Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping

• Published in: PloS one Vol. 10; no. 6; p. e0131211
• Main Authors: Bull, Laura N, Hu, Donglei, Shah, Sohela, Temple, Luisa, Silva, Karla, Huntsman, Scott, Melgar, Jennifer, Geiser, Mary T, Sanford, Ukina, Ortiz, Juan A, Lee, Richard H, Kusanovic, Juan P, Ziv, Elad, Vargas, Juan E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30-06-2015; Public Library of Science (PLoS)
• Subjects: Admixtures; Adult; Alanine Transaminase - blood; Aspartate Aminotransferases - blood; Bile Acids and Salts - blood; Bilirubin - blood; Bioinformatics; Case-Control Studies; Chile; Cholestasis; Cholestasis, Intrahepatic - blood; Cholestasis, Intrahepatic - diagnosis; Cholestasis, Intrahepatic - genetics; Chromosome 2; Chromosomes; Chromosomes, Human, Pair 2 - genetics; Comparative analysis; Confidence intervals; Female; Gallbladder diseases; gamma-Glutamyltransferase - blood; Gene loci; Gene mapping; Genetic factors; Genetic Predisposition to Disease; Genetics; Genomes; Genomics; Genotyping; Gynecology; Hepatology; Hispanic or Latino - genetics; Hospitals; Humans; Internal medicine; Laboratories; Liver; Mapping; Medicine; Minority & ethnic groups; Obstetrics; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy Complications - blood; Pregnancy Complications - diagnosis; Pregnancy Complications - genetics; Pregnant women; Risk; Risk Factors; Single-nucleotide polymorphism; Studies; United States; Womens health; Young Adult; Chile; United States; Los Angeles California; San Francisco California; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0131211

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.