Z Gastroenterol 2012; 50 - P1_26
DOI: 10.1055/s-0031-1295756

Identification of a novel genetic risk factor for liver fibrosis within the adiponutrin (PNPLA3) pathway: elastography-based study in patients with chronic liver diseases

M Krawczyk 1, MG Mahler 1, F Lammert 2, F Grünhage 3
  • 1Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg
  • 2Universitätsklinikum des Saarlandes, Homburg, Deutschland
  • 3Klinik für Innere Medizin II, Homburg

Aims: Lately we have identified the p.I148M adiponutrin (PNPLA3) variant as common genetic risk factor for liver fibrosis1. In humans, PNPLA3 expression is induced by sterol regulatory element binding protein 1c (SREBP1c). Here we investigate two SREBP1c variants (rs2297508 and rs11868035), recently associated with insulin resistance and diabetes2, as genetic determinants for hepatic fibrosis.

Patients and methods: We recruited 899 individuals (age 20–86 years, 548 males) with chronic liver diseases (CLD). Liver status was non-invasively phenotyped by transient elastography (TE, Fibroscan). SREBP1c single nucleotide polymorphisms (SNPs) were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection.

Results: The rs11868035 genotypes were associated with liver fibrosis: Median fibrosis levels differed significantly (ANOVA P=0.01), between [TT] (n=419, median TE 7.2 kPa, range 2.2–75.0), [CT] (n=380, median TE 6.6 kPa, range 2.9–75.0) and [CC] (n=100, median TE 6.0 kPa, range 2.3–73.5) carriers. Comparison of individuals with mild (i.e. TE < 7 kPa, n=480) and enhanced (TE ≥ 7 kPa, n=419) fibrosis showed association of the SNP and TE levels (OR=1.34, P=0.004, 95% CI 1.10–1.63). After inclusion of the PNPLA3 p.I148M variant1 and age in multivariate models, both SREBP1c and PNPLA3 variants as well as age significantly (P=0.03, P=0.004 and P < 0.001, respectively) increased liver fibrosis. Nevertheless, the SNP did not augment the risk of cirrhosis (as displayed by TE levels ≥ 13.0 kPa). Carriers of both PNPLA3 risk [GG] genotype1 and the SREBP1c [T] allele (n=54) displayed significantly (P < 0.05) higher TE levels as compared to patients with other genotypes (median TE 7.7 vs. 6.7 kPa).

Conclusions: The common SREBP1c polymorphism significantly influences early stages of liver fibrosis in individuals with CLD. These findings point to a crucial role of the SREBP1c–PNPLA3 pathway in hepatic fibrogenesis in humans.

Literatur: 1. Krawczyk et al. J Hepatol 2011. 2. Liu et al. Diabetes Res Clin Pract 2008.

adiponutrin - genetic polymorphism - liver fibrosis