title: Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping.
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.
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America; Division of General Internal Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Donglei
authors.initials: D
authors.lastname: Hu
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America.
authors.forename: Sohela
authors.initials: S
authors.lastname: Shah
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America.
authors.forename: Luisa
authors.initials: L
authors.lastname: Temple
authors.affiliation: Center for Research and Innovation in Maternal-Fetal Medicine, Hospital Dr. Sótero del Río, Puente Alto, Chile; Department of Obstetrics and Gynecology, Hospital Dr. Sótero del Río, Puente Alto, Chile.
authors.forename: Karla
authors.initials: K
authors.lastname: Silva
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America; Division of General Internal Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Huntsman
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Melgar
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Geiser
authors.affiliation: Liver Center Laboratory, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America; Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America.
authors.forename: Ukina
authors.initials: U
authors.lastname: Sanford
authors.affiliation: Department of Obstetrics and Gynecology, Hospital Dr. Sótero del Río, Puente Alto, Chile; Department of Obstetrics and Gynecology, Clínica Santa María, Santiago, Chile.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Ortiz
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Keck School of Medicine, Los Angeles County + University of Southern California Medical Center, Los Angeles, California, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Lee
authors.affiliation: Center for Research and Innovation in Maternal-Fetal Medicine, Hospital Dr. Sótero del Río, Puente Alto, Chile; Department of Obstetrics and Gynecology, Hospital Dr. Sótero del Río, Puente Alto, Chile; Division of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Kusanovic
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco California, United States of America; Division of General Internal Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Elad
authors.initials: E
authors.lastname: Ziv
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America; Department of Radiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Juan E
authors.initials: JE
authors.lastname: Vargas
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D016022:Case-Control Studies; D002677:Chile; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D012307:Risk Factors; D014481:United States; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin