TY - JOUR
T1 - History of tuberculosis disease is associated with genetic regulatory variation in Peruvians
AU - Nieto-Caballero, Victor E.
AU - Reijneveld, Josephine F.
AU - Ruvalcaba, Angel
AU - Innocenzi, Gabriel
AU - Abeydeera, Nalin
AU - Asgari, Samira
AU - Lopez, Kattya
AU - Iwany, Sarah K.
AU - Luo, Yang
AU - Nathan, Aparna
AU - Fernandez-Salinas, Daniela
AU - Chiñas, Marcos
AU - Huang, Chuan Chin
AU - Zhang, Zibiao
AU - León, Segundo R.
AU - Calderon, Roger I.
AU - Lecca, Leonid
AU - Budzik, Jonathan M.
AU - Murray, Megan
AU - Van Rhijn, Ildiko
AU - Raychaudhuri, Soumya
AU - Moody, D. Branch
AU - Suliman, Sara
AU - Gutierrez-Arcelus, Maria
N1 - Publisher Copyright:
© 2024 Nieto-Caballero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2024/6/13
Y1 - 2024/6/13
N2 - 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 proteincoding 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.
AB - 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 proteincoding 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.
UR - http://www.scopus.com/inward/record.url?scp=85195858523&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1011313
DO - 10.1371/journal.pgen.1011313
M3 - Article
C2 - 38870230
AN - SCOPUS:85195858523
SN - 1553-7390
VL - 20
JO - PLoS Genetics
JF - PLoS Genetics
IS - 6 June
M1 - e1011313
ER -