2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.239
susceptibility to preeclampsia in relation to ethnicity: multiple
genes case-control study
G. S. Demin1 , T. E. Ivashchenko1 , I. Bouba2 , E. V. Mozgovaia1 , V. S. Baranov1 ,
I. A. Georgiou2 ;
1Ott’s Institute of Obstetrics & Gynecology, St.-Petersburg, Russian Federation,
2University of Ioannina, Ioannina, Greece.
Pathogenesis of preeclampsia suggests endothelial dysfunction during
pregnancy . Considering that endothelial gene polymorphism may
affect relevant protein production the aim of the study was to investigate
whether genetic variability in endothelial dysfunction-related proteins
contributes to individual and ethnic preeclampsia susceptibility
differences .
317 women from Greece and Russia with normal pregnancy or uncomplicated
preeclampsia participated in the case-control study . Polymorphisms
of the TNF-alpha (-308G>A and -238G>A), NOS1 (AAT)n,
NOS2 (CCTTT)n, NOS3 (894G>T and 4a/4b), PAI-1 (4G/5G) and ACE
(I/D) genes were determined by a PCR-based RFLP method .
Considering genetic heterogeneity between populations we carried
out the comparison of allelic frequencies between controls from Russia
and Greece and between patients from these countries . Analyzing
results revealed that the frequencies of variants of NOS2, NOS3 and
TNF-alpha genes differed between controls and patients according to
ethnic origin . Our results show that it is incorrect to join samples from
different countries if significant differences in allelic frequencies have
been revealed .
According to the analysis of the polymorphisms independently and the
development of preeclampsia, an association NOS3 4a/4b genotype
(OR=2 .18, 95%CI:1 .07-4 .45) was observed for Russian population .
Severe preeclampsia was associated with TNF-alpha -308A allele
(OR=5 .07, 95%CI:1 .10-23 .48) in Greek population . When we investigated
an interaction among these polymorphisms on the development
of the preeclampsia, it was revealed that several combined genotypes
were significant risk factors different in various populations.
The study of two populations has shown that preeclampsia is associated
with misbalance in endothelial gene system, but genetic markers
of disease vary in different countries .
P06.240
the X-linked DiAPH2 gene is a risk-factor for Premature Ovarian
Failure (POF) and accounts for female preponderance among
POF patients offspring
S. Bione 1,2 , T. Corre 2 , F. Rizzolio 2 , S. Sansanelli 2 , S. Carrabino 1,2 , M. Testa 2 , R.
Ricotti 1 , D. Toniolo 2 ;
1 IGM-CNR, Pavia, Italy, 2 DIBIT-San Raffaele Scientific Institute, Milan, Italy.
Premature Ovarian Failure (POF) is a complex disorder, resulting in
primary or secondary amenorrhea before the age of 45 and affecting
1% of women . Environmental factors have been shown to play a role
in POF, but a strong genetic component is demonstrated by the prevalence
of familial cases . The X chromosome was shown to be affected
by structural rearrangements in several cases . Mendelian genes mutated
in the disease are rare and the premutated allele at the FMR1 locus
was shown to be a risk factor predisposing for the disease . These
observations lead to the hypothesis of POF being a complex disorder
caused by the additional effect of several risk factors .
The X-linked DIAPH2 gene was identified as interrupted by the breakpoint
of a POF associated balanced transocation but its role in the
pathogenesis of the disorder remains unclear as no causative mutations
were found in a large number of cariotypically normal patients . An
association study was performed in a large cohort of POF patients and
controls revealed the presence of a risk-haplotype significantly associated
to the disorder . Moreover the analysis of the offspring sex-ratio in
the POF cohort demonstrated a strong female preponderance mainly
attributable to the risk-haplotype identified. Taken together these results
demonstrated that the POF condition is preferentially due to additional
risk-factors and thus with a multifactorial pattern of inheritance .
The DIAPH2 gene is one of the susceptibility genes involved and its
role in the process of oogenesis and ovulation will be further investigated
.
