Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB

Tuberculosis (TB) remains a major public health threat globally, especially in sub-Saharan Africa. Both human and <i>Mycobacterium tuberculosis</i> (MTBC) genetic variation affect TB outcomes, but few studies have examined if and how the two genomes interact to affect disease. We hypothe...

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Autores principales:	Michael L. McHenry, Eddie M. Wampande, Moses L. Joloba, LaShaunda L. Malone, Harriet Mayanja-Kizza, William S. Bush, W. Henry Boom, Scott M. Williams, Catherine M. Stein
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tuberculosis severity <i>M. tuberculosis</i> population genetics lineage-based GWAS <i>M. tuberculosis</i>–human coevolution Medicine R
Acceso en línea:	https://doaj.org/article/4ce8188910264aaebe58bdfde9f3c03f
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spelling	oai:doaj.org-article:4ce8188910264aaebe58bdfde9f3c03f2021-11-25T18:38:39ZInteraction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB10.3390/pathogens101114872076-0817https://doaj.org/article/4ce8188910264aaebe58bdfde9f3c03f2021-11-01T00:00:00Zhttps://www.mdpi.com/2076-0817/10/11/1487https://doaj.org/toc/2076-0817Tuberculosis (TB) remains a major public health threat globally, especially in sub-Saharan Africa. Both human and <i>Mycobacterium tuberculosis</i> (MTBC) genetic variation affect TB outcomes, but few studies have examined if and how the two genomes interact to affect disease. We hypothesize that long-term coexistence between human genomes and MTBC lineages modulates disease to affect its severity. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which we identified three MTBC lineages, of which one, L4.6-Uganda, is clearly derived and hence recent. We quantified TB severity using the Bandim TBscore and examined the interaction between MTBC lineage and human single-nucleotide polymorphisms (SNPs) genome-wide, in two independent cohorts of TB cases (<i>n</i> = 149 and <i>n</i> = 127). We found a significant interaction between an SNP in <i>PPIAP2</i> and the Uganda lineage (combined <i>p</i> = 4 × 10<sup>−8</sup>). <i>PPIAP2</i> is a pseudogene that is highly expressed in immune cells. Pathway and eQTL analyses indicated potential roles between coevolving SNPs and cellular replication and metabolism as well as platelet aggregation and coagulation. This finding provides further evidence that host–pathogen interactions affect clinical presentation differently than host and pathogen genetic variation independently, and that human–MTBC coevolution is likely to explain patterns of disease severity.Michael L. McHenryEddie M. WampandeMoses L. JolobaLaShaunda L. MaloneHarriet Mayanja-KizzaWilliam S. BushW. Henry BoomScott M. WilliamsCatherine M. SteinMDPI AGarticletuberculosis severity<i>M. tuberculosis</i>population geneticslineage-based GWAS<i>M. tuberculosis</i>–human coevolutionMedicineRENPathogens, Vol 10, Iss 1487, p 1487 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tuberculosis severity <i>M. tuberculosis</i> population genetics lineage-based GWAS <i>M. tuberculosis</i>–human coevolution Medicine R
spellingShingle	tuberculosis severity <i>M. tuberculosis</i> population genetics lineage-based GWAS <i>M. tuberculosis</i>–human coevolution Medicine R Michael L. McHenry Eddie M. Wampande Moses L. Joloba LaShaunda L. Malone Harriet Mayanja-Kizza William S. Bush W. Henry Boom Scott M. Williams Catherine M. Stein Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB
description	Tuberculosis (TB) remains a major public health threat globally, especially in sub-Saharan Africa. Both human and <i>Mycobacterium tuberculosis</i> (MTBC) genetic variation affect TB outcomes, but few studies have examined if and how the two genomes interact to affect disease. We hypothesize that long-term coexistence between human genomes and MTBC lineages modulates disease to affect its severity. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which we identified three MTBC lineages, of which one, L4.6-Uganda, is clearly derived and hence recent. We quantified TB severity using the Bandim TBscore and examined the interaction between MTBC lineage and human single-nucleotide polymorphisms (SNPs) genome-wide, in two independent cohorts of TB cases (<i>n</i> = 149 and <i>n</i> = 127). We found a significant interaction between an SNP in <i>PPIAP2</i> and the Uganda lineage (combined <i>p</i> = 4 × 10<sup>−8</sup>). <i>PPIAP2</i> is a pseudogene that is highly expressed in immune cells. Pathway and eQTL analyses indicated potential roles between coevolving SNPs and cellular replication and metabolism as well as platelet aggregation and coagulation. This finding provides further evidence that host–pathogen interactions affect clinical presentation differently than host and pathogen genetic variation independently, and that human–MTBC coevolution is likely to explain patterns of disease severity.
format	article
author	Michael L. McHenry Eddie M. Wampande Moses L. Joloba LaShaunda L. Malone Harriet Mayanja-Kizza William S. Bush W. Henry Boom Scott M. Williams Catherine M. Stein
author_facet	Michael L. McHenry Eddie M. Wampande Moses L. Joloba LaShaunda L. Malone Harriet Mayanja-Kizza William S. Bush W. Henry Boom Scott M. Williams Catherine M. Stein
author_sort	Michael L. McHenry
title	Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB
title_short	Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB
title_full	Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB
title_fullStr	Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB
title_full_unstemmed	Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB
title_sort	interaction between <i>m. tuberculosis</i> lineage and human genetic variants reveals novel pathway associations with severity of tb
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4ce8188910264aaebe58bdfde9f3c03f
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Interaction between <i>M. tuberculosis</i> Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB

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