Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation.
<h4>Background</h4>Tuberculosis (TB) remains a major public health problem globally, even compared to COVID-19. Genome-wide studies have failed to discover genes that explain a large proportion of genetic risk for adult pulmonary TB, and even fewer have examined genetic factors underlyin...
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Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010387&type=printable |
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| author | Michael L McHenry Jason Simmons Hyejeong Hong LaShaunda L Malone Harriet Mayanja-Kizza William S Bush W Henry Boom Thomas R Hawn Scott M Williams Catherine M Stein |
| author_facet | Michael L McHenry Jason Simmons Hyejeong Hong LaShaunda L Malone Harriet Mayanja-Kizza William S Bush W Henry Boom Thomas R Hawn Scott M Williams Catherine M Stein |
| author_sort | Michael L McHenry |
| collection | DOAJ |
| description | <h4>Background</h4>Tuberculosis (TB) remains a major public health problem globally, even compared to COVID-19. Genome-wide studies have failed to discover genes that explain a large proportion of genetic risk for adult pulmonary TB, and even fewer have examined genetic factors underlying TB severity, an intermediate trait impacting disease experience, quality of life, and risk of mortality. No prior severity analyses used a genome-wide approach.<h4>Methods and findings</h4>As part of our ongoing household contact study in Kampala, Uganda, we conducted a genome-wide association study (GWAS) of TB severity measured by TBScore, in two independent cohorts of culture-confirmed adult TB cases (n = 149 and n = 179). We identified 3 SNPs (P<1.0 x 10-7) including one on chromosome 5, rs1848553, that was GWAS significant (meta-analysis p = 2.97x10-8). All three SNPs are in introns of RGS7BP and have effect sizes corresponding to clinically meaningful reductions in disease severity. RGS7BP is highly expressed in blood vessels and plays a role in infectious disease pathogenesis. Other genes with suggestive associations defined gene sets involved in platelet homeostasis and transport of organic anions. To explore functional implications of the TB severity-associated variants, we conducted eQTL analyses using expression data from Mtb-stimulated monocyte-derived macrophages. A single variant (rs2976562) associated with monocyte SLA expression (p = 0.03) and subsequent analyses indicated that SLA downregulation following MTB stimulation associated with increased TB severity. Src Like Adaptor (SLAP-1), encoded by SLA, is highly expressed in immune cells and negatively regulates T cell receptor signaling, providing a potential mechanistic link to TB severity.<h4>Conclusions</h4>These analyses reveal new insights into the genetics of TB severity with regulation of platelet homeostasis and vascular biology being central to consequences for active TB patients. This analysis also reveals genes that regulate inflammation can lead to differences in severity. Our findings provide an important step in improving TB patient outcomes. |
| format | Article |
| id | doaj-art-2e0843db2b3d420391bf11e8daa773b9 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-2e0843db2b3d420391bf11e8daa773b92025-08-20T03:25:19ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-03-01193e101038710.1371/journal.pgen.1010387Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation.Michael L McHenryJason SimmonsHyejeong HongLaShaunda L MaloneHarriet Mayanja-KizzaWilliam S BushW Henry BoomThomas R HawnScott M WilliamsCatherine M Stein<h4>Background</h4>Tuberculosis (TB) remains a major public health problem globally, even compared to COVID-19. Genome-wide studies have failed to discover genes that explain a large proportion of genetic risk for adult pulmonary TB, and even fewer have examined genetic factors underlying TB severity, an intermediate trait impacting disease experience, quality of life, and risk of mortality. No prior severity analyses used a genome-wide approach.<h4>Methods and findings</h4>As part of our ongoing household contact study in Kampala, Uganda, we conducted a genome-wide association study (GWAS) of TB severity measured by TBScore, in two independent cohorts of culture-confirmed adult TB cases (n = 149 and n = 179). We identified 3 SNPs (P<1.0 x 10-7) including one on chromosome 5, rs1848553, that was GWAS significant (meta-analysis p = 2.97x10-8). All three SNPs are in introns of RGS7BP and have effect sizes corresponding to clinically meaningful reductions in disease severity. RGS7BP is highly expressed in blood vessels and plays a role in infectious disease pathogenesis. Other genes with suggestive associations defined gene sets involved in platelet homeostasis and transport of organic anions. To explore functional implications of the TB severity-associated variants, we conducted eQTL analyses using expression data from Mtb-stimulated monocyte-derived macrophages. A single variant (rs2976562) associated with monocyte SLA expression (p = 0.03) and subsequent analyses indicated that SLA downregulation following MTB stimulation associated with increased TB severity. Src Like Adaptor (SLAP-1), encoded by SLA, is highly expressed in immune cells and negatively regulates T cell receptor signaling, providing a potential mechanistic link to TB severity.<h4>Conclusions</h4>These analyses reveal new insights into the genetics of TB severity with regulation of platelet homeostasis and vascular biology being central to consequences for active TB patients. This analysis also reveals genes that regulate inflammation can lead to differences in severity. Our findings provide an important step in improving TB patient outcomes.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010387&type=printable |
| spellingShingle | Michael L McHenry Jason Simmons Hyejeong Hong LaShaunda L Malone Harriet Mayanja-Kizza William S Bush W Henry Boom Thomas R Hawn Scott M Williams Catherine M Stein Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation. PLoS Genetics |
| title | Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation. |
| title_full | Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation. |
| title_fullStr | Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation. |
| title_full_unstemmed | Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation. |
| title_short | Tuberculosis severity associates with variants and eQTLs related to vascular biology and infection-induced inflammation. |
| title_sort | tuberculosis severity associates with variants and eqtls related to vascular biology and infection induced inflammation |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010387&type=printable |
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