History of tuberculosis disease is associated with genetic regulatory variation in Peruvians
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 po...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2024
|
| _version_ | 1826313441099382784 |
|---|---|
| author | Nieto-Caballero, VE Reijneveld, JF Ruvalcaba, A Innocenzi, G Abeydeera, N Asgari, S Lopez, K Iwany, SK Luo, Y Nathan, A Fernandez-Salinas, D Chiñas, M Huang, C Zhang, Z León, SR Calderon, RI Lecca, L Budzik, JM Murray, M Van Rhijn, I Raychaudhuri, S Moody, DB Suliman, S Gutierrez-Arcelus, M |
| author_facet | Nieto-Caballero, VE Reijneveld, JF Ruvalcaba, A Innocenzi, G Abeydeera, N Asgari, S Lopez, K Iwany, SK Luo, Y Nathan, A Fernandez-Salinas, D Chiñas, M Huang, C Zhang, Z León, SR Calderon, RI Lecca, L Budzik, JM Murray, M Van Rhijn, I Raychaudhuri, S Moody, DB Suliman, S Gutierrez-Arcelus, M |
| author_sort | Nieto-Caballero, VE |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-09-25T04:13:02Z |
| format | Journal article |
| id | oxford-uuid:fc06e6db-2b3a-44d7-aaf3-1286928b98e5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:13:02Z |
| publishDate | 2024 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:fc06e6db-2b3a-44d7-aaf3-1286928b98e52024-06-27T20:07:56ZHistory of tuberculosis disease is associated with genetic regulatory variation in PeruviansJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fc06e6db-2b3a-44d7-aaf3-1286928b98e5EnglishJisc Publications RouterPublic Library of Science2024Nieto-Caballero, VEReijneveld, JFRuvalcaba, AInnocenzi, GAbeydeera, NAsgari, SLopez, KIwany, SKLuo, YNathan, AFernandez-Salinas, DChiñas, MHuang, CZhang, ZLeón, SRCalderon, RILecca, LBudzik, JMMurray, MVan Rhijn, IRaychaudhuri, SMoody, DBSuliman, SGutierrez-Arcelus, MA 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. |
| spellingShingle | Nieto-Caballero, VE Reijneveld, JF Ruvalcaba, A Innocenzi, G Abeydeera, N Asgari, S Lopez, K Iwany, SK Luo, Y Nathan, A Fernandez-Salinas, D Chiñas, M Huang, C Zhang, Z León, SR Calderon, RI Lecca, L Budzik, JM Murray, M Van Rhijn, I Raychaudhuri, S Moody, DB Suliman, S Gutierrez-Arcelus, M History of tuberculosis disease is associated with genetic regulatory variation in Peruvians |
| title | History of tuberculosis disease is associated with genetic regulatory variation in Peruvians |
| title_full | History of tuberculosis disease is associated with genetic regulatory variation in Peruvians |
| title_fullStr | History of tuberculosis disease is associated with genetic regulatory variation in Peruvians |
| title_full_unstemmed | History of tuberculosis disease is associated with genetic regulatory variation in Peruvians |
| title_short | History of tuberculosis disease is associated with genetic regulatory variation in Peruvians |
| title_sort | history of tuberculosis disease is associated with genetic regulatory variation in peruvians |
| work_keys_str_mv | AT nietocaballerove historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT reijneveldjf historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT ruvalcabaa historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT innocenzig historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT abeydeeran historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT asgaris historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT lopezk historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT iwanysk historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT luoy historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT nathana historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT fernandezsalinasd historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT chinasm historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT huangc historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT zhangz historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT leonsr historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT calderonri historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT leccal historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT budzikjm historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT murraym historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT vanrhijni historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT raychaudhuris historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT moodydb historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT sulimans historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians AT gutierrezarcelusm historyoftuberculosisdiseaseisassociatedwithgeneticregulatoryvariationinperuvians |