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

Abstract

AbstractA quarter of humanity is estimated to be latently infected withMycobacterium tuberculosis(Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses toMtbinfection 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 dendritic cells (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. Five genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was withFAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism.FAHexpression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data ofMtb-infected monocyte-derived dendritic cells, we found thatMtbinfection results inFAHdownregulation 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.