title: A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.
abstract: OBJECTIVE
  Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).
  
  
  METHODS
  ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case-control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test.
  
  
  RESULTS
  Cochran-Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10(-4) (rs3815676) and for ABCB4 it was 4.6×10(-7)(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings.
  
  
  CONCLUSIONS
  Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.
authors.affiliation: 1] Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK [2] Present address: Division of Women's Health, King's College London, London, UK.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dixon
authors.affiliation: Hepatology and Gastroenterology Section, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wadsworth
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chambers
authors.affiliation: The Rotunda Hospital, Dublin, Ireland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Donnelly
authors.affiliation: The Rotunda Hospital, Dublin, Ireland.
authors.forename: Sharon
authors.initials: S
authors.lastname: Cooley
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buckley
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Ramona
authors.initials: R
authors.lastname: Mannino
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Sheba
authors.initials: S
authors.lastname: Jarvis
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.
authors.forename: Argyro
authors.initials: A
authors.lastname: Syngelaki
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Geenes
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Paul
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: Meera
authors.initials: M
authors.lastname: Sothinathan
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kubitz
authors.affiliation: Department of Medicine II, Saarland University Medical Centre, Homburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.affiliation: Division of Women's Health, King's College London, London, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Tribe
authors.affiliation: Department of Gastroenterology, Singleton Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, UK.
authors.forename: Chin Lye
authors.initials: CL
authors.lastname: Ch'ng
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: Antenatal Care, Gothenburg, Primärvårdskansliet, Hisings Backa, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Glantz
authors.affiliation: Hepatology and Gastroenterology Section, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Shahid A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.
authors.forename: Kypros
authors.initials: K
authors.lastname: Nicolaides
authors.affiliation: 1] London School of Hygiene and Tropical Medicine, University of London, London, UK [2] Quantitative Sciences, GlaxoSmithKline, Stevenage, UK.
authors.forename: John
authors.initials: J
authors.lastname: Whittaker
authors.affiliation: The Rotunda Hospital, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Geary
authors.affiliation: 1] Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery and Cancer, Imperial College London, London, UK [2] Present address: Division of Women's Health, King's College London, London, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
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*; D016022:Case-Control Studies; D002780:Cholestasis, Intrahepatic / Q000208:ethnology / Q000235:genetics*; D005060:Europe; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000208:ethnology / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000089762:Multidrug Resistance-Associated Protein 2; C095122:multidrug resistance protein 3