PMID- 36018815
OWN - NLM
STAT- MEDLINE
DCOM- 20230116
LR  - 20230308
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 32
IP  - 1
DP  - 2023 Jan 1
TI  - Large registry-based analysis of genetic predisposition to tuberculosis 
      identifies genetic risk factors at HLA.
PG  - 161-171
LID - 10.1093/hmg/ddac212 [doi]
AB  - Tuberculosis is a significant public health concern resulting in the death of 
      over 1 million individuals each year worldwide. While treatment options and 
      vaccines exist, a substantial number of infections still remain untreated or are 
      caused by treatment resistant strains. Therefore, it is important to identify 
      mechanisms that contribute to risk and prognosis of tuberculosis as this may 
      provide tools to understand disease mechanisms and provide novel treatment 
      options for those with severe infection. Our goal was to identify genetic risk 
      factors that contribute to the risk of tuberculosis and to understand biological 
      mechanisms and causality behind the risk of tuberculosis. A total of 1895 
      individuals in the FinnGen study had International Classification of 
      Diseases-based tuberculosis diagnosis. Genome-wide association study analysis 
      identified genetic variants with statistically significant association with 
      tuberculosis at the human leukocyte antigen (HLA) region (P < 5e-8). Fine mapping 
      of the HLA association provided evidence for one protective haplotype tagged by 
      HLA DQB1*05:01 (P = 1.82E-06, OR = 0.81 [CI 95% 0.74-0.88]), and predisposing 
      alleles tagged by HLA DRB1*13:02 (P = 0.00011, OR = 1.35 [CI 95% 1.16-1.57]). 
      Furthermore, genetic correlation analysis showed association with earlier 
      reported risk factors including smoking (P < 0.05). Mendelian randomization 
      supported smoking as a risk factor for tuberculosis (inverse-variance weighted 
      P < 0.05, OR = 1.83 [CI 95% 1.15-2.93]) with no significant evidence of 
      pleiotropy. Our findings indicate that specific HLA alleles associate with the 
      risk of tuberculosis. In addition, lifestyle risk factors such as smoking 
      contribute to the risk of developing tuberculosis.
CI  - (c) The Author(s) 2022. Published by Oxford University Press.
FAU - Tervi, Anniina
AU  - Tervi A
AUID- ORCID: 0000-0002-9857-2132
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Junna, Nella
AU  - Junna N
AUID- ORCID: 0000-0002-5953-5523
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Broberg, Martin
AU  - Broberg M
AUID- ORCID: 0000-0002-5419-9479
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Jones, Samuel E
AU  - Jones SE
AUID- ORCID: 0000-0003-0153-922X
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
CN  - FinnGen
FAU - Strausz, Satu
AU  - Strausz S
AUID- ORCID: 0000-0001-6778-4848
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Kreivi, Hanna-Riikka
AU  - Kreivi HR
AUID- ORCID: 0000-0002-9361-8322
AD  - Department of Pulmonology, University of Helsinki and Helsinki University 
      Hospital, Helsinki, Finland.
FAU - Heckman, Caroline A
AU  - Heckman CA
AUID- ORCID: 0000-0002-4324-8706
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
FAU - Ollila, Hanna M
AU  - Ollila HM
AUID- ORCID: 0000-0002-5302-6429
AD  - Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, 
      Helsinki, Finland.
AD  - Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General 
      Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
LA  - eng
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
MH  - Humans
MH  - *Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - *Tuberculosis/genetics
MH  - HLA-DQ beta-Chains/genetics
MH  - HLA-DRB1 Chains/genetics
MH  - Haplotypes/genetics
MH  - Risk Factors
MH  - Alleles
MH  - Gene Frequency
PMC - PMC9838093
FIR - Partinen, Markku
IR  - Partinen M
FIR - Pirinen, Matti
IR  - Pirinen M
FIR - Bryson, Bryan
IR  - Bryson B
EDAT- 2022/08/27 06:00
MHDA- 2023/01/17 06:00
PMCR- 2022/08/26
CRDT- 2022/08/26 13:22
PHST- 2022/02/25 00:00 [received]
PHST- 2022/07/27 00:00 [revised]
PHST- 2022/08/23 00:00 [accepted]
PHST- 2022/08/27 06:00 [pubmed]
PHST- 2023/01/17 06:00 [medline]
PHST- 2022/08/26 13:22 [entrez]
PHST- 2022/08/26 00:00 [pmc-release]
AID - 6677343 [pii]
AID - ddac212 [pii]
AID - 10.1093/hmg/ddac212 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2023 Jan 1;32(1):161-171. doi: 10.1093/hmg/ddac212.