부산대학교 도서관

Background: 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. Methods and findings: 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. Conclusions: 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. Author summary: Severity of tuberculosis (TB) is an important determinant of transmission, morbidity, mortality, disease experience and quality of life; it can be affected by human genetic variation. In this study, we performed a genome wide study (GWAS) to examine the role of human genetic variation on TB severity, as measured by the Bandim TBscore, a metric developed for resource-limited environments. Three single nucleotide polymorphisms (SNPs) in one gene, RGS7BP, associated with severity. This gene is expressed in blood vessels and plays a role in infectious disease pathology. In addition, we used the GWAS data to identify pathways linked to TBscore, and found that the platelet homeostasis and transport of organic anion pathways both associated with severity. Functional analyses were also performed, examining the effects of stimulation with Mycobacterium tuberculosis, the causative agent of TB. Down regulation of the gene encoding Src Like Adaptor (SLAP-1) that is highly expressed in immune cells and negatively regulates T cell receptor signaling associated with MTB exposure, providing a potential mechanistic link to TB severity. Together these findings indicate that host factors involved in regulation of platelet homeostasis and vascular biology affect TB severity. These findings may lead to new ways to decrease disease severity. [ABSTRACT FROM AUTHOR]