Z Gastroenterol 2010; 48 - V34
DOI: 10.1055/s-0030-1263388

Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians

F Stickel 1, S Buch 2, K Lau 3, HM zu Schwabedissen 4, T Berg 5, M Ridinger 6, S Wiegandt 6, M Rietschel 7, C Schafmayer 8, F Braun 8, H Hinrichsen 9, R Günther 9, A Arlt 9, M Seeger 9, S Müller 10, HK Seitz 10, M Soyka 11, M Lerch 12, F Lammert 13, C Sarrazin 14, S Zeuzem 14, R Kubitz 15, D Häussinger 15, C Hellerbrand 16, J Schölmerich 16, D Bröring 8, S Schreiber 9, R Spanagel 7, K Mann 7, M Krawczak 17, N Wodarz 6, H Völzke 3, J Hampe 9
  • 1University of Berne, Institute of Clinical Pharmacology and Visceral Research, Bern, Switzerland
  • 2UKSH-Kiel, 1. Medizinische Klinik, Kiel, Germany
  • 3University Hospital Greifswald, Department of Community Medicine, Greifswald, Germany
  • 4University Hospital Greifswald, Department of Pharmacology, Greifswald, Germany
  • 5University Hospital Leipzig, Department of Gastroenterology, Leipzig, Germany
  • 6University of Regensburg, Department of Psychiatry, Regensburg, Germany
  • 7University of Heidelberg, Central Institute of Mental Health, Mannheim, Germany
  • 8University Hospital Schleswig-Holstein, Department of General and Thoracic Surgery, Kiel, Germany
  • 9University Hospital Schleswig-Holstein, Department of Internal Medicine I, Kiel, Germany
  • 10University of Heidelberg, Salem Medical Center, Heidelberg, Germany
  • 11Psychiatric Hospital Meiringen, Meiringen, Switzerland
  • 12University Hospital Greifswald, Department of Gastroenterology, Greifswald, Germany
  • 13University Hospital Homburg, Department of Gastroenterology, Homburg, Germany
  • 14University Hospital Frankfurt, Department of Internal Medicine I, Frankfurt, Germany
  • 15University Hospital Düsseldorf, Department of Gastroenterology, Düsseldorf, Germany
  • 16University Hospital Regensburg, Department of Gastroenterology, Regensburg, Germany
  • 17University Hospital Schleswig-Holstein, Institute of Medical Informatics and Statistics, Kiel, Germany

Background and Aims: A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, PNPLA3 single nucleotide polymorphism (SNP) 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.

Methods: Genotype and allele frequencies of PNPLA3 SNP rs738409 (M148I) were determined in 1043 clinical alcoholics with or without alcoholic liver injury and in 376at-risk drinkers from a population-based cohort.

Results: Relative to alcoholics without liver damage (N=439), rs738409 genotype GG was strongly over-represented in patients with alcoholic liver cirrhosis (N=210, OR=2.79, Pgenotype=1.2×10-5, Pallelic=1.6×10-6) and in non-cirrhotic alcoholics with elevated alanine aminotransferase (N=219, OR=2.33, Pgenotype=0.0085, Pallelic=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 300g/week (OR=4.75, Pgenotype=0.040, Pallelic=0.022). The combined frequency in both cohorts of allele G was lower among individuals with steatosis and normal alanine aminotransferase (ALT) levels than among those without steatosis and normal ALT (Pallelic=0.032). The population-attributable risk for cirrhosis of alcoholics was estimated to be 3.5% for homozygosity and 26.7% for carriership of the G allele of rs738409.

Conclusion: In Caucasian alcoholics, the GG genotype of PNPLA3 SNP rs738409 is associated with alcoholic liver cirrhosis and an increase of ALT.