studies

248A AASLD ABSTRACTS HEPATOLOGY, October, 2015
78
Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas
and Chileans: Ancestry Analysis, Admixture Mapping,
and Biochemical Features
Laura Bull 1,2 , Donglei Hu 2,3 , Sohela Shah 1,2 , Luisa Temple 1,2 ,
Karla Silva 4,5 , Scott Huntsman 2,3 , Jennifer Melgar 1,2 , Mary
Geiser 1,2 , Ukina Sanford 1,2 , Juan Ortiz 5,6 , Richard Lee 7 , Juan P.
Kusanovic 4,5 , Elad Ziv 3,2 , Juan Vargas 8,9 ; 1 Medicine, San Francisco
General Hospital, UCSF, San Francisco, CA; 2 Institute for
Human Genetics, UCSF, San Francisco, CA; 3 Medicine, UCSF,
San Francisco, CA; 4 Center for Research and Innovation in Maternal-Fetal
Medicine, Hospital Dr. Sótero del Río, Puente Alto, Chile;
5 Obstetrics and Gynecology, Hospital Dr. Sótero del Río, Puente
Alto, Chile; 6 Obstetrics and Gynecology, Clínica Santa María,
Santiago, Chile; 7 Obstetrics and Gynecology, Los Angeles County
+ University of Southern California Medical Center, Los Angeles,
CA; 8 Obstetrics, Gynecology and Reproductive Sciences, UCSF,
San Francisco, CA; 9 Radiology, UCSF, San Francisco, CA
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.
Disclosures:
Sohela Shah - Employment: Qiagen Bioinformatics
The following authors have nothing to disclose: Laura Bull, Donglei Hu, Luisa Temple,
Karla Silva, Scott Huntsman, Jennifer Melgar, Mary Geiser, Ukina Sanford,
Juan Ortiz, Richard Lee, Juan P. Kusanovic, Elad Ziv, Juan Vargas
79
The effects of apoptosis inhibition on pulmonary alveolar
type 2 epithelial cell alterations in experimental
hepatopulmonary syndrome after common bile duct
ligation
Wenli Yang, Bingqian Hu, Michael B. Fallon, Junlan Zhang; The
university of Texas Health Science Center, Houston, TX
Introduction: Abnormal oxygenation due to lung ventilation-perfusion
mismatch drives the development of hepatopulmonary
syndrome (HPS). In addition to alterations in microvascular
perfusion, dysfunction in type II alveolar epithelial cells (AT2),
which play a critical role in maintaining alveolar ventilation
through surfactant protein (SPs) production, develops in experimental
HPS. Specifically, AT2 cell apoptosis and decreased
SP production associated with increased circulating bile acid
levels and bile acid nuclear receptor (FXRα) activation, reduce
alveolar airspace and impair ventilation. However, the relative
effects of FXRα activation on AT2 cell apoptosis and SP
expression and whether apoptosis inhibition influences AT2
cells and the development of HPS are unknown. Aim: To evaluate
the effects of apoptosis inhibition on FXRα activation in
AT2 cells and in experimental HPS. Methods: A murine AT2
cell line (MLE-12) was treated with a FXRα agonist (GW4064,
1-10mM) in the presence or absence of a pan caspase inhibitor
(Z-VAD-FMK). SD rats underwent common bile duct ligation
(CBDL) or sham operation and were treated with Z-VAD-FMK
(1.0mg/kg/day, IP, for 3 weeks). Lung and cell apoptosis was
determined by TUNEL staining or cleaved caspase-3 levels.
Co-staining of TUNEL and SP-C was performed to assess lung
AT2 cell apoptosis. SP levels were assessed by westerns or qRT-
PCR. Lung morphology (alveolar mean chord length, Lm) and
gas exchange (PO 2
) were measured to evaluate HPS. Results:
GW4064 treatment in MLE-12 cells caused a dose dependent
increase in cleaved caspase-3 protein expression and reduction
of SP-C and SP-B mRNAs. Z-VAD-FMK pretreatment attenuated
GW4064 induced cleaved caspase-3 protein increases
(76.0±6.1% reduction, p