Abstract
In the Americas, women with Indigenous American ancestry are at increased risk of intrahepatic cholestasis of pregnancy (ICP), relative to women of other ethnicities. We hypothesized that ancestry-related genetic factors contribute to this increased risk. We collected clinical and laboratory data, and performed biochemical assays on samples from U.S. Latinas and Chilean women, with and without ICP. The study sample included 198 women with ICP (90 from California, U.S., and 108 from Chile) and 174 pregnant control women (69 from California, U.S., and 105 from Chile). SNP genotyping was performed using Affymetrix arrays. We compared overall genetic ancestry between cases and controls, and used a genome-wide admixture mapping approach to screen for ICP susceptibility loci. We identified commonalities and differences in features of ICP between the 2 countries and determined that cases had a greater proportion of Indigenous American ancestry than did controls (p = 0.034). We performed admixture mapping, taking country of origin into account, and identified 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, Pcorrected = 0.035). This locus has an odds ratio of 4.48 (95% CI: 2.21-9.06) for 2 versus zero Indigenous American chromosomes. This locus lies on chromosome 2, with a 10 Mb 95% confidence interval which does not contain any previously identified hereditary ‘cholestasis genes.’ Our results indicate that genetic factors contribute to the 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.
Highlights
Among pregnant women, the most common pregnancy-specific hepatic disorder is intrahepatic cholestasis of pregnancy (ICP)
In European populations, cross-sectional and candidate gene studies support a contribution of genetic factors to ICP; the candidate genes most consistently implicated in ICP are ABCB11 and ABCB4 [5,6,7,8,9,10,11,12,13,14,15,16]
Seventyone women diagnosed with ICP were recruited at two University of California San Francisco (UCSF) hospitals and affiliated clinics [most were recruited at San Francisco General Hospital (SFGH) and a few at UCSF Medical Center] and nineteen women with ICP at Los Angeles County + University of Southern California Medical Center
Summary
The most common pregnancy-specific hepatic disorder is intrahepatic cholestasis of pregnancy (ICP). Incidence of ICP differs between populations, and in some, has changed over time, suggesting both genetic and environmental contributions to etiology [4]. In European populations, cross-sectional and candidate gene studies support a contribution of genetic factors to ICP; the candidate genes most consistently implicated in ICP are ABCB11 and ABCB4 [5,6,7,8,9,10,11,12,13,14,15,16]. Additional genetic factors contributing to ICP remain to be identified. No wholegenome studies of ICP have been reported
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have