Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.
A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 × 10(-5) ; P(allelic) = 1.6 × 10(-6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%.


CONCLUSIONS
Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.
Institute of Clinical Pharmacology and Visceral Research, University of Bern, Bern, Switzerland.
Felix
F
Stickel
Stephan
S
Buch
Katharina
K
Lau
Henriette
H
Meyer zu Schwabedissen
Thomas
T
Berg
Monika
M
Ridinger
Marcella
M
Rietschel
Clemens
C
Schafmayer
Felix
F
Braun
Holger
H
Hinrichsen
Rainer
R
Günther
Alexander
A
Arlt
Marcus
M
Seeger
Sebastian
S
Müller
Helmut Karl
HK
Seitz
Michael
M
Soyka
Markus
M
Lerch
Frank
F
Lammert
Christoph
C
Sarrazin
Ralf
R
Kubitz
Dieter
D
Häussinger
Claus
C
Hellerbrand
Dieter
D
Bröring
Stefan
S
Schreiber
Falk
F
Kiefer
Rainer
R
Spanagel
Karl
K
Mann
Christian
C
Datz
Michael
M
Krawczak
Norbert
N
Wodarz
Henry
H
Völzke
Jochen
J
Hampe
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000437:Alcoholism / Q000235:genetics; D005235:Fatty Liver, Alcoholic / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005858:Germany; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D000410:Alanine Transaminase; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent