barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
36 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 37
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
These are TNFα -238A (10) and PNPLA3 rs738409, of which only the latter is supported by robust and
unequivocal data (Table 2). Together, data on PNPLA3 allow for the conclusion that PNPLA3 rs738409 GG
carriers represent a genetically defined subpopulation of high risk subjects susceptible to progression of
clinically inapparent to overt ALD. Whether PNPLA3 genotype represents a marker that will assist decisionmaking
in clinical practice remains to be shown, as well as whether it could serve as a therapeutic target.
Table 2
Study Design Patients Results
Tian et al. *
Seth et al. *
Trépo et al. *
Stickel et al. *
Genetic case control
482 cases (alcoholic
cirrhosis) (Mestizo
subjects with strong
ethnic heterogeneity)
Genetic case control
(British
Caucasians)
Genetic case control
(Belgium Caucasians)
Genetic case control
(German Caucasians)
482 cases (alcoholic cirrhosis)
434 non-cirrhotic ALD
305 alcoholics w/o liver
enzyme elevations
266 cases (alcoholic cirrhosis)
182 controls (heavy drinkers
w/o clinical ALD)
330 cases (97% biopsyproven
ALD; 263 cirrhotics)
328 controls (healthy
individuals without ALD)
Multicenter sample with 1,043
alcoholics (210 cirrhosis,
394 non-cirrhotic ALD, 439
alcoholic controls
Population-based sample
with 376 alcoholics (269 noncirrhotic
ALD, 107 alcoholic
controls)
Non-alcoholic healthy
subjects (n=162)
rs738409 GG associated with cirrhosis
when compared to controls (OR 2.25, 1.74-
2.9; 1.7 x 10 -10 ) and to non-cirrhotic ALD
(OR 1.43, 1.15-1.78, 1.0 x 10 -3 )
Association robust after ancestry correction
(OR 1.81, 1.36-2.41; 4.7 x 10 -5 )
rs738409 G homozygosity associated with
alcoholic cirrhosis (OR 7.34, 2.19-24.52,
p=0.0012)
Carriage of rs738409 G allele associated
with alcoholic cirrhosis (OR 1.95, 1.34-
2.84, p=0.00002)
rs738409 G associated with ALD (OR 1.54;
1.12-2.11, p=0.008) and alcoholic cirrhosis
(OR 2.08; 1.15-3.77, p=0.02)
PNPLA mRNA expression inversely
correlated with cirrhosis and portal
pressure
Genotype rs738409 GG associated with
alcoholic cirrhosis (OR 2.79, 1.55-5.04,
p=1.18 x 10 -5 , cirrhosis vs. controls)
Genotype rs738409 GG associated with
alanine aminotransferase elevation (OR
2.33, 1.27-4.26, p=0.0085)
Confirmation of association in separate
replication sample (OR 4.75, 1.08-20.9,
p=0.04, ALD vs alcoholic controls)
Population-attributable risk of rs738409 to
cirrhosis 26.6%
However, still lacking are data from genome-wide analyses in ALD patients similar to what has been carried
out in other chronic liver diseases. Conducting this kind of global scan would not only help to confirm PNPLA3
rs738409 as an important susceptibility marker of ALD, but also potentially identify novel, yet unkown genetic
variants for better screening of patients, and subsequent clinical and experimental research. Despite the
noted limitations, functional pathway information and the genetic risk factors of ALD start to converge into a
common etiopathogenetic concept allowing for a better understanding of this serious disorder in the future.
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* For full reference, please see ref. 11.