2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
tions) in the GSK3beta gene could partially underlie the susceptibility
to mood disorders, just as much to unipolar major depression as to
bipolar disorder . We performed a genetic case-control study including
440 screened control subjects and 445 patients with MD (257 Unipolar
Major Depressive Disorder, 188 Bipolar Disorder) . First, we selected
a set of 11 TagSNPs polymorphisms representative of the patterns of
common variation identified in European population in the genomic
region containing the GSK3beta gene and genotyped them using SN-
Plex Genotyping System . Moreover, we are replicating the experiment
of Lachman et al . in our Spanish sample of MD patients . They found
a statistical significant increased number of gains in a CNV partially
overlapping GSK3beta in bipolar patients compared with control individuals
. All the results were analyzed using SNPassoc package, from
R software . Regarding TagSNPs analyses, nominal associations were
found once stratified by polarity, even though they did not remain significant
after correction for multiple comparisons. Overall, although genetic
variants in GSK3beta gene might be a contributing factor to the
development of mood disorders, further studies in larger samples are
needed to obtain more conclusive results .
P06.122
Study of an association of deletion/insertion polymorphisms
of GSTM and GSTT genes with a risk of development of
endometriosis
E. Kamenec1 , O. A. Schagina1 , L. F. Kurilo1 , L. M. Michaleva2 , A. V. Polyakov1 ;
1 2 Reseach Centre for Medical Genetics, Moscow, Russian Federation, Institution
of Human Morphology RAMN, Moscow, Russian Federation.
Endometriosis is a common disease defined as a growth of endometrial
tissue outside the uterine cavity that often results a vast array of gynaecological
problems including dysmenorrhoea, pelvic pain, infertility .
Endometriosis is regarded as one of the multifactorial diseases caused
by an interaction between the environment and multiple genes .
Glutathione-S-transferases (GSTs) are enzymes involved in the phase
II detoxification process of xenobiotics including carcinogens and mutagens
. Gene polymorphisms of members of the GSTs family might
impair detoxification function and increase the risk of the disorder. The
present study was carried out to investigate if deletion/insertion polymorphisms
of GSTM1, GSTT1 and there combination are useful markers
for predicting endometriosis susceptibility .
DNA was extracted from blood of 40 patients with reliable diagnosis of
endometriosis and 50 healthy women (control group) . DNA samples
were amplified by polymerase chain reaction and detected by electrophoresis
. The relative frequencies of the GSTM1 wild/null and the
GSTT1 wild/null genotypes between both groups were compared .
The proportion of individuals with GSTM1 null mutation was 45% in
the endometriosis group and 30% in the control group (P > 0 .05), the
proportions of GSTT1 wild/null allels in both groups were 22 .5%/18%
accordingly (P > 0 .05) . The proportions of GSTM1(null/null) +
GSTT1(null/null) genotype were 12 .5%/2% (P > 0 .05) . The distribution
of the polymorphisms and there combination was not significantly different
between the two groups . These results suggest that the GSTM1
and the GSTT1 null mutations aren’t associated with a risk of the development
of endometriosis in Russian women .
P06.123
Risk Factors of inhibitors Development in Haemophilia Patients
M. Mihailov, M. Serban, D. Savescu, S. Arghirescu, C. Petrescu, M. Puiu;
University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania, Timisoara,
Romania.
Introduction . FVIII inhibitors appearance in haemophiliacs is related to
several factors, like substitution with native plasma products, frequent
changing of FVIII concentrates, high rate of HBV and HCV infection,
pseudotumours and other massive muscular haematomas, etc .
Objective . Starting from particularities of haemophilia treatment in our
country, we evaluated the variables impact on inhibitors development .
We assessed frequency and inhibitors titer, in correlation with risk factors
.
Material and method: retrospective single center study based on 219
hemophilia patients registered and treated in the IIIrd Pediatric Clinic
Timisoara, using Bethesda assay. We evaluated the influence of some
parameters on frequency and inhibitors titer: haemophilia severity,
gene mutations, family history, type of substitutive product used, hepatitis
C or B infection, Interferon alpha therapy, surgical interventions,
and bolus vs . intravenous infusion of FVIII .
Results . Between January 1997- 2002, inhibitors frequency was 47 .5%,
whereas after January 2002 only 19 .19% of patients had inhibitors due
to reactants and methodology change . The majority of inhibitors were
in severe haemophilia (78 .95%), 15 of these patients being positive for
intron 22 inversion .
