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

Genetic analysis, linkage, and association
and FEV1 (p=0.018). No association was found among other polymorphisms
and studied clinical parameters. In order to confirm these
preliminary data, we have enlarged our population, and we are now
genotyping a second group of 60 unrelated Italian CF patients.
P0952. Syntaxin 1A: a possible modifier of lung disease in cysic
fibrosis (CF)
J. Racine 1 , R. Kraemer 2 , A. Schaller 1 , T. von Kaenel 1 , M. Schneider 1 , J. Sanz 1 ,
S. Gallati 1 ;
1 Division of Human Genetics, Dept. of Paediatrics, University of Bern, Bern,
Switzerland, 2 Dept. of Paediatrics, University of Bern, Bern, Switzerland.
Phenotypic presentation, primarily progression of lung disease, varies
significantly even among patients with the same CFTR genotype.
There is growing evidence that polymorphic variants in genes besides
CFTR play an important role in phenotype determination. Mainly genes
that modulate the chloride-transport or the cycle of inflammation may
lead to progressive lung disease. Syntaxin 1A (STX1A), a SNARE protein
essential for the docking and fusion of exocytotic vesicles, binds
to the N-terminal tail of CFTR and down-regulates its function by direct
protein-protein interaction making it a promising candidate as a CF
modifier.
DNA from 63 F508del homozygous and clinically well characterized
patients was screened for mutations in the STX1A gene using our very
sensitive (98%) SSCP/HD method followed by direct sequencing of
the variants. Eight different sequence variants (c.31-21T>C, 3.17%;
c.150C>T, p.N50N, 6.35%; c.204T>C, p.D68D, 37.30%, c.284-66G>A,
2.38%; c.467-38A>G, 42.06%; c.540+52C>T, 42.86%; c.790-15C>T,
3.97%, c.959+92C>T, 3.17%) were identified and tested for associations
with lung function parameters such as functional residual capacity
determined by whole-body plethysmography (FRCpleth), lung
clearance index (LCI), trapped gas (VTG) and indexes of flow limitation
(FEV1, FEF50). Most significant associations were found between
c.204T>C and c.467-38A>G and the lung parameters LCI and
FEF50.
Homozygosity for F508del combined with both c.204T/T and c.467-
38G/G predicts a progressive and severe lung disease (n=11), combination
with c.204C/C and c.467-38A/A, however, is associated with
a much milder course (n=18; p = 0.001 for LCI, p=0.002 for FEF50).
Thus, the STX1A gene seems to act as a modifier of lung disease in
CF patients.
P0953. Cystic Fibrosis modifier genes and outcome of the
disease. Correlation with the age of the patients.
J. J. Telleria1 , J. Gobernado2 , C. Vázquez3 , F. Baranda3 , M. J. Alonso1 , I.
Fernández1 , J. M. F. Fernández1 , A. Blanco-Quirós1 ;
1 2 Universidad de Valladolid, Valladolid, Spain, Hospital Clinico Universitario,
Valladolid, Spain, 3Hospital de Cruces, Bilbao, Spain.
In Cystic Fibrosis (CF) patients, the CFTR genotype is not a good predictor
of pulmonary disease, which is the direct cause of death in over
90% of CF patients. Genotype-phenotype studies showed a high variation
in severity of pulmonary disease, even between patients sharing
the same CFTR genotype, suggesting that outcome is under the influence
of other genetic or/and environmental factors.
The aim of this study was to study the role of several potential modifier
genes and if this role changes as the disease progress.
Sixty one cystic fibrosis patients over 23 years were initially included
in the study. CFTR mutations were identified and genotype was carried
out for the following genes: PI (alpha-1-antitrypsin), TNFA, TGFB1
(codons 10 and 25), IL10, IL6 and IFNG.
In order to minimise the role of the CFTR genotype, patients with mild
mutations were excluded of the study. Data corresponding to the basal
forced expiratory volume in 1s (FEV1), Crispin-Norman score, and
forced vital capacity (FVC) were retrospectively recorded.
Results showed a double distribution of modifying effect: PI and IFNG
showed good correlation to FEV1 and FVC between 10 and 15 years,
whereas for TGFB and IL6 we found good correlation in patients over
18 years. Crispin-Norman score showed good correlation only with
TGFB1 codon 10 genotype. We did not find correlation neither for IL10
nor for codon 25 of TGFB1.
