Gene Expression in Cord Blood and Tuberculosis in Early Childhood: A Nested Case-Control Study in a South African Birth Cohort

Author:

Bobak Carly A1ORCID,Botha Maresa2,Workman Lesley2,Hill Jane E3,Nicol Mark P45,Holloway John W67,Stein Dan J8910,Martinez Leonardo11,Zar Heather J2

Affiliation:

1. Department of Biomedical Data Science, Dartmouth College , Hanover, New Hampshire

2. Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and South African Medical Research Council Unit on Child and Adolescent Health , Cape Town , South Africa

3. School of Biomedical Engineering and the School of Chemical and Biological Engineering, University of British Columbia , Vancouver , Canada

4. Marshall Centre, Division of Infection and Immunity, School of Biomedical Sciences, University of Western Australia , Perth , Australia

5. Division of Medical Microbiology, University of Cape Town , South Africa

6. Human Development and Health, Faculty of Medicine, University of Southampton

7. National Institute for Health and Care Research Southampton Biomedical Research Center, University Hospital Southampton , United Kingdom

8. Department of Psychiatry and Mental Health, University of Cape Town

9. Unit on Risk and Resilience in Mental Disorders, South African Medical Research Council

10. Neuroscience Institute, University of Cape Town , South Africa

11. Department of Epidemiology, School of Public Health, Boston University , Massachusetts

Abstract

Abstract Background Transcriptomic profiling of adults with tuberculosis (TB) has become increasingly common, predominantly for diagnostic and risk prediction purposes. However, few studies have evaluated signatures in children, particularly in identifying those at risk for developing TB disease. We investigated the relationship between gene expression obtained from umbilical cord blood and both tuberculin skin test conversion and incident TB disease through the first 5 years of life. Methods We conducted a nested case-control study in the Drakenstein Child Health Study, a longitudinal, population-based birth cohort in South Africa. We applied transcriptome-wide screens to umbilical cord blood samples from neonates born to a subset of selected mothers (N = 131). Signatures identifying tuberculin conversion and risk of subsequent TB disease were identified from genome-wide analysis of RNA expression. Results Gene expression signatures revealed clear differences predictive of tuberculin conversion (n = 26) and TB disease (n = 10); 114 genes were associated with tuberculin conversion and 30 genes were associated with the progression to TB disease among children with early infection. Coexpression network analysis revealed 6 modules associated with risk of TB infection or disease, including a module associated with neutrophil activation in immune response (P < .0001) and defense response to bacterium (P < .0001). Conclusions These findings suggest multiple detectable differences in gene expression at birth that were associated with risk of TB infection or disease throughout early childhood. Such measures may provide novel insights into TB pathogenesis and susceptibility.

Funder

Medical Research Council

National Research Foundation South Africa

Burroughs Wellcome Fund institutional program

Dartmouth College

US National Institutes of Health

(NIH)

US Cystic Fibrosis Foundation

the Australian Research Council

National Sciences and Engineering Research Council of Canada

NIH

Wellcome Trust UK

MRC South Africa

Bill & Melinda Gates Foundation

Australian National Health and Medical Research Council

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

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