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Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians
Author(s) -
Stickel Felix,
Buch Stephan,
Lau Katharina,
zu Schwabedissen Henriette Meyer,
Berg Thomas,
Ridinger Monika,
Rietschel Marcella,
Schafmayer Clemens,
Braun Felix,
Hinrichsen Holger,
Günther Rainer,
Arlt Alexander,
Seeger Marcus,
Müller Sebastian,
Seitz Helmut Karl,
Soyka Michael,
Lerch Markus,
Lammert Frank,
Sarrazin Christoph,
Kubitz Ralf,
Häussinger Dieter,
Hellerbrand Claus,
Bröring Dieter,
Schreiber Stefan,
Kiefer Falk,
Spanagel Rainer,
Mann Karl,
Datz Christian,
Krawczak Michael,
Wodarz Norbert,
Völzke Henry,
Hampe Jochen
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24017
Subject(s) - alcoholic liver disease , medicine , cirrhosis , gastroenterology , steatosis , fatty liver , genotype , population , liver disease , hepatology , liver injury , alcoholic hepatitis , allele frequency , allele , biology , genetics , disease , gene , environmental health
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%. Conclusion: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians. (H EPATOLOGY 2011)