studies

1234A AASLD ABSTRACTS HEPATOLOGY, October, 2015
2105
Genetic variants associated with liver disease in α-1-antitrypsin
deficiency
Richard J. Thompson 1 , Jeid Turquet 1 , Rosamond Nuamah 2 , Patrick
J. McKiernan 3 , Robert Stockley 4 , Gerome Breen 5 , Nedim Hadzic 6 ;
1 Institute of Liver Studies, King’s College London, London, United
Kingdom; 2 BRC Genomics Facility, Guy’s and St Thomas’ NHS
Foundation Trust, London, United Kingdom; 3 Liver Unit, Birmingham
Children’s Hospital, Birmingham, United Kingdom; 4 Lung
Immuno Biochemical Research Laboratory, University of Birmingham,
Birmingham, United Kingdom; 5 Institute of Psychiatry, King’s
College London, London, United Kingdom; 6 Paediatric Liver, GI
and Nutrition Centre, King’s College Hospital, London, United
Kingdom
Background Alpha-1-antitrysin is a major plasma serine protease
inhibitor. It is encoded by SERPINA1. Several deficient
alleles have been described. The Z allele (p.E342K) leads to
protein polymerisation and intracellular retention. In homozygous
form this allele is seen in patients with lung and liver
disease; α-1-antitrypsin deficiency (A1ATD). The respiratory disease
is highly penetrant, whereas neonatal cholestasis is seen
in only 10-15% of Z homozygotes. The cause of the reduced
penetrance seen in this liver phenotype is unexplained. Aim
To identify genetic loci associated with neonatal presentation
of A1ATD associated liver disease. Methods All patients were
homozygous for p.E342K, the Z allele. One group consisted
of 384 patients followed in an adult respiratory clinic. The
second group consisted of 132 patients presenting with neonatal
cholestasis. All were genotyped using Illumina Infinium
HumanCoreExome arrays; interrogating >240,000 tagSNPs.
Data was analysed using several software tools including
GenomeStudio, PLINK and PRSice. Thus allowed single locus
and polygenic associations to be identified. Results Differences
in SNP allele frequencies between the 2 groups of patients
were studied. Three separate loci with a lod score of >6 were
identified. They are on chromosomes 1, 12 and 14. The latter
is 10 Mb from the SERPINA1 gene. A large number of other
loci have been subject to further analysis, looking for polygenic
and pathway effects. Only 1 of the three loci lies within a gene.
This in turn has not been linked to liver disease. Conclusions
Although AIATD-associated liver disease is thought of as being
genetic, the major locus (SERPINA1) shows markedly reduced
penetrance. The fact that all Z alleles are inherited from a
relatively recent ancestor means that all affected individuals
are much more closely related than in nearly all similar studies.
This in turn means that between phenotypically diverse
groups, genetic associations can be identified using relatively
small sample sizes. This proved to be the case and allowed the
identification of 3 quite separate loci conferring susceptibility
to liver disease. The mechanisms by which this risk is conferred
remain to be identified, however this is the first step in the identification
of the cause of A1ATD liver disease.
Disclosures:
Richard J. Thompson - Grant/Research Support: Shire; Speaking and Teaching:
Shire
Patrick J. McKiernan - Consulting: Alnylam Pharmaceuticals
Nedim Hadzic - Consulting: Alnylam; Speaking and Teaching: Synageva
The following authors have nothing to disclose: Jeid Turquet, Rosamond Nuamah,
Robert Stockley, Gerome Breen
2106
Clinical features, biochemical measures and liver histology
in Hereditary Hemochromatosis Argentinian
patients with and without HFE gene mutations.
Florencia Yamasato, Marcelo Castro, Alejandra Avagnina, Alejandra
Vellicce, Alejandra Pernazza, Jorge Rey, Esteban González
Ballerga, Juan A. Sorda, Jorge Daruich; Gastroenterologia, Hospital
de Clínicas José de San Martín. Universidad de Buenos Aires,
Buenos Aires, Argentina
Introduction: Inclusion of HFE gene mutations, present in
90-96% of Hereditary Hemochromatosis (HH) Anglo-Saxon
patients (Pt), has been a great advance in diagnosis algorithm.
However, the percentage of these mutations among HH Pt
could be different in our population. Objectives: To describe
in HH Pt, the differences in clinical and biochemical features,
and the presence of cirrhosis among subjects with HFE gene
mutations (G1) and those without them (G2). Materials and
Methods: Cross sectional study. 277 Pt with HH diagnosis
between 1989 and 2014 were included. Only Pt with studied
HFE gene mutations were included. HH diagnosis was
performed by internationally accepted criteria and compatible
liver histology. HOMA, Diabetes Mellitus (DM), alcohol
intake (>30g/d), articular and cardiac features, liver histology
(cirrhosis) and non-alcoholic fatty liver disease (NAFLD) were
investigated and compared between both groups. Statistical
analysis: Descriptive statistics are displayed as Median values
with 95% Confidence Intervals (CI). Mann Whitney method
and logistic regressions were performed. P Values