Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis
File(s)
Accepted version
Author(s)
Atkinson, SR
Way, MJ
McQuillin, A
Morgan, MY
Thursz, MR
Type
Journal Article
Abstract
Background & Aims: Carriage of rs738409:G in PNPLA3 is associated
with an increased risk of developing alcohol-related cirrhosis
and has a significant negative effect on survival. Short-term mortality
in patients with severe alcoholic hepatitis is high; drinking behaviour
is a major determinant of outcome in survivors. The aim of
this study was to determine whether carriage of rs738409:G has
an additional detrimental effect on survival in this patient group.
Methods: Genotyping was undertaken in 898 cases with severe
alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline
for Alcoholic Hepatitis (STOPAH) trial, and 1188 White
British/Irish alcohol dependent controls with no liver injury,
recruited via University College London. Subsequent drinking
behaviour was classified, in cases surviving 90 days, as abstinent
or drinking. The relationship between rs738409 genotype,
drinking behaviour and survival was explored.
Results: The frequency of rs738409:G was significantly higher in
cases than controls (29.5% vs. 18.9%; p = 2.15 10 15; odds ratio
1.80 [95% confidence interval (CI) 1.55–2.08]). Case-mortality at
days 28, 90 and 450 was 16%, 25% and 41% respectively. There
was no association between rs738409:G and 28-day mortality.
Mortality in the 90 to 450-day period was higher in survivors
who subsequently resumed drinking (hazard ratio [HR] 2.77,
95% CI 1.79–4.29; p <0.0001) and in individuals homozygous for
rs738409:G (HR 1.69, 95% CI 1.02–2.81, p = 0.04).
Conclusion: Homozygosity for rs738409:G in PNPLA3 confers significant
additional risk of medium-term mortality in patients with
severe alcoholic hepatitis. Rs738409 genotype may be taken into
account when considering treatment options for these patients.
Lay summary: Individuals misusing alcohol who carry a particular
variant of the gene PNPLA3 are more at risk of developing severe
alcoholic hepatitis, a condition with a poor chance of survival.
The longer-term outcome in people with this condition who survive
the initial illness is strongly influenced by their ability to
remain abstinent from alcohol. However, carriers of this gene
variant are less likely to survive even if they are able to stop
drinking completely. Knowing if someone carries this gene variant
could influence the way in which they are managed.
with an increased risk of developing alcohol-related cirrhosis
and has a significant negative effect on survival. Short-term mortality
in patients with severe alcoholic hepatitis is high; drinking behaviour
is a major determinant of outcome in survivors. The aim of
this study was to determine whether carriage of rs738409:G has
an additional detrimental effect on survival in this patient group.
Methods: Genotyping was undertaken in 898 cases with severe
alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline
for Alcoholic Hepatitis (STOPAH) trial, and 1188 White
British/Irish alcohol dependent controls with no liver injury,
recruited via University College London. Subsequent drinking
behaviour was classified, in cases surviving 90 days, as abstinent
or drinking. The relationship between rs738409 genotype,
drinking behaviour and survival was explored.
Results: The frequency of rs738409:G was significantly higher in
cases than controls (29.5% vs. 18.9%; p = 2.15 10 15; odds ratio
1.80 [95% confidence interval (CI) 1.55–2.08]). Case-mortality at
days 28, 90 and 450 was 16%, 25% and 41% respectively. There
was no association between rs738409:G and 28-day mortality.
Mortality in the 90 to 450-day period was higher in survivors
who subsequently resumed drinking (hazard ratio [HR] 2.77,
95% CI 1.79–4.29; p <0.0001) and in individuals homozygous for
rs738409:G (HR 1.69, 95% CI 1.02–2.81, p = 0.04).
Conclusion: Homozygosity for rs738409:G in PNPLA3 confers significant
additional risk of medium-term mortality in patients with
severe alcoholic hepatitis. Rs738409 genotype may be taken into
account when considering treatment options for these patients.
Lay summary: Individuals misusing alcohol who carry a particular
variant of the gene PNPLA3 are more at risk of developing severe
alcoholic hepatitis, a condition with a poor chance of survival.
The longer-term outcome in people with this condition who survive
the initial illness is strongly influenced by their ability to
remain abstinent from alcohol. However, carriers of this gene
variant are less likely to survive even if they are able to stop
drinking completely. Knowing if someone carries this gene variant
could influence the way in which they are managed.
Date Issued
2017-02-02
Date Acceptance
2017-01-13
Citation
Journal of Hepatology, 2017, 67 (1), pp.120-127
ISSN
1600-0641
Publisher
Elsevier
Start Page
120
End Page
127
Journal / Book Title
Journal of Hepatology
Volume
67
Issue
1
Copyright Statement
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000403335600017&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
MR/M003132/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
Alcohol dependence
Hepatitis, alcoholic
Liver cirrhosis, alcoholic
Genetic polymorphism
PNPLA3
Genotype
Prednisolone
Prognostic scores
Risk allele
Survival
HEPATOCELLULAR-CARCINOMA OCCURRENCE
STAGE LIVER-DISEASE
GREATER-THAN-G
NATURAL-HISTORY
TERM SURVIVAL
CIRRHOSIS
RISK
METAANALYSIS
VARIANT
POLYMORPHISM
Genetic polymorphism, PNPLA3
1103 Clinical Sciences
Publication Status
Published