2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.264
support for the involvement of NRG1 in schizophrenia in iranian
population: Evidence from a case: control association study
S. A. M. Shariati 1 , M. Behmanesh 1 , H. Galehdari 2 , A. Fathian 2 , A. Foroughmand
2 ;
1 Department of Genetics, School of Basic Sciences, Tarbiat Modares University,
Tehran, Islamic Republic of Iran, 2 Department Of Genetics, School of Basic
Sciences, Chamran University, Ahwaz, Islamic Republic of Iran.
It has been accepted widely that schizophrenia is a multifactorial disorder
and evidence in support of the involvement of genetic factor
in pathology of schizophrenia is compelling . As a result of extensive
study, a list of genes has emerged as candidate genes for schizophrenia
. Research into genetics of schizophrenia has found Neurgulin1
(NRG1) among the most promising candidate genes for schizophrenia.
For the first time in 2002, Steafansson et al suggested NRG1 as
a candidate susceptibility gene for schizophrenia in a linkage study
carried out in an Icelandic population . Since then, the association
of NRG1 with schizophrenia was further confirmed by several studies
in different population . However, analyzing allele and haplotype
frequencies of NRG1 in distinct populations have yielded varying results
and also different alleles or haplotypes have been associated
with schizophrenia . Meanwhile, some studies have failed to replicate
the association . In this work we attempted to study the association of
two NRG1 polymorphisms with schizophrenia in Iranian population .
SNP8NRG241930 and SNP8NRG221533 were studied in 100 cases
of schizophrenia matched with 100 healthy individuals. For the first
time in Iranian population, we showed a positive association between
NRG1 and Schizophrenia . Our statistical analyses indicate that there
are significant differences in allelic and genotypic frequencies between
two studied groups .
P06.265
Autosomal recessive form is the predominant pattern in iranian
patients with Severe Combined Immune Deficiency Disease
S. Safaei;
Immunology, Asthma and Allergy Research Institute, Tehran University of Medical
Sciences, Tehran, Islamic Republic of Iran.
Severe Combined Immune Deficiency is a X-linked and Autosomal Recessive
disorder . World investigations showed nearly 48% X-linked inheritance
which caused by mutations of the IL-2RG .This form of SCID
is characteristically T-/NK-/B+ . Also many genes invovled in Autosomal
Recessive pattern . The aim of this study was to determine the inherited
pattern of SCID affected families in Iranian patients .
Methods: Genomic DNA of 5 male unrelated patients with T-B+ clinical
symptoms of SCID was purified from peripheral blood. The sequencing
of IL2RG was performed to find out if they harbour any mutation in
these exones or not .
Result: We analyzed the IL-2RG (The X-linked mode of inheritance ) of
the patient for mutations by direct genemic sequencing, but found it to
be normal, suggesting an autosomal mode of inheritance of SCID .
Discussion: About 48% of SCID patient were reported to have IL2RG
deficiency in the word but our result showes that autosomal recessive
pattern is the predominant in Iranian SCID patients even the number
of patients is not enough to say strongly that . Because of counsanguity
marriage it is also very hard to say that the patient who lost boy because
of SCID had cause from IL2RG gene . Because of complexcity
of SCID we suggest that for those family who lost boy first linkage with
Chromosome X and then if it is negative for that linkage with other causetive
genes . This is pilot study and much more investigation need to
clarify that which gene is more frequently causetive in Iranian Patient .
P06.266
Association of a GABA(B) gene haplotype and temporal Lobe
Epilepsy
I. Manna 1 , A. Gambardella 1,2 , P. Forabosco 3 , A. Labate 1,2 , E. Colosimo 2 , R.
Ambrosio 2 , E. Le Piane 4 , U. Aguglia 4 , G. Di Palma 1 , A. Quattrone 1,2 ;
1 Institute of Neurological Sciences, National Research Council, Piano Lago di
Mangone, Cosenza, Italy, 2 Institute of Neurology, University Magna Graecia,
Catanzaro, Italy, 3 Department of Medical and Molecular Genetics, King’s College
London School of Medicine at Guy’s, London, United Kingdom, 4 Regional
Epilepsy Centre, Hospital of Reggio Calabria, Reggio Calabria, Italy.
