Research

Why do some people progress to active TB and others don’t? We think this is, in part, because of a genetic predisposition that makes someone more susceptible to TB. What about your genes makes you prone to getting a disease? We’re looking into that by identifying the specific genes and how your genes make proteins your immune system uses to fight infections.

Human genetic architecture of TB susceptibility

We use genome wide association studies, or GWASs, to discover the genes that cause disease. GWASs are the mainstay for identifying the genes scientists think are responsible for phenotypes, that is the physical expression of our genetics, like height, hair color, or diseases such as diabetes or TB.

From our GWASs and epidemiological dataset we will create a predictive polygenic risk score, or PRS, for each individual to determine their risk, or probability, of converting to active TB from a latent infection.

Here's some more detail:

Genetic Architecture

The genetics of the immune response to M.tb

We follow-up our GWAS discoveries delving deeper into the specific genes and alleles in the regions of the genome associated with immune function, the human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIRs).

To further understand the biology of TB infection, we take whole blood from 100 participants who are latently infected and expose their blood to live M.tb in the laboratory, tracking the transcriptional signature, that is, taking a snapshot of which genes are turning on and off to make proteins.

Here's some more details:

HLA/KIR

GENE EXPRESSION

Studying the host genetics of TB susceptibility among the South African Coloured population in the Northern Cape has the strong potential for discovery of critical susceptibility loci for the following reasons:

High incidence of TB: High TB incidence (971/100K)4 in the Northern Cape and widespread LTBI (75% of South Africans >25 years old) afford us consistent phenotypes across cases and controls.
Equal proportion of cases and controls: We have demonstrated feasibility collecting close to 1:1 ratio of cases to controls (48%, 52%, respectively, n=1100), obtaining maximum power for binary outcomes.
Admixture: The portability of GWAS variants has met with mixed success when discovery occurs first in European-descent study populations. Genetic discoveries made in admixed populations have a higher degree of transference across populations. Admixed individuals carry a greater diversity of variants and LD patterns which facilitate accurate identification of GWAS hits relevant to multiple ancestries.

Why do this research in Africa among Africans and finally, why focus on Coloured people?

South Africa is at the epicenter of the TB epidemic and upwards of 80-90% of the population has latent TB, MTBI. Widespread infection, high incidence, and a large sample size afford us maximum statistical power to discover the underlying genes in people who have active TB, the main limitation in other TB GWAS.

Africans have the most genetic diversity in the world, this is because as humans migrated out of Africa and colonized Earth, they went through an evolutionary process called, genetic drift —in this case known as, bottlenecks—which decrease genetic diversity in a population. This matters because the more genetic diversity a population has, the more likely we can discover the critical genes in TB susceptibility. Taking that one-step further, we have developed method to leverage the unique genetic diversity in recently admixed populations* to discover more genes and alleles.

South African Coloured folks have recent admixture from four distinct ancestries, two African ancestries (KhoeSan and Bantu-speaking), European, and South Asian. The graph here shows how the variation in proportion of genetic ancestry among 200 participants from our pilot study.

We have made a global promise to end TB, we must study TB in the places and among the people it’s hitting the hardest to follow through on that promise.

*Genetic admixture is the presence of a combination of genes from populations that can be differentiated by their unique population-specific variants. For example, many Mexicans, though not all, are admixed, they have unique genetic variants that are found among Native Americans, Spanish (i.e., Iberian) folks, and Africans, and those proportions of admixture vary from person to person.