These findings suggest that the role played by the modifier genes
deppends on the stage of the disease, and changes as the disease
progress
P0954. Polymorphisms of the IL1B and IL1RN genes are
associated with essential hypertension in Tatars from Russia
Y. R. Timasheva1 , T. R. Nasibullin1 , A. N. Zakirova2 , O. E. Mustafina1 ;
1 2 Institute of Biochemistry and Genetics, Ufa, Russian Federation, Bashkir
State Medical University, Ufa, Russian Federation.
Essential hypertension (EH) is a common disease and a major risk
factor for many cardiovascular events. The hereditary nature of hypertension
is well established. Inflammation plays a pivotal role in the
pathogenesis of cardiovascular disease. Inflammatory damage of endothelium
leads to impairment of the vascular tone. Interleukin-1 (IL-1)
regulates the expression of genes involved in inflammatory response.
IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1
signaling. The rare allele (IL1RN*2) of a variable number tandem repeat
polymorphism in the IL1RN gene was demonstrated to significantly
reduce IL-1Ra level.
The aim of the present study was to investigate the association between
IL1B and IL1RN polymorphisms with EH in Tatar ethnic group
(Bashkortostan, Russia).
Our study comprised 360 hypertensive patients. The control group
consisted of 242 healthy individuals. Genomic DNA was isolated from
peripheral blood by phenol-chloroform extraction. Genotyping was
performed using polymerase chain reaction followed by AvaI digestion
(for IL1B-511T/C polymorphism). Genotypes and allele frequencies
distribution was estimated using Fisher’s exact test. Odds ratios with
95% confidential interval were calculated.
IL1RN*2 allele was found to be associated with risk of early onset (before
45 years) of EH (OR=3.27, CI: 1.65-6.49). We have shown that
IL1B-511*C/*C genotype was less frequent among hypertensive patients
who had stroke (37.5% versus 57.52% in group of patients with
non-complicated EH, P=0.03). We may conclude that IL1B-511*C/*C is
associated with decreased risk of stroke in patients with EH (OR=0.44,
CI: 0.22-09).
Our results suggest a significant role for IL1 family genes in the development
of cardiovascular disease.
P0955. Screening for SLC26A4 gene mutation in unilateral
hearing impairment and same-side EVA
L. Jonard 1 , D. Feldmann 1 , A. David 2 , H. Dollfus 3 , V. Drouin-Garraud 4 , F. Fellmann
5 , C. Francannet 6 , B. Gilbert 7 , H. Journel 8 , E. Garabedian 1 , R. Couderc 1 ,
C. Petit 9 , F. Denoyelle 1 , S. Marlin 1 ;
1 AP-HP, Trousseau, Paris, France, 2 CHU, Nantes, France, 3 CHU, Strasbourg,
France, 4 CHU, Rouen, France, 5 CHU, Besançon, France, 6 CHU, Clermont Ferrand,
France, 7 CHU, Poitiers, France, 8 CHU, Vannes, France, 9 INSERM U587,
Institut Pasteur, Paris, France.
Mutations of the SLC26A4 (PDS) gene are involved in either syndromic
deafness, characterized by congenital sensorineural hearing loss and
goitre (Pendred syndrome), or congenital isolated deafness (DFNB4).
In our previous studies, we identified mutations in cases with bilateral
hearing impairment and unilateral enlarged vestibular aqueduct
(EVA) in two cohorts (Pendred and DFNB4). In the present study, we
screened SLC26A4 by DHPLC in 25 patients presenting with unilateral
hearing impairment associated with same-side EVA. None of these patients
had two deleterious genetic changes in trans. Seven of them had
a single heterozygous SLC26A4 variation. Among these variations, we
found three established mutations and three potentially deleterious
genetic changes.
We conclude that causative SLC26A4 mutations in patients with unilateral
deafness and same-side EVA are at best infrequent.
P0956. No evidence for an association of the
methylenetetrahydrofolate reductase gene C T polymorphism
with major depressive disorder
D. Gaysina 1,2 , S. Cohen 2 , F. Hoda 2 , N. Craddock 3 , A. Korzsun 4 , M. Owen 3 , I.
Craig 2 , A. Farmer 2 , P. McGuffin 2 ;
1 Institute of Biochemistry and Genetics, Ufa, Russian Federation, 2 MRC SGDP
Centre, Institute of Psychiatry, King’s College London, London, United Kingdom,
3 Department of Psychological Medicine, Cardiff University, School of
Medicine, Cardiff, United Kingdom, 4 Centre for Psychiatry, Wolfson Institute of
Preventive Medicine, Barts and The London Queen Mary’s School of Medicine,
London, United Kingdom.
Major Depressive Disorder (MDD) is a complex disorder thought to
result from multiple genes interacting with environmental and developmental
components. The 5,10-methylentetrahydrofolate reductase
2