Tuberculosis (TB) is one of the leading causes of death worldwide, responsible for 1.7 million deaths in 2016 [1]. The majority of deaths from TB occur in low- and middle-income countries. In Ethiopia, TB was the fourth leading cause of death in 2016 and the country is one of the world’s 30 high TB burden countries [2, 3].
Being infected with Mycobacterium tuberculosis (Mtb) does not necessarily result in progression to active TB disease. The immune system is thought to play an important role in this process, which may be modified by genetic polymorphisms that could be associated with susceptibility or resistance to TB. A better understanding of susceptibility and resistance to TB is important for informing public health policy, particularly in countries with a high TB burden, such as Ethiopia.
In order to better understand TB disease progression, studies have investigated the role of genetic variation in this process. Numerous studies have found genetic variation is associated with the differences in the immune response to TB observed between individuals and ethnic groups. However, it is important that these genetic association signals are validated through replication studies. Many attempts at this have been unsuccessful, largely due to differences in study design as well as the lack of accounting for confounding variables [4].
In our recent studies we aimed to replicate a previously identified significant association signal of two innate immunity genes (NOD1 and TICAM2), originally identified in a Ugandan population [5], in an Ethiopian population. We also tested a new candidate gene: FMO2.
In this study, we developed TB phenotype definitions that closely reflect the stepwise natural history of TB progression from Mtb exposure to development of latent infection (LTBI) and then progression to active pulmonary TB (PTB). First, we sequenced the coding regions (exons) of the candidate genes. We further analysed which specific allelic variants (single nucleotide polymorphisms=SNPs) and inferred aggregates of SNPs, inherited en bloc (haplotypes), that are enriched in cases (individuals with active or latent TB) compared with controls (no Mtb infection). To address some of the limitations of previous replication studies, we accounted for confounding in our statistical analyses by adjusting for the possible effects of sex, age and population stratification.
For the first time, we were able to replicate the genetic association signals for both genes (NOD1 and TICAM2), in the Ethiopian population [6]. Our rigorous study design also enabled the identification of a novel association of FMO2 with TB [7]. Our results identified genetic variants associated with either susceptibility or resistance to TB. The findings also suggest the possibility of population-specific associations of these genes with TB disease progression as a result of pathogen-driven local adaptation to TB in sub-Saharan Africa, where both Mtb and humans are considered to have originated and co-evolved [8].
This study provides a useful framework that can inform future genetic epidemiological investigations of complex diseases, especially in sub-Saharan Africa, where there is enormous human genetic variation.
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References
1. World Health Organization. Tuberculosis. 2018 [Accessed 31 January 2018]; Available from: http://www.who.int/mediacentre/factsheets/fs104/en/.
2. World Health Organization. Global tuberculosis report 2017. 2017: Geneva.
3. Institute for Health Metrics and Evaluation. Ethiopia. [Accessed 31 January 2018]; Available from: http://www.healthdata.org/ethiopia.
4. Stein CM, Baker AR. Tuberculosis as a complex trait: impact of genetic epidemiological study design, Mamm Genome, 2010; DOI 10.1007/s00335-010-9301-7.
5. Hall NB, et al. Polymorphisms in TICAM2 and IL1B are associated with TB, Genes and Immunity, 2015; Vol. 16: 127–133.
6. Mekonnen E, Bekele E, Stein CM. Novel polymorphisms in TICAM2 and NOD1 associated with tuberculosis progression phenotypes in Ethiopian populations, 2018; Vol. 3, e1.
7. Mekonnen E, Bekele E. An ancestral human genetic variant linked to an ancient disease: A novel association of FMO2 polymorphisms with tuberculosis (TB) in Ethiopian populations provides new insight into the differential ethno-geographic distribution of FMO2*1, PLoS ONE, 2017; 12(10):e0184931.
8. Brites D, Gagneux S. Co-evolution of Mycobacterium tuberculosis and Homo sapiens, Immunological Reviews, 2015; Vol. 264: 6–24.