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A Comprehensive Analysis of Common Genetic Variation Around Six Candidate Loci for Intrahepatic Cholestasis of Pregnancy

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Peter H Dixon, Christopher A Wadsworth, Jennifer Chambers, Jennifer Donnelly, Sharon Cooley, Rebecca Buckley, Ramona Mannino, Sheba Jarvis, Argyro Syngelaki, Victoria Geenes, Priyadarshini Paul, Meera Sothinathan, Ralf Kubitz, Frank Lammert, Rachel M Tribe, Chin Lye Ch'ng, Hanns-Ulrich Marschall, Anna Glantz, Shahid A Khan, Kypros Nicolaides & 3 more John Whittaker, Michael Geary, Catherine Williamson

Original languageEnglish
Pages (from-to)76-84
Number of pages9
JournalThe American Journal of Gastroenterology
Volume109
Early online date24 Dec 2013
DOIs
Publication statusPublished - Jan 2014

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Abstract

OBJECTIVES: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.Am J Gastroenterol advance online publication, 24 December 2013; doi:10.1038/ajg.2013.406.

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