title: Variant adiponutrin confers genetic protection against cholestatic itch.
abstract: Lysophosphatidic acid (LPA) mediates cholestatic pruritus. Recently the enzyme PNPLA3, expressed in liver and skin, was demonstrated to metabolise LPA. Here we assess the association of the PNPLA3 variant p.Ile148Met, known to be associated with (non-)alcoholic fatty liver disease (NAFLD) in genome-wide association studies, with cholestatic itch in 187 patients with primary biliary cirrhosis (PBC) and 250 PBC-free controls as well as 201 women with intrahepatic cholestasis of pregnancy (ICP) and 198 female controls without a history of ICP. Our hypothesis was that the intensity of cholestatic itch differs in carriers of distinct PNPLA3 p.Ile148Met genotypes. Patients with PBC carrying the allele p.148Met that confers an increased NAFLD risk reported less itching than carriers of the p.148Ile allele (ANOVA P = 0.048). The PNPLA3 p.148Ile allele increased the odds of requiring plasmapheresis for refractory pruritus (OR = 3.94, 95% CI = 0.91-17.00, P = 0.048). In line with these findings, the PNPLA3 p.148Met allele was underrepresented in the ICP cohort (OR = 0.66, 95% CI = 0.47-0.92, P = 0.013). Notwithstanding the need for further replication of these findings, we conclude that the PNPLA3 allele p.148Met might confer protection against cholestatic pruritus, possibly due to increased LPA-acyltransferase activity in liver and/or skin.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
authors.forename: Marcin
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Milkiewicz
authors.affiliation: Sahlgrenska Academy, Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum Saarbrücken, Saarbrücken, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Bartz
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.affiliation: Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wunsch
authors.affiliation: 1] Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland [2] Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland [3].
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.affiliation: 1] Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany [2].
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002780:Cholestasis, Intrahepatic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications; D011537:Pruritus / Q000235:genetics* / Q000473:pathology; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008246:Lysophospholipids; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent; C032881:lysophosphatidic acid