PMID- 35905417
OWN - NLM
STAT- MEDLINE
DCOM- 20220802
LR  - 20231102
IS  - 2155-384X (Electronic)
IS  - 2155-384X (Linking)
VI  - 13
IP  - 7
DP  - 2022 Jul 1
TI  - Whole Exome Sequencing Reveals Genetic Variants in HLA Class II Genes Associated 
      With Transplant-free Survival of Indeterminate Acute Liver Failure.
PG  - e00502
LID - 10.14309/ctg.0000000000000502 [doi]
LID - e00502
AB  - INTRODUCTION: Indeterminate acute liver failure (IND-ALF) is a rare clinical 
      syndrome with a high mortality rate. Lacking a known etiology makes rapid 
      evaluation and treatment difficult, with liver transplantation often considered 
      as the only therapeutic option. Our aim was to identify genetic variants from 
      whole exome sequencing data that might be associated with IND-ALF clinical 
      outcomes. METHODS: Bioinformatics analysis was performed on whole exome 
      sequencing data for 22 patients with IND-ALF. A 2-tier approach was used to 
      identify significant single-nucleotide polymorphisms (SNPs) associated with 
      IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk 
      in the IND-ALF population compared with those identified in control populations. 
      Tier 2 determined the SNPs connected to transplant-free survival and associated 
      with model for end-stage liver disease serum sodium and Acute Liver Failure Study 
      Group prognostic scores. RESULTS: Thirty-one SNPs were found associated with a 
      higher relative risk in the IND-ALF population compared with those in controls, 
      of which 11 belong to the human leukocyte antigen (HLA) class II genes but none 
      for the class I. Further analysis showed that 5 SNPs: rs796202376, rs139189937, 
      and rs113473719 of HLA-DRB5; rs9272712 of HLA-DQA1; and rs747397929 of IDO1 were 
      associated with a higher probability of IND-ALF transplant-free survival. Using 3 
      selected SNPs, a model for the polygenic risk score was developed to predict 
      IND-ALF prognoses, which are comparable with those by model for end-stage liver 
      disease serum sodium and Acute Liver Failure Study Group prognostic scores. 
      DISCUSSION: Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found 
      associated with IND-ALF transplant-free survival. Once validated, these 
      identified SNPs may help elucidate the mechanism of IND-ALF and assist in its 
      diagnosis and management.
CI  - Copyright (c) 2022 Written work prepared by employees of the Federal Government as 
      part of their official duties is, under the U.S. Copyright Act, a "work of the 
      United States Government" for which copyright protection under Title 17 of the 
      United States Code is not available. As such, copyright does not extend to the 
      contributions of employees of the Federal Government.
FAU - Liao, Tsung-Jen
AU  - Liao TJ
AD  - Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration 
      (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA.
FAU - Pan, Bohu
AU  - Pan B
AD  - Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration 
      (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA.
FAU - Hong, Huixiao
AU  - Hong H
AD  - Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration 
      (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA.
FAU - Hayashi, Paul
AU  - Hayashi P
AD  - Division of Hepatology and Nutrition, Office of New Drugs, FDA Center for Drug 
      Evaluation and Research, Silver Spring, Maryland, USA.
FAU - Rule, Jody A
AU  - Rule JA
AD  - Division of Gastroenterology and Hepatology, University of Texas Southwestern, 
      Dallas, Texas, USA.
FAU - Ganger, Daniel
AU  - Ganger D
AD  - Division of Gastroenterology and Hepatology, Northwestern University, Chicago, 
      Illinois, USA.
FAU - Lee, William M
AU  - Lee WM
AD  - Division of Gastroenterology and Hepatology, University of Texas Southwestern, 
      Dallas, Texas, USA.
FAU - Rakela, Jorge
AU  - Rakela J
AD  - Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA.
FAU - Chen, Minjun
AU  - Chen M
AD  - Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration 
      (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA.
LA  - eng
GR  - R01 DK058369/DK/NIDDK NIH HHS/United States
GR  - U01 DK058369/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20220602
PL  - United States
TA  - Clin Transl Gastroenterol
JT  - Clinical and translational gastroenterology
JID - 101532142
RN  - 0 (HLA-DRB5 Chains)
RN  - 9NEZ333N27 (Sodium)
SB  - IM
MH  - *End Stage Liver Disease
MH  - Genes, MHC Class II
MH  - HLA-DRB5 Chains/genetics
MH  - Humans
MH  - *Liver Failure, Acute/diagnosis/genetics/surgery
MH  - Severity of Illness Index
MH  - Sodium
MH  - Exome Sequencing
PMC - PMC10476814
COIS- Guarantor of the article: Minjun Chen, PhD. Specific author contributions: 
      Conception: M.C. and J.R. Data collection: J.R. Data analysis and interpretation: 
      T.J., B.P., H.H., P.H., J.R., D.G., W.L., J.R., and M.C. Manuscript draft: T.J. 
      and M.C. Revision and review: M.C., J.R., T.J., B.P., H.H., P.H., J.R., D.G., and 
      W.L. Financial support: None to report. Potential competing interests: None to 
      report.
EDAT- 2022/07/30 06:00
MHDA- 2022/08/03 06:00
PMCR- 2022/06/02
CRDT- 2022/07/29 15:32
PHST- 2022/02/16 00:00 [received]
PHST- 2022/05/17 00:00 [accepted]
PHST- 2022/07/29 15:32 [entrez]
PHST- 2022/07/30 06:00 [pubmed]
PHST- 2022/08/03 06:00 [medline]
PHST- 2022/06/02 00:00 [pmc-release]
AID - 01720094-202207000-00013 [pii]
AID - CTG-22-0069 [pii]
AID - 10.14309/ctg.0000000000000502 [doi]
PST - ppublish
SO  - Clin Transl Gastroenterol. 2022 Jul 1;13(7):e00502. doi: 
      10.14309/ctg.0000000000000502. Epub 2022 Jun 2.