Chapter 19 : The Role of Host Genetics (and Genomics) in Tuberculosis

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Familial risk of tuberculosis (TB) has been recognized for centuries; indeed, Greek, Arabic, Chinese, and Sanskrit texts are said to include descriptions of the familial nature of disease as early as 600 BCE, and many scholars, including Aristotle (300 BCE), Francastoro (1546), and Marten (1720), explicitly conjectured that this may be because the disease is contagious. However, largely through studies of mono- and dizygotic twin concordance rates, studies of families with Mendelian susceptibility to mycobacterial disease (MSMD), and candidate gene studies performed in the 20th century, it was recognized that susceptibility to TB disease has a substantial host genetic component. Limitations in candidate gene studies and early linkage studies made robust identification of specific loci associated with disease challenging, and few loci have been convincingly associated across multiple populations. Genome-wide association studies (GWAS) and transcriptome-wide association studies, based on microarray (commonly known as genechip) technologies, conducted in the past decade have helped shed some light on pathogenesis, but only a handful of new pathways have been identified. This apparent paradox, of high heritability but few replicable associations, has spurred current large-scale collaborative projects, such as the International Tuberculosis Host Genetics Consortium (ITHGC), that aim to take into account heterogeneity in both host and pathogen genetics, variation in exposure rates, and outcome definitions (referred to as phenotypes by geneticists). Recent studies that also leverage low-cost, high-throughput sequencing to interrogate genetic, transcriptomic, and epigenetic changes in the context of TB are also beginning to be reported.

Citation: Naranbhai V. 2017. The Role of Host Genetics (and Genomics) in Tuberculosis, p 413-452. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0011-2016
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Figure 1

Host “omics” in tuberculosis. The haploid human genome consists of 3 billion bp, encoding 20,687 expressed functional units (genes), the majority of which are translated into protein products. Most (98.86%) of the genome does not code for any specific gene or protein product, but these intergenic or intronic regions may act as enhancers and repressors and modify gene expression. The small proportion of coding sequence, collectively known as the exome, is responsible for protein coding. Each gene undergoes variable splicing of exons to form a full-length transcript leading to transcript variation; on average, each gene has about four different isoforms, but this varies considerably by gene. Approximately 90% of all DNA sequence variation is in the form of single-nucleotide change known as a single-nucleotide polymorphism (SNP); about 10,000 SNPs have been reported, and these occur approximately every 100 to 300 bp, clustered around genes. Other forms of sequence variation include insertions, deletions, and copy number variation. The major force generating diversity is homologous recombination during meiosis, when crossing-over of segments of maternal and paternal chromosomes occurs. Because contiguous blocks of DNA between recombination hot spots recombine, genetic variants tend to be coinherited, resulting in linkage disequilibrium between variants. DNA sequence variation can be studied in a per gene manner (a candidate gene approach), using microsatellites that recur frequently across the genome in the context of pedigrees (linkage mapping), studying specific genes (candidate gene studies), genotyping >0.5M variants across the genome (as in a GWAS) and leveraging linkage disequilibrium to infer additional variants (imputation), or sequencing the exome (exome sequencing) or entire genome (whole-genome sequencing). DNA sequence variation may bear its effect through any variety of different mechanisms including altering the quantity of, or type of, transcript leading to transcriptomic variation, or by altering the resulting protein. Genetic loci that affect expression are known as expression quantitative loci (eQTL), and those that affect transcription only in response to stimulation, for example, with , are known as response QTL (reQTL). Additional epigenetic features that may affect the quantity of a gene expression are methylation of cytosine nucleotides in DNA (studying in methylation QTL [mQTL] studies) and methylation or acetylation of lysine residues of histone proteins that together make up a nucleosome.

Citation: Naranbhai V. 2017. The Role of Host Genetics (and Genomics) in Tuberculosis, p 413-452. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0011-2016
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Image of Figure 2
Figure 2

Mendelian susceptibility to mycobacterial disease (MSMD) affects the IFN-γ/IL-12 pathway, focused on interaction between phagocytes/dendritic cells and lymphocytes/natural killer cells during mycobacterial infection. Molecules in blue are mutated in patients with a broad infectious phenotype including mycobacterial diseases. Molecules in red are mutated in patients with isolated mycobacterial diseases. Molecules in blue with red dots indicate that specific mutations in the corresponding genes are responsible for isolated mycobacterial diseases. Patients with acquired or inherited profound T-cell deficiency are also susceptible to mycobacterial infections. Adapted from reference with permission from the publisher.

Citation: Naranbhai V. 2017. The Role of Host Genetics (and Genomics) in Tuberculosis, p 413-452. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0011-2016
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Figure 3

Karyogram highlighting host-genetic correlates of tuberculosis susceptibility according to the type of study from which evidence arose.

Citation: Naranbhai V. 2017. The Role of Host Genetics (and Genomics) in Tuberculosis, p 413-452. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0011-2016
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