title: A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals.
abstract: Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37232, USA; Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Rafal S
authors.initials: RS
authors.lastname: Sobota
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA; Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Stein
authors.affiliation: Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37232, USA; Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nuri
authors.initials: N
authors.lastname: Kodaman
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Coriell Institute for Medical Research, Camden, NJ 08103, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Scheinfeldt
authors.affiliation: Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Isaac
authors.initials: I
authors.lastname: Maro
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Wieland-Alter
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Igo
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Albert
authors.initials: A
authors.lastname: Magohe
authors.affiliation: Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: LaShaunda L
authors.initials: LL
authors.lastname: Malone
authors.affiliation: Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Chervenak
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Noemi B
authors.initials: NB
authors.lastname: Hall
authors.affiliation: Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA; Botswana-UPenn Partnership, 214 Independence Avenue, Gaborone, Botswana; Department of Medicine, University of Botswana, Gaborone, Botswana.
authors.forename: Chawangwa
authors.initials: C
authors.lastname: Modongo
authors.affiliation: Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA; Botswana-UPenn Partnership, 214 Independence Avenue, Gaborone, Botswana; Department of Medicine, University of Botswana, Gaborone, Botswana.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zetola
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Mecky
authors.initials: M
authors.lastname: Matee
authors.affiliation: Uganda-CWRU Research Collaboration, Kampala, Uganda; College of Health Sciences Makerere University and Mulago Hospital, Kampala, Uganda.
authors.forename: Moses
authors.initials: M
authors.lastname: Joloba
authors.affiliation: UMR 208, Institut de Recherche pour le Développement and Musée de l'Homme, Muséum National d'Histoire Naturelle, 75116 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Froment
authors.affiliation: Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nyambo
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lahey
authors.affiliation: Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA; Uganda-CWRU Research Collaboration, Kampala, Uganda.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: C Fordham
authors.initials: CF
authors.lastname: von Reyn
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tishkoff
authors.affiliation: Centro di Ricerca, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.affiliation: Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: smw154@case.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
mesh_terms: D000293:Adolescent; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000382:microbiology; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D009169:Mycobacterium tuberculosis; D011446:Prospective Studies; D012307:Risk Factors; D013636:Tanzania; D014376:Tuberculosis / Q000175:diagnosis / Q000235:genetics*; D014454:Uganda
chemical_list: C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40
keywords: East Africa; HIV; IL12B; UBLCP1; histone acetylation; selection