Review
Genetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives

https://doi.org/10.1016/S1473-3099(17)30623-0Get rights and content

Summary

Tuberculosis is an ancient human disease, estimated to have originated and evolved over thousands of years alongside modern human populations. Despite considerable advances in disease control, tuberculosis remains one of the world's deadliest communicable diseases with 10 million incident cases and 1·8 million deaths in 2015 alone based on the annual WHO report, due to inadequate health service resources in less-developed regions of the world, and exacerbated by the HIV/AIDS pandemic and emergence of multidrug-resistant strains of Mycobacterium tuberculosis. Recent findings from studies of tuberculosis infection and of patients with Mendelian predisposition to severe tuberculosis have started to reveal human loci influencing tuberculosis outcomes. In this Review, we assess the current understanding of the contribution of host genetics to disease susceptibility and to drug treatment. Despite remarkable progress in technology, only a few associated genetic variants have so far been identified, strongly indicating the need for larger global studies that investigate both common and under-represented rare variants to develop new approaches to combat the disease. Pharmacogenomic discoveries are also likely to lead to more efficient drug design and development, and ultimately safer and more effective therapies for tuberculosis.

Section snippets

Background

Infectious diseases have ravaged mankind throughout the ages; therefore, they represent a major force in human evolution.1, 2 Response to pathogen exposure is highly variable between people, and a better understanding of the biological basis of interindividual differences in infection outcomes could result in new preventive and therapeutic strategies. Exploration of the genetic underpinning of human susceptibility to infections started decades ago, but only increased in size and scope in the

Early observations on the genetic basis for tuberculosis susceptibility

In Lübeck, Germany, from Dec 10, 1929, to April 30, 1930, 251 neonates were accidentally given preparations of the BCG vaccine that had been contaminated with virulent M tuberculosis.13 Of the vaccinated children, 72 died of tuberculosis and the surviving 174 children (five children died of non-tuberculosis causes) presented with a wide range of clinical presentations. A careful follow-up investigation of the accident identified variable concentrations of contamination (ie, the infectious dose)

Insight from inbred animal models of tuberculosis susceptibility

Mice and rabbits have often been used in studies to investigate genetic susceptibility to tuberculosis. Cross-breeding between resistant and susceptible inbred mice strains has shown that resistance to tuberculosis follows a complex, non-Mendelian inheritance.24 In 1981, Gros and colleagues25 found that susceptibility to infection with avirulent BCG derived from Mycobacterium bovis was determined by a host genetic locus Bcg on mouse chromosome 1. Subsequently, the gene encoding the natural

Genetic control of tuberculosis infection

There is no direct test for infection with M tuberculosis, and the latent tuberculosis infection phenotype is inferred indirectly from quantitative measurements of antimycobacterial immunity.11, 39 TST is the most widely used method to test for latent infection.40 Additionally, two in-vitro blood assays measuring either the secretion of interferon γ by lymphocytes or the frequency of interferon-γ-producing blood cells in response to M tuberculosis antigens (interferon-γ release assays [IGRAs])

Future direction and perspectives

The identification of the genetic factors involved in tuberculosis susceptibility has proven difficult. As in several other human diseases, the role of common variants in pulmonary tuberculosis seems to be scarce, leading to the concept of missing heritability.131 Among the several non-mutually exclusive hypotheses that might account for this concept, an important one in tuberculosis is the oversimplification of the studied phenotypes.12 For example, tests used to assess tuberculosis infection

Conclusion

Historical observations, heritability estimates, linkage analyses, and genome-wide scans indicate that human resistance to tuberculosis infection has a strong genetic basis, which is likely to be a consequence of evolutionary counter-response to microbial virulence. Mendelian studies have also provided the first evidence that severe tuberculosis in children could be due to single gene inborn errors of immunity. However, much is yet to be learned regarding susceptibility to disease, in

Search strategy and selection criteria

We identified data for this Review from MEDLINE and PubMed with the search terms “host genomics AND tuberculosis”, “susceptibility to tuberculosis”, and “innate resistance to tuberculosis”. Because the Review traces the history of tuberculosis through the 20th century including the colonial period, we have included articles published in English from the database search between Jan 1, 1940, and January 31, 2017. We also identified data from our earlier work and from the references cited in these

References (168)

  • CM Greenwood et al.

    Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family

    Am J Hum Genet

    (2000)
  • AV Grant et al.

    Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region

    Am J Hum Genet

    (2013)
  • P Aliahmad et al.

    The many roles of TOX in the immune system

    Curr Opin Immunol

    (2012)
  • RS Sobota et al.

    A locus at 5q33.3 confers resistance to tuberculosis in highly susceptible individuals

    Am J Hum Genet

    (2016)
  • YS Huang et al.

    Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis

    Hepatology

    (2002)
  • YS Huang et al.

    Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis

    Hepatology

    (2003)
  • JL Casanova et al.

    The genetic theory of infectious diseases: a brief history and selected illustrations

    Annu Rev Genomics Hum Genet

    (2013)
  • L Quintana-Murci et al.

    Population genetic tools for dissecting innate immunity in humans

    Nat Rev Immunol

    (2013)
  • SJ Chapman et al.

    Human genetic susceptibility to infectious disease

    Nat Rev Genet

    (2012)
  • DA Joy et al.

    Early origin and recent expansion of Plasmodium falciparum

    Science

    (2003)
  • Reappraisal of known malaria resistance loci in a large multicenter study

    Nat Genet

    (2014)
  • C Tournamille et al.

    Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals

    Nat Genet

    (1995)
  • J Fellay et al.

    A whole-genome association study of major determinants for host control of HIV-1

    Science

    (2007)
  • DL Thomas et al.

    Genetic variation in IL28B and spontaneous clearance of hepatitis C virus

    Nature

    (2009)
  • Global tuberculosis report 2015

  • A O'Garra et al.

    The immune response in tuberculosis

    Annu Rev Immunol

    (2013)
  • L Abel et al.

    Human genetics of tuberculosis: a long and winding road

    Philos Trans R Soc Lond B Biol Sci

    (2014)
  • G Fox et al.

    Tuberculosis in newborns: the lessons of the “Lübeck disaster” (1929–1933)

    PLoS Pathog

    (2016)
  • Tuberculosis report: tuberculosis in the Navy and Marine Corps, 2016 report

  • AJ DiStasio et al.

    The investigation of a tuberculosis outbreak in the closed environment of a US Navy ship, 1987

    Mil Med

    (1990)
  • JE Lamar et al.

    Tuberculosis outbreak investigation of a US Navy amphibious ship crew and the Marine expeditionary unit aboard, 1998

    Mil Med

    (2003)
  • S Akhtar et al.

    A chain-binomial model for intra-household spread of Mycobacterium tuberculosis in a low socio-economic setting in Pakistan

    Epidemiol Infect

    (2007)
  • M Lux

    Perfect subjects: race, tuberculosis, and the Qu'Appelle BCG vaccine trial

    Can Bull Med Hist

    (1998)
  • N MacDonald et al.

    Tuberculosis in Nunavut: a century of failure

    CMAJ

    (2011)
  • AO Sousa et al.

    An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon

    Proc Natl Acad Sci USA

    (1997)
  • FJ Kallman et al.

    Twin studies on the significance of genetic factors in tuberculosis

    Am Rev Tuberc

    (1942)
  • GW Comstock

    Tuberculosis in twins: a re-analysis of the Prophit study

    Am Rev Respir Dis

    (1978)
  • WW Stead et al.

    Racial differences in susceptibility to infection by Mycobacterium tuberculosis

    N Engl J Med

    (1990)
  • CJ Lynch et al.

    A genetic study of susceptibility to experimental tuberculosis in mice infected with mammalian tubercle bacilli

    J Exp Med

    (1965)
  • P Gros et al.

    Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice

    J Immunol

    (1981)
  • S Vidal et al.

    The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene

    J Exp Med

    (1995)
  • E Medina et al.

    The Bcg gene (Nramp1) does not determine resistance of mice to virulent Mycobacterium tuberculosis

    Ann N Y Acad Sci

    (1996)
  • I Kramnik et al.

    Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis

    Proc Natl Acad Sci USA

    (2000)
  • H Pan et al.

    Ipr1 gene mediates innate immunity to tuberculosis

    Nature

    (2005)
  • MB Lurie

    Hereditary, constitution and tuberculosis. An experimental study

    Am Rev Tuberc

    (1941)
  • MB Lurie

    Experimental epidemiology of tuberculosis: hereditary resistance to attack by tuberculosis and to the ensuing disease and the effect of the concentration of tubercle bacilli upon these two phases of resistance

    J Exp Med

    (1944)
  • AM Dannenberg

    Pathogenesis of human pulmonary tuberculosis: insights from the rabbit model

    (2006)
  • DH Brown et al.

    Growth of Mycobacterium tuberculosis in BCG-resistant and -susceptible mice: establishment of latency and reactivation

    Infect Immun

    (1995)
  • BS Yan et al.

    Progression of pulmonary tuberculosis and efficiency of bacillus Calmette–Guerin vaccination are genetically controlled via a common sst1-mediated mechanism of innate immunity

    J Immunol

    (2007)
  • A Bhaladhare et al.

    Single nucleotide polymorphisms in toll-like receptor genes and case-control association studies with bovine tuberculosis

    Vet World

    (2016)
  • Cited by (95)

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