Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component.
Heterozygous mutations of canalicular transporters occur in a subset of intrahepatic cholestasis of pregnancy cases and a population susceptibility allele (p.444A) has been identified in ABCB11.
Dr Dixon and colleagues from the United Kingdom investigated common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).
The team analyzed 563 intrahepatic cholestasis of pregnancy patients of white western European origin, and 642 controls in a case–control design.
Single-nucleotide polymorphism (SNP) markers were selected from the HapMap data set.
|There is a key role for common variation around the ABCB4 and ABCB11 loci|
|American Journal of Gastroenterology|
The team performed genotyping by allelic discrimination assay on a robotic platform.
Following quality control, SNP data were analyzed by Armitage's trend test.
Cochran–Armitage trend testing identified 6 SNPs in ABCB11 together with 6 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).
The team performed conditional analysis of the 2 clusters of association signals that suggested a single signal in ABCB4 but evidence for 2 independent signals in ABCB11.
To confirm these findings, the team performed a second study in a further 227 cases, which confirmed and strengthened the original findings.
Dr Dixon's team concludes, "Our analysis of a large cohort of intrahepatic cholestasis of pregnancy cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of intrahepatic cholestasis of pregnancy susceptibility."