SP110 Polymorphisms Are Genetic Markers for Vulnerability to Latent and Active Tuberculosis Infection in Taiwan

One-fourth of the human population is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) and carries the infection in its latent form. This latent infection presents a lifelong risk of developing active tuberculosis (TB) disease, and persons with latent TB infection (LTBI) are significant contributors to the pool of active TB cases. Genetic polymorphisms among hosts have been shown to contribute to the outcome of Mtb infection. The SP110 gene, which encodes an interferon-induced nuclear protein, has been shown to control host innate immunity to Mtb infection. In this study, we provide experimental data demonstrating the ability of the gene to control genetic susceptibility to latent and active TB infection. Genetic variants of the SP110 gene were investigated in the Taiwanese population (including 301 pulmonary TB patients, 68 LTBI individuals, and 278 healthy household contacts of the TB patients), and their association with susceptibility to latent and active TB infection was examined by performing an association analysis in a case-control study. We identified several SNPs (rs7580900, rs7580912, rs9061, rs11556887, and rs2241525) in the SP110 gene that are associated with susceptibility to LTBI and/or TB disease. Our studies further showed that the same SNPs may have opposite effects on the control of susceptibility to LTBI versus TB. In addition, our analyses demonstrated that the SP110 rs9061 SNP was associated with tumor necrosis factor-α (TNFα) levels in plasma in LTBI subjects. The results suggest that the polymorphisms within SP110 have a role in controlling genetic susceptibility to latent and active TB infection in humans. To the best of our knowledge, this is the first report showing that the SP110 variants are associated with susceptibility to LTBI. Our study also demonstrated that the identified SP110 SNPs displayed the potential to predict the risk of LTBI and subsequent TB progression in Taiwan.

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Whole blood mRNA expression-based targets to discriminate active tuberculosis from latent infection and other pulmonary diseases

Scientific Reports ◽

10.1038/s41598-020-78793-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jéssica D. Petrilli ◽

Luana E. Araújo ◽

Luciane Sussuchi da Silva ◽

Ana Carolina Laus ◽

Igor Müller ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Whole Blood ◽

Lung Diseases ◽

Latent Infection ◽

Single Gene ◽

High Sensitivity ◽

Active Tuberculosis ◽

Latent Tb ◽

Latent Tb Infection ◽

Main Barrier

AbstractCurrent diagnostic tests for tuberculosis (TB) are not able to predict reactivation disease progression from latent TB infection (LTBI). The main barrier to predicting reactivation disease is the lack of our understanding of host biomarkers associated with progression from latent infection to active disease. Here, we applied an immune-based gene expression profile by NanoString platform to identify whole blood markers that can distinguish active TB from other lung diseases (OPD), and that could be further evaluated as a reactivation TB predictor. Among 23 candidate genes that differentiated patients with active TB from those with OPD, nine genes (CD274, CEACAM1, CR1, FCGR1A/B, IFITM1, IRAK3, LILRA6, MAPK14, PDCD1LG2) demonstrated sensitivity and specificity of 100%. Seven genes (C1QB, C2, CCR2, CCRL2, LILRB4, MAPK14, MSR1) distinguished TB from LTBI with sensitivity and specificity between 82 and 100%. This study identified single gene candidates that distinguished TB from OPD and LTBI with high sensitivity and specificity (both > 82%), which may be further evaluated as diagnostic for disease and as predictive markers for reactivation TB.

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Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation

Journal of Clinical Microbiology ◽

10.1128/jcm.01990-15 ◽

2015 ◽

Vol 54 (2) ◽

pp. 274-282 ◽

Cited By ~ 26

Author(s):

Nicholas D. Walter ◽

Mikaela A. Miller ◽

Joshua Vasquez ◽

Marc Weiner ◽

Adam Chapman ◽

...

Keyword(s):

