# History of tuberculosis disease is associated with genetic regulatory variation in Peruvians

## TL;DR

This study shows how genetic differences in Peruvians affect gene expression in immune cells, influencing the risk of developing tuberculosis.

## Contribution

The study identifies genetic regulatory variation linked to TB progression and highlights FAH as a candidate gene in tyrosine metabolism affecting TB risk.

## Key findings

- 330 and 257 eQTL genes were identified in dendritic cells and macrophages, respectively.
- FAH gene expression was associated with genetic regulatory variation in TB cases but not controls.
- Mtb infection downregulates FAH and causes DNA methylation changes in the gene locus.

## Abstract

A quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) with a 5–10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n = 63) or did not progress to TB (controls, n = 63). Transcriptomic profiling of monocyte-derived DCs and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Four genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb-infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a leading cause of mortality globally. Mtb-exposed individuals have heterogeneous outcomes following infection with Mtb, where some progress to TB, while many remain asymptomatic. We hypothesized that genetic variation could partly explain risk of TB, by regulating the expression of genes involved in the control of Mtb infection. In this study in Peru, we recruited former TB patients and Mtb-exposed household contacts of TB patients who remained asymptomatic to define how genetic variation regulates expression of genes in the innate immune system. We identified 4 genetic variants that have different effects on gene expression based on the TB history of the participant. The lead variant regulated expression of a key enzyme (Fumarylacetoacetate Hydrolase; FAH) in tyrosine catabolism. Knocking out the gene in myeloid cells increased susceptibility to Mtb infection. The results implicate FAH as a candidate host factor involved in TB progression.