There is experimental evidence that dysfunctions of the GABA(B) receptor
l gene (GABBRl) are implicated in the pathogenesis of temporal
lobe epilepsy (TLE) . Using a candidate gene approach, we recently illustrated
that the G1465A polymorphism in the GABBRI is a strong risk
factor for non-lesional TLE . Afterwards, other studies observed no evidence
of association . To better investigate this association, we set out
to examine whether common variations in GABBR1 predisposes to the
development of non-lesional TLE . We performed a genetic association
analysis of GABBR1 sequence variants by evaluating three SNPs and
an (AC)n repeat in a sample of 236 patients with non-lesional TLE and
380 age and geographic origin matched healthy controls . The program
UNPHASED was used to compare genotype, allele and haplotype frequencies
between cases and controls, including age and gender as
covariates in the model .
We found that each variation conferred an increased risk of disease
development . In addition, the four-SNP haplotypes were associated
with the disease .
Our data show that genetic variability in GABBR1 is highly associated
with susceptibility to non-lesional TLE, further corroborating our earlier
observations . Further studies in different TLE patient-control cohorts
are needed .
P06.267
interleukin-23 receptor (iL23R) gene polymorphisms in patients
with sjögren syndrome
E. Sáfrány 1 , V. Csöngei 1 , L. Járomi 1 , L. Magyari 1 , A. Maász 1 , C. Sipeky 1 , M.
Zeher 2 , B. Melegh 1 ;
1 Department of Medical Genetics and Child Development, University of Pécs,
Pécs, Hungary, 2 Medical and Health Science Center, Institute for Internal Medicine,
3rd Department of Medicine, University of Debrecen, Debrecen, Hungary.
Sjögren syndrome (SS) is an autoimmune disease that mainly effects
the exocrine glands . It is clinically characterized by keratoconjunctivitis
sicca and xerostomia . Duerr et al . (Science, 2006; 314:1461-1463)
found an association between Crohn’s disease and the intreleukin-23
receptor gene using genome-wide association; amongst the reported
SNPs the 3’-UTR C2370A (rs10889677) conferred risk for Crohn’s
disease, the Arg381Gln (rs11209026) showed the strongest protective
effect and the Pro310Leu (rs7530511) had no association with
the disease . Since the IL23 pathway is known to associate also with
other autoimmune diseases, we theoretized that these SNPs might
also have significance in the development of SS. We performed genotyping
using DNA samples collected from 156 patients with SS and
182 unrelated, healthy controls . The genotypes were analysed using
PCR/RFLP-methods. We found no significant difference between the
allele frequencies of the two groups, as for rs10889677 the distribution
of genotypes were CC 45 .5%, CA 43 .6%, AA 10 .9% in patients with
SS, while we observed CC 45 .6%, CA 48 .4%, AA 6 .04% in the control
group (not significant). For rs11209026 the genotypes were GG 87.8%,
GA 12 .2% and GG 86 .3%, GA 13 .7% in the examined groups . Similar
results were obtained for rs7530511 also: CC 73 .7%, CT 22 .4%, TT
3 .85% and CC 72 .5%, CT 25 .3%, TT 2 .20% in the groups of patients
and controls, respectively . Our results suggest that these SNPs do not
play a role in the development of Sjögren syndrome .
P06.268
The STK11-PRKAA2-CRTC2 genes are play a major role in the
genetic susceptibility to type 2 diabetes
P. Keshavarz1 , H. Inoue2 , M. Itakura2 ;
1 2 Guilan University of Medical Science, Rasht, Islamic Republic of Iran, The
university of Tokushima, Tokushima, Japan.
The activation of hepatic LKB1-AMPK-TORC2 signaling pathway,
which is the probable target for the antidiabetic drug metformin, have
a key role for development of type 2 diabetes (T2D) . We hypothesized
that genetic polymorphisms of the STK11, PRKAA2 (encoding AMPK
α subunit) and CRTC2 (encoding TORC2) could influence the suscep-
2
tibility to T2D . We screened STK11 and CRTC2 by direct sequencing
and genotyped in 1787Japanese subjects . Additionally, the previously
described association between the PRKAA2 haplotype and T2D was
tested for replication . According to single locus association test, an
intronic SNP in the STK11 (rs741765; OR 1 .33, 95% CI 1 .05-1 .67, p
= 0 .017, under a recessive model), and a non-synonymous SNP in
the CRTC2 (6909C > T: Arg379Cys; OR 3 .01, 95% CI 1 .18-7 .66, p
= 0.016, under a dominant model) showed a nominal significant association
with T2D . In PRKAA2, two non coding SNPs, rs1418442
and rs932447 were associated moderately with T2D (OR 0 .62, 95%