wieland-Alter W, Igo RP, et al. A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa. PLoS Genet. 2017;13:e1006710.
Stein CM, Hall NB, Malone LL, Mupere E. The household contact study design for genetic epidemiological studies of infectious diseases. Front Genet. 2013;4:61.
Stein CM, Zalwango S, Malone LL, Thiel BA, Mupere E, Nsereko M, et al. Resistance and susceptibility to Mycobacterium tuberculosis infection and disease in tuberculosis households in Kampala, Uganda. Am J Epidemiol 2018; https://doi.org/10.1093/aje/kwx380.
Ma N, Zalwango S, Malone LL, Nsereko M, Wampande EM, Thiel BA, et al. Clinical and epidemiological characteristics of individuals resistant to M. tuberculosis infection in a longitudinal TB household contact study in Kampala, Uganda. BMC Infect Dis. 2014;14:352.
Simmons J, Stein CM, Seshadri C, Campo M, Alter G, Fortune S et al. Immunologic mechanisms of human resistance to persistent Mycobacterium tuberculosis infection. Nat Rev Immunol 2018; https://doi.org/10.1038/s41577-018-0025-3.
Hawn TR, Day TA, Scriba TJ, Hatherill M, Hanekom WA, Evans TG, et al. Tuberculosis vaccines and prevention of infection. Microbiol Mol Biol Rev. 2014;78:650–71.
Verrall AJ, Netea MG, Alisjahbana B, Hill PC, Van Crevel R. Early clearance of Mycobacterium tuberculosis: a new frontier in prevention. Immunology. 2014;141:506–13.
Hall NB, Igo RP Jr., Malone LL, Truitt B, Schnell A, et al. Polymorphisms in TICAM2 and IL1B are associated with TB. Genes Immun. 2015;16:127–33.
Guwatudde D, Nakakeeto M, Jones-Lopez EC, Maganda A, Chiunda A, Mugerwa RD, et al. Tuberculosis in household contacts of infections cases in Kampala, Uganda. Am J Epidemiol. 2003;158:887–98.
Mupere E, Malone L, Zalwango S, Okwera A, Nsereko M, Tisch DJ, et al. Wasting among Uganda men with pulmonary tuberculosis is associated with linear regain in lean tissue mass during and after treatment in contrast to women with wasting who regain fat tissue mass: prospective cohort study. BMC Infect Dis. 2014;14:24.
Mupere E, Malone L, Zalwango S, Chiunda A, Okwera A, Parraga I, et al. Lean tissue mass wasting is associated with increased risk of mortality among women with pulmonary tuberculosis in urban Uganda. Ann Epidemiol. 2012;22:466–73.
Mupere E, Zalwango S, Chiunda A, Okwera A, Mugerwa R, Whalen C. Body composition among HIV-seropositive and HIV-seronegative adult patients with pulmonary tuberculosis in Uganda. Ann Epidemiol. 2010;30:210–6.
Mupere E, Parraga IM, Tisch DJ, Mayanja HK, Whalen CC. Low nutrient intake among adult women and patients with severe tuberculosis disease in Uganda: a cross-sectional study. BMC Public Health. 2012;12:1050.
Ezeamama AE, Mupere E, Oloya J, Martinez L, Kakaire R, Yin X, et al. Age, sex and nutritional status modify the CD4+T-cell recovery rate in HIV-tuberculosis co-infected patients on combination antiretroviral therapy. Int J Infect Dis. 2015;35:73–9.
Aslibekyan S, Demerath EW, Mendelson M, Zhi D, Guan W, Liang L, et al. Epigenome-wide study indentifies novel methylation loci associated with body mass index and waist circumference. Obesity. 2015;23:1493–501.
Wu LM, Wang J, Conidi A, Zhao C, Wang H, Ford Z, et al. Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination. Nat Neurosci. 2016;19:1060–72.
Seshadri C, Sedaghat N, Campo M, Peterson G, Wells RD, Olson GS, et al. Transcriptional networks are associated with resistance to Mycobacterium tuberculosis infection. PLoS ONE. 2017;12:e0175844.
Pérez-Guzmán C, Vargas MH. Hypocholesterolemia: a major risk factor for developing pulmonary tuberculosis? Med Hypotheses. 2006;66:1227–30.
Han R, Kornfeld H, Martens G. Is hypercholesterolemia a friend or foe of tuberculosis? Infect Immun. 2009;77:3514.
