2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
osteocalcine level (p=0,05) when girls with CC genotype .
Conclusion: in our study we have revealed that GG genotype and G
allele BclI GCR was associated with osteopenia in JIA girls with high
osteocalcine level .
P06.040
S2G (Syndrome to Gene): Novel software for the identification of
genes associated with human genetic syndromes
A. Gefen, R. Cohen, O. S. Birk;
National Institute for Biotechnology in the Negev, Beer-sheva, Israel.
The identification of genomic loci associated with human genetic syndromes
has been significantly facilitated through the generation of
high density SNP arrays. However, the identification of the specific disease-associated
genes within such loci is still a tedious labor-intensive
bottleneck. Optimal selection of candidate genes from within a defined
genomic locus is a crucial step in the process .
We have generated novel software that selects optimal candidate
genes, using a two step procedure . For any given syndrome, the software
seeks all genes associated with syndromes containing similar
phenotypes . It then searches through the entire human genome for
other genes that are associated with these reference genes . This
search takes into account interacting biochemical pathways, proteinprotein
interactions, transcription factor cascades, etc . A gene list is
generated with an order of priority (degree of possible interaction with
the reference gene(s)). This list is then filtered for the specific genomic
locus in question - and a prioritized list of candidate genes is generated
.
S2G can be used also in clinical genetics: when S2G gets a query
for related syndromes of a given one, the score vector of the given
syndrome is sorted creating a list of syndromes starting with the closest
related syndrome . The result of the query is a list of syndromes
with their known causing genes, so one can view and explore which
genes are associated with similar phenotypes to those of the query
syndrome .
P06.041
Dystrobrevin binding protein 1 gene (DTNBP ) in a Bipolar casecontrol
study (BAccs)
D. Gaysina 1,2 , S. Cohen 1 , P. C. Chow 1 , L. Martucci 1 , A. Schosser 1,3 , H. A. Ball 1 ,
F. Tozzi 4 , J. Perry 5 , P. Muglia 4 , I. W. Craig 1 , P. McGuffin 1 , A. Farmer 1 ;
1 MRC SGDP, Institute of Psychiatry, London, United Kingdom, 2 Institute of Biochemistry
and Genetics, Ufa, Russian Federation, 3 Medical University Vienna,
Vienna, Austria, 4 GSK Research & Development, Verona, Italy, 5 GSK Research
& Development, Greenford, United Kingdom.
Background: Recent studies suggest a substantial degree of overlap in
genetic susceptibility across the traditional categories of schizophrenia
and bipolar disorder . There is consistent evidence for an association
of the DTNBP1 gene with schizophrenia, and thus this gene has also
become a focus of further investigation in bipolar disorder (BD) .
Methods: The aim of our study is to explore the association of DTNBP1
gene with BD and with a sub phenotype such as presence/ absence
of psychotic symptoms in a sample of 465 patients with BD (ICD10/
DSMIV) and 478 ethnically matched control subjects recruited from
the UK . Seven SNPs of the DTNBP1: rs2743852 (SNP C), rs760761
(P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655),
rs16876571 and rs17470454 were investigated using SNPlex genotyping
system .
Results: We report significant differences in genotypic and allelic frequencies
of rs3213207 and rs760761 of DTNBP1 gene between the
bipolar patients and controls . We also show a global haplotypic association
and an association of a specific haplotype within this gene
with BD .
Conclusions: Our results are consistent with previous studies in term
of a general association between the dysbindin gene and bipolar disorder
and provide additional molecular genetic evidence that a portion
of the genotypic overlap between schizophrenia and bipolar affective
disorder is attributable to this gene .
Acknowledgements: Russian Science Support Foundation Grant
(Gaysina), MRC UK PhD studentship (Cohen), Erwin-Schrodinger
Fellowship (Schosser), ESRC UK PhD studentship (Ball) . The casecontrol
collection was supported by GlaxoSmithKline, Research and
Development .
P06.042
A 7 mb region within 11q13 is candidate to contain a high
penetrance gene for breast cancer
J. M. Rosa Rosa 1 , G. Pita 1 , A. González-Neira 1 , V. Fernández 1 , R. Oldenburg 2 ,
P. Devilee 3 , J. Benítez 1 ;
1 Human Cancer Genetics Programme, Madrid, Spain, 2 Dept. of Clinical Genetics,
Leiden, The Netherlands, 3 Dept. of Human Genetics, Leiden, The Netherlands.
