20. March 2015 · Comments Off on Genetic study sheds new light on TB pathogenesis · Categories: Papers, Science · Tags: , , ,

One of the world’s most ancient diseases

Tuberculosis, also known as consumption, was first recorded in Greek literature around 460 BCE. Hippocrates identified it as the most widespread and fatal disease of his time. Tuberculosis (TB) is caused by a pathogen called Mycobacterium tuberculosis (M.tb). In Greek myco refers to a mushroom-like shape, vividly describing these fungal looking bacterium that float into the human system through the airways.

TB accounted for approximately 25% of total deaths in Europe from the 17th to 19th centuries. Many of the writers and artists of the Victorian era suffered and died from the disease and painted it with a pathological – yet somehow romantic – extreme: febrile, unrelenting and breathless.

Experiment eleven

It was not until 1943 when a young Ph.D. student called Albert Schatz, from Professor Selman Waksman’s lab at Rutger’s University in the US, discovered the first effective cure for treating TB. On Schatz’s eleventh experiment on a common bacterium found in farmyard soil, the first antibiotic agent for treating TB, streptomycin, was discovered. The battle for the ownership of streptomycin became a famous scientific scandal [Experiment Eleven], when Waksman took credit and the Nobel prize for the discovery, downplaying Schatz’s contributions. Thanks to a sustained effort from the government and society, including better nutrition, housing, improved sewage systems and ventilation, the number of TB cases was reduced significantly by the 1980s. The efforts to seek cures for TB have not only brought TB mortality down, but also helped to shape modern medicine and our understanding towards infectious illness.

A genetic insight

However, at present, TB still remains a major threat to public health. According to the World Health Organization, in 2012 alone, M.tb caused 8.6 million cases of infection and 1.3 million deaths. Today, 2 billion people are estimated to be infected with M.tb, but only 10% of infected individuals eventually develop active TB. The majority of people can unknowingly carry the pathogen and show no symptoms of the clinical disease.

To understand the host of genetic factors that are important in determining susceptibilities to M.tb, in our recently published study we undertook the largest TB genome-wide association study (GWAS) to date. After studying more than 15,000 subjects, we were able to identify a new gene (ASAP1) that is associated with a host’s susceptibility to M.tb. Early experimental work also showed strong evidence that reducing ASAP1 expression leads to impaired migration of dendritic cells. Our finding is the first of its kind to identify a potential biological pathway in TB pathogenesis.

Though the discovery of a new biological mechanism in TB is exciting, and worthy of a small celebration, many questions around the genetics of TB still remain unsolved, and I would like to point out a few in this post.

Unanswered questions

In our study, the M.tb infection status in the control cohort is undetermined, which means the role of the ASAP1-mediated pathway in TB pathogenesis is yet to be studied. While pulmonary TB patients have a very well-defined phenotype which is confirmed by a culture of M.tb from sputum in our cases, the status of M.tb infection is unclear in our controls. This leaves us with limited power to assess whether the ASAP1 gene affects early infection of M.tb or progression from latent to active TB. To clarify this further, further studies are required consisting of cohorts with:

(1) individuals who are exposed to M.tb but were not infected,
(2) M.tb infected individuals but didn’t progress to active TB, and
(3) active TB patients only.

Such a systematic study would most likely call on the effort of a large TB consortium.

In our paper, we have also looked for the overlap with published genetic association in another human mycobacterial infectious disease, leprosy. To our surprise, leprosy-associated variants did not show any association with TB. Leprosy, caused by Mycobacterium leprae wreaked havoc in Europe and the Middle East from biblical times through to the late medieval period. But cases declined during the 14th and 15th centuries, coinciding with a sharp increase in the TB rate. Evidence from DNA samples of both Mycobacterium Leprae and M.tb have been found in human remains all over the world, and a recent review shows that the co-infection is not so uncommon in the modern endemic area. Therefore, the lack of leprosy-associated signals in our TB dataset suggests either that genetic predisposition to mycobacterial infection is not broadly shared across infecting species, or that the leprosy-associated genes have much weaker effects on susceptibility to TB.

We have also looked into 163 inflammatory bowel disease (IBD) associated loci, which are known to be enriched with genes involved in defence against mycobacteria [Jostins et al], but none of these variants was significantly associated with TB after Bonferroni correction. The absence of overlap between IBD loci indicates that our GWAS might be underpowered to detect these weak effects.

It was also surprising to find that the previously reported HLA association did not reach genome-wide significance in our study (minimum P-value of 3.61e-5). This may be explained by the extreme diversity of HLA loci and the geographically distinct strains of M. tb. Suggesting that further studies which consider host and pathogen genetics together will further advance our understanding towards the pathogenesis of TB.

An ongoing battle

Compared to other complex diseases, GWA studies of TB and other infectious diseases have enjoyed much less success in identifying novel risk variants. Popular hypotheses such as strong selective pressure exerted by the ancient and widespread pathogen might have resulted in small effect size of common polymorphisms predisposing to TB. Further studies that account for other susceptibility factors such as poverty and household information may improve the likelihood of identifying genetic risk factors.

In a way, the lack of association found in TB poses many interesting questions in itself and the long battle between us and TB continues. As Susan Sontag argued powerfully in her book Illness as Metaphor, TB, along with cancer, drain vitality… stretch out the encounter with death… [and] in both cases, dying, even more than death, defines illness. Genetics studies using modern technologies will have a lot to contribute to understand the disease that in many ways has shaped our understanding of illnesses and their cure.

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