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

Abstract

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.

Figure 1:. Influence of host genetics on disease response to tuberculosis in rabbit and mouse models

(A) Image captured at 40x magnification. A granuloma from a rabbit, showing central necrosis and tissue destruction. (B) Image captured at 100x magnification. A granuloma from a BALB/c mouse. (C) Image captured at 40x magnification. A necrotising granuloma from a C3HeB/FeJ mouse. Differences in pathology and host response in the C3HeB/FeJ mouse were mapped to an allele in the sst locus. (D) Pathological response to Mycobacterium tuberculosis infection in disease models compared with the pattern observed in human disease. (E) Pattern of bacterial burden after infection in the resistant and susceptible inbred rabbits of Max Lurie. (F) Pattern of bacterial burden after infection in BALB/c mice carrying a BCG-susceptible allele mapped to the Bcg locus. (G) Pattern of bacterial burden after infection in B6 mice compared with congenic B6 mice engineered with the sst-susceptible locus characterised in C3HeB/FeJ mice. ···=human disease hallmark frequently observed in model. ··=human disease hallmark sometimes observed in model. ·=human disease hallmark rarely observed in model. 0=human disease pattern not observed in model.

Figure 2:. Complex drug–drug interaction between isoniazid and efavirenz, and involving several pharmacogenes

(A) Efavirenz is converted to inactive metabolites by cytochrome P450 (CYP) 2B6, with minor metabolism by CYP2A6. Individuals carrying two CYP2B6 loss-of-function alleles (rs3745274 or rs28399499, or both; circle 1) have increased plasma efavirenz exposure, which is further increased with concomitant CYP2A6 loss-of-function polymorphisms (eg, rs28399433; circle 2). When individuals with two CYP2B6 loss-of-function alleles are prescribed isoniazid, inhibition of CYP2A6 by isoniazid can also increase efavirenz exposure (circle 3), particularly with concomitant NAT2 genotypes that increase plasma isoniazid exposure (eg, rs1801280, rs1799930, and rs1799931; circle 4). (B) Depicts approximate plasma efavirenz trough concentrations by CYP2B6, CYP2A, and NAT2 genotype and isoniazid exposure. *Data are absent for CYP2A6 in isoniazid recipients with concomitant CYP2B6 and NAT2 loss-of-function genotypes, but this combination of CYP2B6, NAT2, and CYP2A6 genotypes is expected to confer even higher efavirenz concentrations.

Figure 3:. Interplay between epigenetic remodelling of the host cell by Mycobacterium tuberculosis and the role of germline variants in controlling host gene expression

Opening of chromatin, a prerequisite for binding of transcription factors, is induced by histone modifications such as monomethylation at lysine 4 in histone H3 (H3K4me1). In the example shown, M tuberculosis triggered H3K4me1 histone modification that mediates chromatin accessibility in a regulatory region that carries a transcription factor binding site (GGGC or GGGA). Only the GGGA allele allows efficient binding of the transcription factor and induction of gene expression, whereas the GGGC allele does not.