European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Genetic analysis, linkage, and association
moderate to major effect.
We are coordinating two large multi-national collaborative stature gene
mapping efforts: 1) the GenomEUtwin and the 2) Marshfield Mammalian
Genotyping Service stature projects. Both studies include family
data from multiple populations with genome-wide genotype data - the
former containing 8.450 individuals from 3.817 families and the latter
11.149 individuals from 3.272 families. Using genome-wide linkage
analyses we have localized multiple putative QTLs for stature on
2p, 2q, 3p, 3q, 8q, 9q, 10p, 11q, 20q and Xq25, some shared across
multiple populations. Data from further fine mapping analyses of these
major loci will be presented.
In line with analyses of other complex traits it has become obvious that
these types of massive data sets are needed to provide solid evidence
for QTLs contributing to human stature.
P0989. Modulation of HFE-hemochromatosis penetrance by the
BMP2, BMP4 and HJV genes of the hepcidin regulation pathway
J. Milet 1,2 , V. Dehais 3 , C. Bourgain 1,2 , A. M. Jouanolle 3 , M. Perrin 4,5 , J. Morcet 5 ,
P. Brissot 3,6 , Y. Deugnier 3,7 , J. Mosser 3,8 ;
1 INSERM UMR_S535, Villejuif F-94817, France, 2 Univ. Paris Sud, Villejuif
F-94817, France, 3 CHU, Rennes F-35033, France, 4 Univ. Rennes 1, Rennes
F-35043, France, 5 INSERM, CIC 0203, Rennes F-35033, France, 6 INSERM,
U522, Rennes F-35033, France, 7 IFR 140, Rennes F-35033, France, 8 CNRS,
UMR 6061, Rennes F-35043, France.
Most cases of genetic hemochromatosis (GH) are associated to the
HFE C282Y/C282Y genotype in Caucasian populations. The biochemical
or clinical symptoms expressed by C282Y homozygotes are extremely
variable and only a few suffer from an overt disease. Several
studies have suggested that, in addition to environmental factors, a
genetic component could explain a substantial part of this phenotypic
variation, though very few genetic factors have been identified so far.
The aim of the present study was to search for genes modifying hemochromatosis
penetrance in a large sample of C282Y homozygotes, using
pre-therapeutic serum ferritin level as marker of hemochromatosis
penetrance. We used a candidate gene approach and focused on 2
biologically relevant gene categories: genes involved in non HFE-GH
(TfR2, Hamp, SLC40A1) and genes from the BMP hepcidin regulation
pathway (BMP 2, BMP4, HJV, Smad 1, Smad4 and Smad5). We also
considered the IL6 gene involved in the inflammation hepcidin regulation
pathway.
A significant association between serum ferritin level and a SNP in the
BMP2 genic region (rs235756, P=4.42 x 10-5) was detected. Mean
ferritin level adjusted for age and sex was 651.97 ng/ml among TT
genotypes, 518.01 ng/ml in TC genotypes and 350.72 ng/ml in CC
genotypes. Testing the biologically relevant gene interactions along
the BMP regulation pathway, we detected a significant interactive effect
of BMP2 and HJV with a small additive effect of BMP4 on ferritin
level.
All together, our results suggest that the HJV-BMP complex genes are
involved in the modulation of iron burden in C282Y homozygotes.