Martens GW, Arikan MC, Lee J, Ren F, Vallerskog T, Kornfeld H. Hypercholesterolemia impairs immunity to tuberculosis. Infect Immun. 2008;76:3464–72.
Martens GW, Vallerskog T, Kornfeld H. Hypercholesterolemic LDL receptor-deficient mice mount a neutrophilic response to tuberculosis despite the timely expression of protective immunity. J Leukoc Biol. 2012;91:849–57.
Parihar SP, Guler R, Khutlang R, Lang DM, Hurdayal R, Mhlanga MM, et al. Statin therapy reduces the Mycobacterium tuberculosis burden in human macrophages and in mice by enhancing autophagy and phagosome maturation. J Inf Dis. 2014;209:754–63.
VanItallie TB, Yang MU, Heymsfield SB, Funk RC, Boileau RA. Height-normalized indices of the body’s fat-free mass and fat mass: potentially useful indicators of nutritional status. Am J Clin Nutr. 1990;52:953–9.
Purcell S, Neale B, Todd-Brow K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet. 2007;81:559–75.
Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genomewide association studies. PLoS Genet. 2009;5:e1000529.
Delaneau O, Zagury J-F, Marchini J. Improved whole-chromosome phasing for disease and population genetic studies. Nat Methods. 2013;10:5–6.
Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet. 2010;11:499–511.
Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, et al. Genes mirror geography within Europe. Nature. 2008;456:98–101.
Patterson N, Price AL, Reich D. Population structure and eigenanalysis. PLoS Genet. 2006;2:e190.
Conomos MP, Miller MB, Thornton TA. Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. Genet Epidemiol. 2015;39:276–93.
Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004.
Sobota RS, Shriner D, Kodaman N, Goodloe R, Zheng W, Gao Y-T, et al. Addressing population-specific multiple testing burdens in genetic association studies. Ann Hum Genet. 2015;79:136–47.
Stein CM. Genetics of susceptibility to tuberculosis. In: Cooper DN, ed. Encyclopedia of Life Sciences (eLS).Chichester: John Wiley & Sons; 2012.
Bacanu S-A, Devlin B, Roeder K. The power of genomic control. Am J Hum Genet. 2000;66:1933–44.
Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011;88:76–82.
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.
Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–4.
GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5.
Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22:1790–7.
The authors wish to acknowledge the contributions made by senior physicians, medical officers, health visitors, laboratory and data personnel: Dr. Lorna Nshuti, Dr. Roy Mugerwa, Dr. Alphonse Okwera, Dr. Deo Mulindwa, Dr. Christopher Whalen, Denise Johnson, Allan Chiunda, Mark Breda, Dennis Dobbs, Mary Rutaro, Albert Muganda, Richard Bamuhimbisa, Yusuf Mulumba, Deborah Nsamba, Barbara Kyeyune, Faith Kintu, Gladys Mpalanyi, Janet Mukose, Grace Tumusiime, Pierre Peters, Annet Kawuma, Saidah Menya, Joan Nassuna, Keith Chervenak, Karen Morgan, Alfred Etwom, Micheal Angel Mugerwa, and Lisa Kucharski. We would like to acknowledge Dr. Francis Adatu Engwau, former Head of the Uganda National Tuberculosis and Leprosy Program, for supporting this project. We would like to acknowledge the medical officers, nurses, and counselors at the National Tuberculosis Treatment Centre, Mulago Hospital, the Ugandan National Tuberculosis and Leprosy Program, and the Uganda Tuberculosis Investigation Bacteriological Unit, Wandegeya, for their contributions to this study. Clinical study implementation and data management were supported by the National Institutes of Health, grants N01-AI95383, HHSN266200700022C/N01-AI70022. Genotyping and data analysis was supported by R01HL096811 and analyses were also supported by T32HL007567. This study would not be possible without the generous participation of the Ugandan patients and families.
E.M., M.J., W.H.B., and C.M.S. conceived and designed the study. E.M. and M.J. recruited families and collected the study sample. L.L.M. maintained the database of clinical study data. R.P.I., N.H.B., B.T., F.Q., L.T., and A.S. processed the raw genotype data and conducted quality control. T.R.H., W.H.B., and C.M.S. developed the conceptual biologic model. R.P.I., N.H.B., J.B.H., and W.S.B. performed statistical analyses. R.P.I. and C.M.S. drafted the manuscript. All authors read and approved the final manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
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Frontiers in Immunology (2018)