Familial breast cancer represents up to 5% of the total breast cancer
cases . Only a fraction of families affected by breast cancer is explained
by mutation in BRCA1 and BRCA2 . Recently, our group has
performed a new SNP-based linkage study in 19 non-BRCA1/2 families
from Spain, Netherlands and USA We found that a single family
was linked to two different chromosomes (regions 11q13 and 14q21),
and showed a non-parametric LOD score of 11 .5 in both regions . The
regions spanned 28 and 14 .5 Mb respectively . We ruled out any possible
translocation between both chromosomes using cytogenetic
techniques . We used both a panel of STRs and an indirect approach
based on HapMap data to narrow down these two regions from 28
to 7Mb in chromosome 11 and from 14 .5 to 8 .5 Mb in chromosome
14 . We selected the 11q13 region to perform a mutational screening
on some candidate genes (NuMA1, FGF3, CCND1, RAD9A, RNF121,
FADD and has-mir-192) . Although we have not found any deleterious
mutation in the coding sequence of these genes, data from infrequent
markers located in different genes confirms 11q13 as a candidate
region to contain a breast cancer susceptibility gene . A larger study
involving new families could limit their size and facilitate a more extensive
mutational screening .
P06.043
PPP R and NFATC polymorphisms have no influence on
cardiac parameters in healthy individuals and related to cardiac
remodeling in patients with cardiovascular disease
O. G. Ivanova 1 , O. A. Makeeva 1 , I. V. Tsimbal’uk 2 , K. V. Puzyrev 3 , O. Y. Byichkova
1 , A. A. Lezhnev 3 , V. A. Kazakov 3 , V. M. Shipulin 3 , V. P. Puzyrev 1,2 ;
1 Research Institute of Medical Genetics, Tomsk, Russian Federation, 2 Siberian
State Medical University, Tomsk, Russian Federation, 3 Research Institute of
Cardiology, Tomsk, Russian Federation.
Numerous data appeared supporting the notion about an important
role which calcineurin pathway plays in myocardial hypertrophy, cardiac
remodeling and human heart failure . Though only few studies had
been reported to date which demonstrate an association of calcineurin
pathway genes polymorphisms with cardiac parameters or other cardiovascular
measurements .
In this study we analyzed association of two calcineurin pathway
genes polymorphisms (5-base pair deletion in calcineurin B promoter
- 5I/5D PPP3R1 gene polymorphism and SNP rs2228309 in exon 2
of NFATC4 gene - G160A) with echocardiographic parameters in 216
healthy individuals . Two polymorphisms under study had previously
been shown by us to be associated with left ventricular (LV) remodeling
in patients with arterial hypertension .
In healthy subjects we did not find association of those two polymorphisms
with LV myocardium mass index, wall thickness, LV remodeling
index, end diastolic size, ejection fraction or other cardiovascular
parameters .
To further analyze the role of two functional genetic variants we collected
a group of patients with ischemic heart disease and ischemic cardiomyopathy
(n=104) . We had revealed that patients differed from healthy
subjects in A160G NFATC4 gene allele frequencies (p=0,046) .
Our data supports the assumption that calcineurin pathway components
may be involved in pathological types human heart remodeling .
P06.044
study of genetic risk factors for cardiovascular disease in são
miguel island population (Azores)
T. Pereirinha 1 , C. C. Branco 1,2 , P. R. Pacheco 1,2 , R. Cabral 1,2 , L. Mota-Vieira 1,2 ;
1 Mol Genetics & Pathology Unit; Hospital of Divino Espirito Santo of Ponta
Delgada, EPE, Azores, Portugal, 2 Instituto Gulbenkian de Ciencia, Oeiras,
Portugal.
Several genetic variants − factor V Leiden (G1691A), prothrombin
(G20210A) and MTHFR (C677T and A1298C) − were found to be associated
with cardiovascular disease (CVD), a frequent cause of death
in many populations . The aim of this study is to investigate the preva-