Family history and exposure to FVIII were important risk factors of inhibitors
development . Hepatitis C or B infection, Interferon alpha therapy,
surgical interventions and intravenous infusion of FVIII haven’t
been significantly correlated with inhibitors’ development.
Conclusions . In our patients, we found only the following risk factors for
inhibitors development: exposure to FVIII, type of FVIII gene mutations
and familial predisposition . Accuracy of technique and experience of
laboratory technician is decisive for inhibitor evaluation .
P06.124
Association of the iL4R single-nucleotide polymorphism s411L
with Hand Osteoarthritis
M. Vargiolu1 , T. Silvestri2 , E. Bonora1 , P. Dolzani2 , L. Punzi3 , A. Fioravanti4 , G.
Romeo1 , R. Meliconi2,5 ;
1U.O. Genetica Medica, Policlinico S. Orsola-Malpighi via Massarenti, Bologna,
Italy, 2Laboratorio di Immunologia e Genetica, Istituti Ortopedici Rizzoli,
Bologna, Italy, 3Rheumatology Unit, University of Padova, Italy, Padova, Italy,
4 5 Rheumatology Unit, Policlinico “Le Scotte”, Siena, Italy, Rheumatology Unit,
Istituti Ortopedici Rizzoli, Bologna, Italy.
Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates
a complex mode of transmittance with both joint-site and
gender-specific heterogeneity. In OA anti-inflammatory and anabolic
cytokines which are usually responsible for the control of cartilage
homeostasis are altered or inadequate . Hitherto, functional study had
been mainly focused on the IL13/IL-4/IL-4R system which has a strong
chondroprotective role and it is reasonable to speculate that polymorphism
within these genes may be risk factors for OA . We therefore
investigated polymorphisms in these genes as potential OA susceptibility
loci by genotyping fifteen SNPs using TaqMan® Technology in
413 patients (26 male, 387 female) with hand OA and 326 healthy
controls (14 male, 312 female) .Although the majority of these SNPs
had already shown an association with OA in previous studies, in our
case-control study only one SNP (dbSNP rs1805013) was associated
with P-values of 0 .0125 . This association was attributable to an increased
frequency in the probands of the minor T allele regardless of
gender and disease severity . This SNP results in the substitution of a
serine with a leucine in the codon 411 of IL4R and consequently of an
aliphatic hydrophobic residue for a polar hydrophilic one, a change that
could have effects on protein function . Further functional studies for
the S411L substitutions will clarify the role of this SNP on osteoarthritis
predisposition .
P06.125
tmc1 but Not tmc2 is Responsible for Autosomal Recessive
Nonsyndromic Hearing impairment in tunisian Families
A. Tlili 1,2 , I. Ben Rebeh 2 , M. Aifa-Hmani 2 , J. Tlili-Chouchène 1 , H. Dhouib 3 , J.
Moalla 3 , M. Ben Said 2 , I. Lahmar 4 , Z. Benzina 5 , I. Charfedine 3 , N. Driss 4 , A.
Ghorbel 3 , H. Ayadi 2 , S. Masmoudi 2 ;
1 Laboratoire de Génétique Moléculaire Humaine, Sfax, Tunisia, 2 Unité Cibles
pour le Diagnostic et la Thérapie , Centre de Biotechnologie de Sfax, Sfax,
Tunisia, 3 Service d’O.R.L., C.H.U.H. Bourguiba de Sfax, Sfax, Tunisia, 4 Service
d’O.R.L., C.H.U. de Mahdia, Mahdia, Tunisia, 5 Service d’Ophtalmologie, C.H.U.
H. Bourguiba de Sfax, Sfax, Tunisia.
Hereditary nonsyndromic hearing impairment (HI) is extremely heterogeneous
. Mutations of the transmembrane channel-like gene 1
(TMC1) have been shown to cause autosomal dominant and recessive
forms of nonsyndromic HI linked to the loci DFNA36 and DFNB7/
B11, respectively . TMC1 is 1 member of a family of 8 genes encoding
transmembrane proteins . In the mouse, MmTmc1 and MmTmc2 are
both members of Tmc subfamily A and are highly and almost exclusively
expressed in the cochlea . The restricted expression of Tmc2 in
the cochlea and its close phylogenetic relationship to Tmc1 makes it
a candidate gene for nonsyndromic HI . We analyzed 3 microsatellite
markers linked to the TMC1 and TMC2 genes in 85 Tunisian families
with autosomal recessive nonsyndromic HI and without mutations in
the protein-coding region of the GJB2 gene . Autozygosity by descent
analysis of 2 markers bordering the TMC2 gene allowed us to rule