P0990. Association of Interferon-gamma (IFN-g) Polymorphisms
with Susceptibility of Hepatitis B Virus (HBV) Infection in the
Hong Kong Chinese
W. Lee 1 , P. W. Lee 1 , W. H. Wong 1 , M. F. Yuen 2 , T. P. Poon 3 , Y. L. Lau 1 ;
1 Department of Paediatrics and Adolescent Medicine, Hong Kong Jockey Club
Clinical Research Centre, Li Ka Shing Faculty of Medicine, The University of
Hong Kong, Pokfulam, Hong Kong, China, 2 Department of Medicine, Hong
Kong Jockey Club Clinical Research Centre, Li Ka Shing Faculty of Medicine,
The University of Hong Kong, Pokfulam, Hong Kong, China, 3 Department of
Surgery, Hong Kong Jockey Club Clinical Research Centre, Li Ka Shing Faculty
of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Background: Hepatitis B virus (HBV) infection is the most common
cause of acute hepatitis and may progress to chronic liver disease,
including cirrhosis or hepatocellular carcinoma (HCC). Host genetic
factors are important for this progression. Interferon-gamma (IFN-γ)
is a pro-inflammatory T-helper 1 (Th1) cytokine. It plays crucial roles
in downregulation of HBV replication and its clearance. 1 Serum IFN-γ
levels were lower in the chronic hepatitis B patients than the normal
controls, supporting that IFN-γ is involved in the progression of HBV
infection. 2
Objective: We aimed to determine whether a functional single nucleotide
polymorphism (SNP) of IFN-γ may affect the susceptibility of HBV
infection in Hong Kong Chinese population.
Methods: We recruited 460 chronic HBV carriers and 87 individuals
who had spontaneously recovered from HBV infection as evidenced
by the presence of anti-HBs and anti-HBc antibodies. The SNP of IFNγ
at +874 A/T at intron 1 at the 5’ end of a CA repeat microsatellite
sequence was detected using Genescan analysis.
Results: For the spontaneous recovered individuals, the genotype frequencies
were 54.0% for A/A, 39.1% for A/T and 6.9% for T/T. For the
chronic HBV carriers, the genotype frequencies were 72.8% for A/A,
24.6% for A/T and 2.6% for T/T. The A/A genotype was predominant in
the chronic carriers (odd ratio=4.09, CI=1.35-12.4), and its frequency
was significantly higher than those with spontaneous recovery after
adjusting for age and gender (pg,g.4486delG, g.4487_4498del12) in
flanking regions of exons 3, 4 and 7, respectively, in four families (12
%). Mutations that affect splice sites are supposed to reduce or abolish
normal splicing by either exon skipping or activation of cryptic splite
sites. Inhibition of splicing was proved in one case.
Supported by grant IGA-MZ-CR #NR7921-3.
P0992. Whole Genome Scan in a Maltese Family with a rare case
of Hereditary Persistence of Fetal Hemoglobin
J. Borg 1 , R. Galdies 1,2 , R. Schot 3 , A. Verkerk 3 , P. van der Spek 3 , P. Schembri
Wismayer 4 , A. G. Fenech 5 , W. Cassar 1,2 , S. Bezzina Wettinger 1,2 , M. R. Caruana
2 , C. A. Scerri 1,2 , F. Grosveld 6 , S. Philipsen 6 , G. Patrinos 6 , A. E. Felice 1,2 ;
1 Laboratory of Molecular Genetics, Department of Physiology and Biochemistry,
University of Malta, Msida, Malta, 2 Thalassaemia and Molecular Genetics Clinic,
Division of Pathology, St’Lukes Hospital, Department of Health, G’Mangia,
Malta, 3 Erasmus Centre for Bioinformatics, Erasmus MC, Rotterdam, The Netherlands,
4 Department of Cell Biology and Anatomy, University of Malta, Msida,
Malta, 5 Department of Clinical Pharmacology and Therapeutics, University of
Malta, Msida, Malta, 6 Department of Cell Biology, Erasmus MC, Rotterdam, The
Netherlands.
Hereditary Persistence of Fetal Hemoglobin (HPFH) is an inherited
condition resulting in high fetal hemoglobin (HbF) levels in adults.
Although this condition is caused by large deletions, removing large
segments from the human β-globin cluster or point mutation within the
human γ-globin gene promoters, there have been few cases where the
HbF-increasing genetic determinant is located outside the human βglobin
locus, e.g. in chromosomes 6q22.3-q23.1, 8q and Xp22.2-22.3.
2