title: Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene.
abstract: BACKGROUND
  Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut-off level for serum bile acid (> or =40 micromol/l) was determined for increased risk of fetal complications.
  
  
  OBJECTIVE
  To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP-binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy.
  
  
  METHODS
  For genetic analysis, 52 women with bile acid levels > or =40 micromol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing.
  
  
  RESULTS
  In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at-risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012).
  
  
  CONCLUSIONS
  Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.
authors.affiliation: Third Department of Medicine, University Hospital Aachen, Germany.
authors.forename: H E
authors.initials: HE
authors.lastname: Wasmuth
authors.forename: A
authors.initials: A
authors.lastname: Glantz
authors.forename: H
authors.initials: H
authors.lastname: Keppeler
authors.forename: E
authors.initials: E
authors.lastname: Simon
authors.forename: C
authors.initials: C
authors.lastname: Bartz
authors.forename: W
authors.initials: W
authors.lastname: Rath
authors.forename: L-A
authors.initials: LA
authors.lastname: Mattsson
authors.forename: H-U
authors.initials: HU
authors.lastname: Marschall
authors.forename: F
authors.initials: F
authors.lastname: Lammert
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008111:Liver Function Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: C093491:ABCB11 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C095122:multidrug resistance protein 3