title: Identification of combined genetic determinants of liver stiffness within the SREBP1c-PNPLA3 pathway.
abstract: The common PNPLA3 (adiponutrin) variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c), we investigate two common SREBP1c variants (rs2297508 and rs11868035) for their association with liver stiffness. In 899 individuals (aged 17-83 years, 547 males) with chronic liver diseases, hepatic fibrosis was non-invasively phenotyped by transient elastography (TE). The SREBP1c single nucleotide polymorphisms (SNPs) were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection. The SREBP1c rs11868035 variant affected liver fibrosis significantly (p = 0.029): median TE levels were 7.2, 6.6 and 6.0 kPa in carriers of (TT) (n = 421), (CT) (n = 384) and (CC) (n = 87) genotypes, respectively. Overall, the SREBP1c SNP was associated with low TE levels (5.0-8.0 kPa). Carriers of both PNPLA3 and SREBP1c risk genotypes displayed significantly (p = 0.005) higher median liver stiffness, as compared to patients carrying none of these variants. The common SREBP1c variant may affect early stages of liver fibrosis. Our study supports a role of the SREBP1c-PNPLA3 pathway as a "disease module" that promotes hepatic fibrogenesis.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg 66421, Germany. frank.lammert@uks.eu.
authors.forename: Marcin
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D055815:Young Adult; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; D051780:Sterol Regulatory Element Binding Protein 1; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent