PMID- 34871961
OWN - NLM
STAT- MEDLINE
DCOM- 20220321
LR  - 20220321
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 74
DP  - 2021 Dec
TI  - Resistance to TST/IGRA conversion in Uganda: Heritability and Genome-Wide 
      Association Study.
PG  - 103727
LID - S2352-3964(21)00521-1 [pii]
LID - 10.1016/j.ebiom.2021.103727 [doi]
LID - 103727
AB  - BACKGROUND: Pulmonary tuberculosis (TB) is one of the most deadly pathogens on 
      earth. However, the majority of people have resistance to active disease. 
      Further, some individuals, termed resisters (RSTRs), do not develop traditional 
      latent tuberculosis (LTBI). The RSTR phenotype is important for understanding 
      pathogenesis and preventing TB. The host genetic underpinnings of RSTR are 
      largely understudied. METHODS: In a cohort of 908 Ugandan subjects with 
      genome-wide data on single nucleotide polymorphisms, we assessed the heritability 
      of the RSTR phenotype and other TB phenotypes using restricted maximum likelihood 
      estimation (REML). We then used a subset of 263 RSTR and LTBI subjects with high 
      quality phenotyping and long-term follow-up to identify DNA variants genome-wide 
      associated with the RSTR phenotype relative to LTBI subjects in a case-control 
      GWAS design and annotated and enriched these variants to better understand their 
      role in TB pathogenesis. RESULTS: The heritability of the TB outcomes was very 
      high, at 55% for TB vs. LTBI and 50.4% for RSTR vs. LTBI among HIV- subjects, 
      controlling for age and sex. We identified 27 loci associated with the RSTR 
      phenotype (P<5e-05) and our annotation and enrichment analyses suggest an 
      important regulatory role for many of them. INTERPRETATION: The heritability 
      results show that the genetic contribution to variation in TB outcomes is very 
      high and our GWAS results highlight variants that may play an important role in 
      resistance to infection as well as TB pathogenesis as a whole.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - McHenry, Michael L
AU  - McHenry ML
AD  - Department of Population & Quantitative Health Sciences, Case Western Reserve 
      University, Cleveland, OH, USA.
FAU - Benchek, Penelope
AU  - Benchek P
AD  - Department of Population & Quantitative Health Sciences, Case Western Reserve 
      University, Cleveland, OH, USA.
FAU - Malone, LaShaunda
AU  - Malone L
AD  - Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
FAU - Nsereko, Mary
AU  - Nsereko M
AD  - Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
FAU - Mayanja-Kizza, Harriet
AU  - Mayanja-Kizza H
AD  - Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
FAU - Boom, W Henry
AU  - Boom WH
AD  - Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
FAU - Williams, Scott M
AU  - Williams SM
AD  - Department of Population & Quantitative Health Sciences, Case Western Reserve 
      University, Cleveland, OH, USA.
FAU - Hawn, Thomas R
AU  - Hawn TR
AD  - Department of Medicine, University of Washington, Seattle, WA, USA.
FAU - Stein, Catherine M
AU  - Stein CM
AD  - Department of Population & Quantitative Health Sciences, Case Western Reserve 
      University, Cleveland, OH, USA; Department of Medicine, Case Western Reserve 
      University, Cleveland, OH, USA.
LA  - eng
GR  - R01 AI124348/AI/NIAID NIH HHS/United States
GR  - TL1 TR002549/TR/NCATS NIH HHS/United States
GR  - U01 AI115642/AI/NIAID NIH HHS/United States
GR  - R33 AI138272/AI/NIAID NIH HHS/United States
GR  - N01AI70022/AI/NIAID NIH HHS/United States
GR  - N01AI95383/AI/NIAID NIH HHS/United States
GR  - T32 HL007567/HL/NHLBI NIH HHS/United States
GR  - T32 GM007250/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20211204
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Case-Control Studies
MH  - Child
MH  - Child, Preschool
MH  - *Drug Resistance
MH  - Female
MH  - Genome-Wide Association Study
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Latent Tuberculosis/*genetics
MH  - Likelihood Functions
MH  - Male
MH  - Middle Aged
MH  - Phenotype
MH  - *Polymorphism, Single Nucleotide
MH  - *Quantitative Trait, Heritable
MH  - Sequence Analysis, DNA
MH  - Tuberculosis, Pulmonary/drug therapy/*genetics
MH  - Uganda
MH  - Young Adult
PMC - PMC8652006
OTO - NOTNLM
OT  - GWAS
OT  - M. tuberculosis
OT  - TB outcomes
OT  - phenotype definition
OT  - resistance to tuberculosis infection
COIS- Declaration of Competing Interest The authors have no conflicts of interest to 
      report.
EDAT- 2021/12/07 06:00
MHDA- 2022/03/22 06:00
PMCR- 2021/12/04
CRDT- 2021/12/06 20:23
PHST- 2021/07/21 00:00 [received]
PHST- 2021/11/17 00:00 [revised]
PHST- 2021/11/17 00:00 [accepted]
PHST- 2021/12/07 06:00 [pubmed]
PHST- 2022/03/22 06:00 [medline]
PHST- 2021/12/06 20:23 [entrez]
PHST- 2021/12/04 00:00 [pmc-release]
AID - S2352-3964(21)00521-1 [pii]
AID - 103727 [pii]
AID - 10.1016/j.ebiom.2021.103727 [doi]
PST - ppublish
SO  - EBioMedicine. 2021 Dec;74:103727. doi: 10.1016/j.ebiom.2021.103727. Epub 2021 Dec 
      4.