Case Control Study ◽

The United States ◽

Case Control ◽

Support Vector ◽

Time Curve ◽

Disease Spectrum ◽

Latent Tb ◽

Sub Saharan ◽

Latent Tb Infection ◽

Control Study

Blood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S. patients. To be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy to classifiers from published studies. Blood samples from HIV-uninfected U.S. adults with active TB, pneumonia, or latent TB infection underwent whole-transcriptome microarray. We used support vector machines to classify disease state based on transcriptional patterns. We externally validated our classifiers using data from sub-Saharan African cohorts and evaluated previously published transcriptional classifiers in our population. Our classifier distinguishing active TB from pneumonia had an area under the concentration-time curve (AUC) of 96.5% (95.4% to 97.6%) among U.S. patients, but the AUC was lower (90.6% [89.6% to 91.7%]) in HIV-uninfected Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 90.0% (87.7% to 92.3%) and 82.9% (80.8% to 85.1%) when tested in U.S. patients. Our classifier distinguishing active TB from latent TB had AUC values of 95.9% (95.2% to 96.6%) among U.S. patients and 95.3% (94.7% to 96.0%) among Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 98.0% (97.4% to 98.7%) and 94.8% (92.9% to 96.8%) when tested in U.S. patients. Blood transcriptional classifiers accurately detected active TB among U.S. adults. The accuracy of classifiers for active TB versus that of other diseases decreased when tested in new populations with different disease controls, suggesting additional studies are required to enhance generalizability. Classifiers that distinguish active TB from latent TB are accurate and generalizable across populations and can be explored as screening assays.

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Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

BMC Cancer ◽

10.1186/1471-2407-11-339 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 21

Author(s):

Anna Abulí ◽

◽

Ceres Fernández-Rozadilla ◽

Virginia Alonso-Espinaco ◽

Jenifer Muñoz ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Susceptibility ◽

Case Control Study ◽

Case Control ◽

Cancer Genetic ◽

Control Study

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Lack of genetic susceptibility in takotsubo cardiomyopathy: a case-control study

BMC Medical Genetics ◽

10.1186/s12881-018-0544-6 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Emma Mattsson ◽

Peter Saliba-Gustafsson ◽

Ewa Ehrenborg ◽

Per Tornvall

Keyword(s):

Genetic Susceptibility ◽

Takotsubo Cardiomyopathy ◽

Case Control Study ◽

Case Control ◽

Control Study

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Tumor necrosis factor-alpha G-308 A polymorphism and risk of coronary heart disease and myocardial infarction: A case–control study and meta-analysis

Journal of Cardiovascular Disease Research ◽

10.4103/0975-3583.95359 ◽

2012 ◽

Vol 3 (2) ◽

pp. 84-90 ◽

Cited By ~ 25

Author(s):

Hongxia Chu ◽

Jun Yang ◽

Shaohua Mi ◽

Soumitra Sudip Bhuyan ◽

Jun Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Heart Disease ◽

Tumor Necrosis ◽

Case Control Study ◽

Meta Analysis ◽

Case Control ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor ◽

Control Study

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HLA-DQB genetic susceptibility and rheumatic heart disease: a case-control study

Asian Cardiovascular and Thoracic Annals ◽

10.1177/0218492320908988 ◽

2020 ◽

Vol 28 (3) ◽

pp. 147-151

Author(s):

Neha Sharma ◽

Devinder Toor ◽

Lokajeet Baro ◽

Mriganka S Chaliha ◽

Giriraj Kusre ◽

...

Keyword(s):

Socioeconomic Status ◽

Heart Disease ◽

Genetic Susceptibility ◽

Rheumatic Heart Disease ◽

Case Control Study ◽

Case Control ◽

Clinical Profile ◽

Predominant Allele ◽

Control Study ◽

Rheumatic Heart

Background Rheumatic heart disease is a major global health concern, especially in low- and middle-income countries. The pathogenesis is attributable to an aberrant immune response, host genetic factors, and socioeconomic status. The objective of this study was to screen HLA-DQB1 alleles as genetic susceptibility markers in rheumatic heart disease patients in Assam, North East India, and to correlate the predominant allele with socioeconomic status and clinical profile. Methods A case-control study of 100 echocardiography-confirmed rheumatic heart disease patients and age- and sex-matched healthy controls from Assam Medical College and Hospital was conducted. Human leukocyte antigen typing was performed using HLA-DQ typing kit. A questionnaire was designed to study the socioeconomic status and clinical profile of rheumatic heart disease patients. Results Among the 9 alleles studied, HLA-DRBQ1*03:01 was found to be the statistically significant predominant allele in this population, especially in the Ahom ethnic group. In the HLA-DRBQ1*03:01-positive population, rural dwelling was found to be a significantly increased risk factor for rheumatic heart disease. Among severe cases, 90% of mitral stenosis, 40% of mitral regurgitation, and 33.3% of aortic regurgitation cases were HLA-DRBQ1*03:01-positive. Also, 50% of aortic valve thickening and 36.8% of mitral valve thickening cases were found in this population. Conclusion Our data suggest that HLA-DRBQ1*03:01 is a significant susceptibility marker in this population, and predominant in the rural population. Furthermore, it may play an important role in determining the pattern of valve damage in rheumatic heart disease patients.

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