Petrographische und geochemische Provenanz-Indikatoren der Hochwipfel Formation (Karbon, Karawanken) / Petrographie and geochemical provenance indicators of the Carboniferous Hochwipfel Formation (Karawanken Mountains)

In the eastern Karawanken Mountains, the siliciclastic sedimentary succession of the Hochwipfel Formation was deposited within a narrow marginal basin of the western Paleotethys. Variations of detrital sandstone modes define four petrofacies types, and allow the succession to be stratigraphically divided into Lower and Upper Hochwipfel Formation. Petrographical and geochemical provenance analysis indicate that the basal quartz-rich sandstones derived mainly from the Intraalpine Terrane in the north and the passive Gondwana margin in the south. In the sediments of the Upper Hochwipfel Formation, an increase of (meta)sedimentary as well as of magmatic lithoclasts is discernible indicating a convergent tectonic situation and increased sediment supply derived from a magmatic arc. Zusammenfassung: Die klastische Sedimentabfolge der karhonen HochwipfelFormation der Ostkarawanken wurde in einem schmalen Randbecken der westlichen Paläotethys abgelagert. Auf Grund der Modalzusammensetzung der Sandsteine lassen sich vier Petrofaziestypen unterscheiden, und die sedimentäre Abfolge in eine Untere und eine Obere Hochwipfel-Formation gliedern. Petrographische und geochemische Provenienz-Indikatoren deuten darauf hin, dass die basalen quarzreichen Sandsteine der unteren Hochwipfel-Formation überwiegend von dem nördlich gelegenen Intraalpinen Terran bzw. dem südlich gelegenen passiven Kontinentalrand Gondwanas stammen. In den Sedimenten der oberen Hochwipfel-Formation ist eine Zunahme von (meta)sedimentären Lithoklasten sowie magmatischen Gesteinsbruchstücken zu beobachten. Dies zeigt den Übergang zu einer konvergenten tektonischen Situation und den verstärkten Sedimenteintrag aus einem magmatischen Bogen an

The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.

BACKGROUND: An isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC). METHODS: We compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection. RESULTS: PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p = 0.545) and HCC (30.2%; p = 0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68-42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24-6.42; p = 0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50-11.52; p = 0.006). CONCLUSION: The PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should be taken into account in future HCC prevention studies

Frequencies of the <i>PNPLA3</i> rs738409 alleles in the study groups.

<p>This figure illustrates the frequencies of the 148I (grey part of columns) and 148M (dark part of columns) alleles of the <i>PNPLA3</i> (rs738409) polymorphism in patients with HCV-associated and alcohol-related HCC, patients with alcoholic and HCV-related cirrhosis, who do not have liver cancer, and healthy controls, respectively. Differences between the groups were compared by chi²-statistics.</p

Distribution of <i>PNPLA3</i> rs738409 (I148M) variants.

<p><b>Significance and odds ratios for the heterozygous genotype (I/M)</b>.</p><p>Alcoholic cirrhosis with HCC versus HCV/HCC:   2.852; 95%-CI (1.373–5.925); p<0.005.</p><p>Alcoholic cirrhosis with HCC versus HCV cirrhosis without HCC: 3.416; 95%-CI (1.648–7.080); p<0.001.</p><p>Alcoholic cirrhosis with HCC versus healthy controls:  3.819; 95%-CI (2.010–7.257); p<0.001.</p><p>Alcoholic cirrhosis without HCC versus healthy controls:  1.928; 95%-CI (1.103–3.367); p = 0.020.</p><p><b>Significance and odds ratios for the homozygous genotype (M/M)</b>.</p><p>Alcoholic cirrhosis with HCC versus alcoholic cirrhosis without HCC: 4.329; 95%-CI (1.679–11.16); p<0.002.</p><p>Alcoholic cirrhosis with HCC versus HCV/HCC:   6.765; 95%-CI (2.528–18.11); p<0.001.</p><p>Alcoholic cirrhosis with HCC versus HCV cirrhosis without HCC: 12.18; 95%-CI (3.987–37.19); p<0.001.</p><p>Alcoholic cirrhosis with HCC versus healthy controls:  16.84; 95%-CI (6.682–42.43); p<0.001.</p><p>Alcoholic cirrhosis without HCC versus healthy controls:  3.889; 95%-CI (1.456–10.39); p<0.005.</p><p><b>Significance and odds ratios for the minor allele frequencies</b>.</p><p>Alcoholic cirrhosis with HCC versus alcoholic cirrhosis without HCC: 2.281; 95%-CI (1.466–3.551); p<0.001.</p><p>Alcoholic cirrhosis with HCC versus HCV/HCC:   2.680; 95%-CI (1.697–4.233); p<0.001.</p><p>Alcoholic cirrhosis with HCC versus HCV cirrhosis without HCC: 3.430; 95%-CI (2.141–5.494); p<0.001.</p><p>Alcoholic cirrhosis with HCC versus healthy controls:  4.369; 95%-CI (2.969–6.429); p<0.001.</p><p>Alcoholic cirrhosis without HCC versus HCV cirrhosis without HCC: 1.678; 95%-CI (1.040–2.709); p = 0.033.</p><p>Alcoholic cirrhosis without HCC versus healthy controls:  1.915; 95%-CI (1.282–2.861); p<0.002.</p

Demographic and Clinical Data of the Study Groups.

<p>Demographic and Clinical Data of the Study Groups.</p

Regression analysis of putative HCC risk factors in alcoholic cirrhosis.

<p>*including all significant parameters from the univariate analysis (<i>PNPLA3</i> 148MM genotype).</p><p>CI, confidence interval; OR, odds ratio.</p