P06.241
Correlation of genotype/phenotype in primary Congenital
Glaucoma patients from different ethnic groups of the israeli
population
D. Bercovich 1,2 , C. Shochat 1 , S. Korem 1 , O. Geyer 3 ;
1 , Migal - Galilee Bio-Technology Center, Kiryat-Shmona, Israel, 2 Tel Hai Academic
College, Tel Hai, Israel, 3 Department of Ophthalmology, Carmel Medical
Center, Haifa, Israel.
Mutations in the CYP1B1 gene are responsible for more than 50%
of primary congenital glaucoma (PCG) and mutations in the MYOC
gene have also been associated with this disease . The OPTN gene is
known to be associated with primary open-angle glaucoma and lowtension
glaucoma . We noticed a different clinical presentation of PCG
in our patients according to ethnicity. Our goal was to find a correlation
between genotype and phenotype in people with PCG according to
their ethnic origin . We screened the CYP1B1 gene in 86-individuals
from 22-families of Israeli Moslem Arabs, Druze family and Ashkenazi
and non-Ashkenazi Jewish, using the DHPLC apparatus . The screening
revealed the cause for PCG in 11 of these 22-families . The mutations,
includes a homozygous missense mutation R469W in exon-3 of
the CYP1B1 gene in 4 different Druze and one Moslem families . Two
Druze and two Moslem Arabs and one non-Ashkenazi families with the
typical severe type of PCG were found to be compound heterozygous
for two different DNA alterations . Screening the MYOC gene reviled in
one of the non-Ashkenazi patient a heterozygous missense mutation
and the patient was compound to another mutation in the CYP1B1
gene . No mutations were found in the OPTN gene in the families with
no mutations in the CYP1B1 or MYOC . Establishing the genotypephenotype
correlations of PCG in our various ethnic backgrounds may
add valuable knowledge for predicting the prognosis of the disease,
for guiding therapeutic decision making and for genetic counseling of
carriers of this cause of blindness in children .
P06.242
Gene screening for primary lateral sclerosis on chromosome
4ptel-4p16.1 in a French-canadian family
V. V. Belzil1 , P. N. Valdmanis1,2 , J. St-Onge1 , N. Dupre1,3 , G. A. Rouleau1 ;
1Universite de Montreal, Hopital Notre-Dame-CHUM, Montreal, QC, Canada,
2Department of Human Genetics, McGill University, Montreal, QC, Canada,
3Department of Neurological Sciences, CHAUQ Enfant-Jesus, Quebec, QC,
Canada.
Primary lateral sclerosis (PLS) is a degenerative disease of upper motor
neurons, characterized by a progressive spasticity resulting from
the degeneration of cortical motor neurons which affects mainly the
descending pathway of the corticospinal system . The lower extremities
are first affected, followed by a spasticity of the trunk, of upper extremities
and of bulbar muscles . A 550-marker whole genome scan was
performed on a French-Canadian family with 12 individuals affected
with PLS. This lead to the identification of a locus on chromosome 4
between the telomere and marker D4S2928 (4ptel-4p16 .1) . This is the
first locus described for PLS. A maximum LOD score of 3.01 has been
found for marker D4S2936 . This region spans 10 .2 megabase pairs
and encompasses about 130 genes; 29 of those genes are clearly
expressed in the brain . Five genes have already been screened without
the detection of a coding mutation . We are currently screening the
remaining genes in the candidate region. The identification of a gene
responsible for PLS would help better understand motor neuron biology
and pathology .
P06.243
Haplotype associations of the mHc with psoriasis vulgaris in
Russian patients
E. Galimova 1 , V. Akhmetova 1 , L. Gazizova 2 , Z. Sultanova 2 , E. Shushenacheva 3 ,
M. Kizlasova 3 , E. Khusnutdinova 1 ;
1 Institute of Biochemistry ang Genetics, Ufa Scientific Center of Russian Academy
of Sciences, Ufa, Russian Federation, 2 Dermato-Venereology Hospital,
Ufa, Russian Federation, 3 Dermato-Venereology Hospital, Abakan, Russian
Federation.
Psoriasis is a common inflammatory skin disease with a strong genetic
component . Although eight psoriasis susceptibility loci (PSORS1-9)
have been identified by genome-wide screening, linkage and association
analysis have defined that MHC is the major genetic determinant
related to psoriasis susceptibility . Haplotype associations of the MHC