Parallel 12: Clinical and Translational Advances in Complications of Cirrhosis

Purpose: In the Americas, women with Indigenous American ancestry are at increased risk of intrahepatic cholestasis of pregnancy (ICP).We hypothesized that ancestry-related genetic factors contribute to this increased risk, and that the statistically powerful genetic admixture mapping approach could allow mapping of an ICP susceptibility locus.We considered that diagnosis, features, and management of ICP might differ between U.S. and Chilean clinical sites.Methods: We collected patient data and performed biochemical assays and SNP genotyping on samples from U.S. Latinas and Chilean women, with and without ICP.The study sample included 198 women with ICP (90 from the U.S. and 108 from Chile) and 174 pregnant control women (69 from the U.S. and 105 from Chile).We compared overall genetic ancestry between cases and controls, and performed genome-wide admixture mapping, taking country of enrollment into account, to screen for ICP susceptibility loci.We characterized features of ICP at the U.S. and Chilean clinical sites.Results: Cases had a greater proportion of Indigenous American ancestry than did controls (p=0.034);when U.S. and Chilean study samples were analyzed separately, this difference was apparent in the U.S., but not the Chilean, study sample, potentially due to differences in population history.Admixture mapping allowed identification of one locus for which Native American ancestry was associated with increased risk of ICP at a genome-wide level of significance (P = 3.1 x 10 -5 , P corrected = 0.035).This locus, on chromosome 2, has an odds ratio of 4.48 (95% CI: 2.21-9.06)for 2 versus zero Indigenous American chromosomes; the 10 Mb 95% confidence interval does not contain any previously identified hereditary 'cholestasis genes.'ICP appears biochemically more severe in the U.S., than Chilean, study sample.Differences in management include 1) ursodeoxycholate was prescribed to a greater proportion of U.S. than Chilean patients (48% vs 1%); 2) most U.S. cases were delivered by 37 weeks gestation (or at time of diagnosis if later), while induction of labor is not usually performed until 40 weeks at the Chilean site; and 3) cesarean birth is more common in Chilean cases than controls, while rates are similar between U.S. cases and controls.Conclusions: Our results indicate that genetic factors contribute to risk of developing ICP in the Americas, and support the utility of clinical and genetic studies of ethnically mixed populations for increasing our understanding of ICP.Greater characterization of diagnosis, management and outcomes of ICP in different countries may improve our understanding of ICP, and its potential subtypes.

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