title: Differential gene expression of activating Fcγ receptor classifies active tuberculosis regardless of human immunodeficiency virus status or ethnicity.
abstract: New diagnostics and vaccines for tuberculosis (TB) are urgently needed, but require an understanding of the requirements for protection from/susceptibility to TB. Previous studies have used unbiased approaches to determine gene signatures in single-site populations. The present study utilized a targeted approach, reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA), to validate these genes in a multisite study. We analysed ex vivo whole blood RNA from a total of 523 participants across four sub-Saharan countries (Ethiopia, Malawi, South Africa, and The Gambia) with differences in TB and human immunodeficiency virus (HIV) status. We found a number of genes that were expressed at significantly lower levels in participants with active disease than in those with latent TB infection (LTBI), with restoration following successful TB treatment. The most consistent classifier of active disease was FCGR1A (high-affinity IgG Fc receptor 1 (CD64)), which was the only marker expressed at significantly higher levels in participants with active TB than in those with LTBI before treatment regardless of HIV status or genetic background. This is the first study to identify a biomarker for TB that is not affected by HIV status or geo-genetic differences. These data provide valuable clues for understanding TB pathogenesis, and also provide a proof-of-concept for the use of RT-MLPA in rapid and inexpensive validation of unbiased gene expression findings.
authors.affiliation: Medical Research Council Unit, Fajara, The Gambia.
authors.forename: J S
authors.initials: JS
authors.lastname: Sutherland
authors.forename: A G
authors.initials: AG
authors.lastname: Loxton
authors.forename: M C
authors.initials: MC
authors.lastname: Haks
authors.forename: D
authors.initials: D
authors.lastname: Kassa
authors.forename: L
authors.initials: L
authors.lastname: Ambrose
authors.forename: J-S
authors.initials: JS
authors.lastname: Lee
authors.forename: L
authors.initials: L
authors.lastname: Ran
authors.forename: D
authors.initials: D
authors.lastname: van Baarle
authors.forename: J
authors.initials: J
authors.lastname: Maertzdorf
authors.forename: R
authors.initials: R
authors.lastname: Howe
authors.forename: H
authors.initials: H
authors.lastname: Mayanja-Kizza
authors.forename: W H
authors.initials: WH
authors.lastname: Boom
authors.forename: B A
authors.initials: BA
authors.lastname: Thiel
authors.forename: A C
authors.initials: AC
authors.lastname: Crampin
authors.forename: W
authors.initials: W
authors.lastname: Hanekom
authors.forename: M O C
authors.initials: MO
authors.lastname: Ota
authors.forename: H
authors.initials: H
authors.lastname: Dockrell
authors.forename: G
authors.initials: G
authors.lastname: Walzl
authors.forename: S H E
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: T H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara; D015415:Biomarkers / Q000097:blood*; D001769:Blood; D005006:Ethnicity; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D017452:Receptors, IgG / Q000097:blood*; D014376:Tuberculosis / Q000175:diagnosis*; D055815:Young Adult
chemical_list: D015415:Biomarkers; C489017:FCGR1A protein, human; D017452:Receptors, IgG
keywords: Biosignature; RT-MLPA; gene expression; tuberculosis