PMID- 30681738
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20200622
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 70
IP  - 1
DP  - 2019 Jul
TI  - Alpha-1 Antitrypsin Deficiency Liver Disease, Mutational Homogeneity Modulated by 
      Epigenetic Heterogeneity With Links to Obesity.
PG  - 51-66
LID - 10.1002/hep.30526 [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) liver disease is characterized by marked 
      heterogeneity in presentation and progression, despite a common underlying gene 
      mutation, strongly suggesting the involvement of other genetic and/or epigenetic 
      modifiers. Variation in clinical phenotype has added to the challenge of 
      detection, diagnosis, and testing of new therapies in patients with AATD. We 
      examined the contribution of DNA methylation (5-methylcytosine [5mC]) to AATD 
      liver disease heterogeneity because 5mC responds to environmental and genetic 
      cues and its deregulation is a major driver of liver disease. Using liver 
      biopsies from adults with early-stage AATD and the ZZ genotype, genome-wide 5mC 
      patterns were interrogated. We compared DNA methylation among patients with early 
      AATD, and among patients with normal liver, cirrhosis, and hepatocellular 
      carcinoma derived from multiple etiologic exposures, and linked patient 
      clinical/demographic features. Global analysis revealed significant genomic 
      hypomethylation in AATD liver-impacting genes related to liver cancer, cell 
      cycle, and fibrosis, as well as key regulatory molecules influencing growth, 
      migration, and immune function. Further analysis indicated that 5mC changes are 
      localized, with hypermethylation occurring within a background of genome-wide 5mC 
      loss and with patients with AATD manifesting distinct epigenetic landscapes 
      despite their mutational homogeneity. By integrating clinical data with 5mC 
      landscapes, we observed that CpGs differentially methylated among patients with 
      AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte 
      degeneration and polymer accumulation) and further reveal links to well-known 
      sex-specific effects of liver disease progression. Conclusion: Our data reveal 
      molecular epigenetic signatures within this mutationally homogeneous group that 
      point to ways to stratify patients for liver disease risk.
CI  - (c) 2019 by the American Association for the Study of Liver Diseases.
FAU - Wang, Liguo
AU  - Wang L
AD  - Division of Biomedical Statistics and Informatics, Department of Health Science 
      Research, Mayo Clinic, Rochester, MN.
FAU - Marek, George W 3rd
AU  - Marek GW 3rd
AD  - Division of Pulmonary, Critical Care & Sleep Medicine, College of Medicine, 
      University of Florida, Gainesville, FL.
FAU - Hlady, Ryan A
AU  - Hlady RA
AUID- ORCID: 0000-0002-2829-4237
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 
      Rochester, MN.
FAU - Wagner, Ryan T
AU  - Wagner RT
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 
      Rochester, MN.
FAU - Zhao, Xia
AU  - Zhao X
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 
      Rochester, MN.
FAU - Clark, Virginia C
AU  - Clark VC
AD  - Division of Gastroenterology, Hepatology & Nutrition, University of Florida, 
      Gainesville, FL.
FAU - Fan, Alex Xiucheng
AU  - Fan AX
AD  - Division of Pulmonary, Critical Care & Sleep Medicine, College of Medicine, 
      University of Florida, Gainesville, FL.
FAU - Liu, Chen
AU  - Liu C
AD  - Department of Pathology and Laboratory Medicine, New Jersey Medical School, 
      Rutgers, The State University of New Jersey, Newark, NJ.
FAU - Brantly, Mark
AU  - Brantly M
AD  - Division of Pulmonary, Critical Care & Sleep Medicine, College of Medicine, 
      University of Florida, Gainesville, FL.
FAU - Robertson, Keith D
AU  - Robertson KD
AUID- ORCID: 0000-0002-7508-3328
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 
      Rochester, MN.
AD  - Center for Individualized Medicine Epigenomics Program, Mayo Clinic, Rochester, 
      MN.
LA  - eng
GR  - Alpha-1 Foundation/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190320
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - alpha-1-Antitrypsin Deficiency, Autosomal Recessive
SB  - IM
CIN - Hepatology. 2019 Jul;70(1):5-7. PMID: 31058323
MH  - Aged
MH  - Case-Control Studies
MH  - Cohort Studies
MH  - *DNA Methylation
MH  - Female
MH  - Humans
MH  - Liver Diseases/*etiology
MH  - Male
MH  - Middle Aged
MH  - Obesity/*complications
MH  - alpha 1-Antitrypsin Deficiency/*complications
EDAT- 2019/01/27 06:00
MHDA- 2020/06/23 06:00
CRDT- 2019/01/26 06:00
PHST- 2018/09/18 00:00 [received]
PHST- 2019/01/15 00:00 [accepted]
PHST- 2019/01/27 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/01/26 06:00 [entrez]
AID - 10.1002/hep.30526 [doi]
PST - ppublish
SO  - Hepatology. 2019 Jul;70(1):51-66. doi: 10.1002/hep.30526. Epub 2019 Mar 20.