2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
Resolution Melting technology in the LightCycler 480 . We performed
linkage disequilibrium (LD) and haplotype analysis using the Haploview
and SNPstats programs .
Six of the nine polymorphisms initially selected from the public databases
were validated in our population . SSCP/HD analysis allowed
for the identification of 9 novel SNPs (3 in TFF1, 4 in TFF2 and 2 in
TFF3), 7 of which could be functional, and a novel insertion polymorphism
c .*66_67InsCTT, in the 3’UTR region of TFF2. Preliminary LD
analysis indicates that each TFF gene is located in independent LD
blocks and that high LD exists between SNPs in TFF2 . Genotyping
of these polymorphisms in case-control studies of gastric cancer is at
present underway .
P06.282
investigation of genetic component of susceptibility to atopic
bronchial asthma and tuberculosis: xenobiotic-metabolising
enzymes.
E. Bragina 1 , M. Freidin 1 , A. Rudko 1 , O. Kolokolova 2 , L. Ogorodova 2 , A. Strelis 2 ,
V. Pusyrev 1 ;
1 Institute of Medical Genetics of Tomsk Scientific Center of Siberian Branch of
Russian Academy of Medical Sciences, Tomsk, Russian Federation, 2 Siberian
State Medical University, Tomsk, Russian Federation.
The relationships of polymorphic variants of the genes encoding xenobiotic-metabolising
enzimes (CYP2C19, CYP2E1, GSTT1, GSTM1,
GSTP1) with atopic bronchial asthma and lung tuberculosis, were studied
in people of Tomsk region . An association of a deletion polymorphism
of the GSTM1 gene and a 7632T>A exchange of the CYP2E1
gene with bronchial asthma were revealed (p=0 .008 and p=0 .049, respectively)
. Prevalence of a “null” genotype of the GSTT1 gene was
significantly different in groups of patients with various severity of bronchial
asthma (p=0 .045) . It was shown that 313G/G genotype of the
GSTP1 gene is a factor of resistance to tuberculosis (OR=0 .43; 95%CI:
0 .20-0 .91; p=0 .026) . 681G>A polymorphism of the CYP2C19 gene
was associated with scope of a pulmonary tissue damage (p=0 .040)
and with amount of erythrocytes in tuberculosis patients (p=0 .027) .
313A>G polymorphism of the GSTP1 gene was associated with variability
of alanine aminotransferase levels (p=0 .021) . The combination
of the GSTM1 +/+ and GSTP1 313G/G, played a protective role for the
both studied diseases (OR=0 .10; p=0 .018 for the asthma; OR=0 .37;
p=0 .045 for the tuberculosis) .This suggests that the genotypes and
their combinations of CYP2C19, GSTT1, GSTM1 and GSTP1 genes
have influence on predisposition and clinical polymorphisms of atopic
asthma and lung tuberculosis .
P06.283
Sex-specific genetic determinants in plasma levels of fibrinogen
M. Sabater-Lleal 1 , A. Buil 2 , J. Souto 1 , L. Almasy 3 , J. Blangero 3 , J. Fontcuberta 1 ,
J. Soria 1,2 ;
1 Haemostasis and Thrombosis Unit, Department of Hematology, Barcelona,
Spain, 2 Bioinformatic of Complex Diseases Unit. Research Institute of Hospital
de la Santa Creu i Sant Pau, Barcelona, Spain, 3 Department of Population
Genetics. Southwest Foundation for Biomedical Research, San Antonio, TX,
United States.
A major challenge of biomedical research is the identification of risk
factors for complex diseases . One well-established risk factor for cardiovascular
disease is the plasma fibrinogen levels. These levels are
influenced largely by genetic factors. But the exact nature of these
genetic factors is unknown .
Our aim was to localize QTL responsible for the plasma levels of fibrinogen
. We present the results of a Genome Wide Scan for fibrinogen
levels that includes a gender-specific analysis in 21 Spanish families
from the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project .
We used 500 DNA microsatellites scattered throughout the genome .
Our results revealed a highly significant LOD score (3.52, nominal
p=0 .00003) on Chromosome 17 that was only detected in females, indicating
that a QTL on this chromosome was responsible for fibrinogen
levels only in women .
A bioinformatic study in the region of Chromosome 17 revealed the
presence of some hormone-related genes (steroid hormone receptors)
that affect fibrinogen levels and that could explain this gender-specific
finding.
To our knowledge, this is the first report of a gender-specific QTL related
to cardiovascular disease. It demonstrates that a gender-specific
genetic analysis can increase our ability to detect phenotypes that are
affected by sex . We hope that our results will help to understand the
regulation of fibrinogen plasma levels that determine the susceptibility
of cardiovascular disease . Our results may provide a template for future
genetic studies of quantitative traits affecting complex diseases .
P06.284
Genetic variants of the tBX15 gene associated with thyroid
cancer susceptibility
M. Akdi1 , P. Galofré2 , R. Marcos1 , A. Velázquez1 ;
1 2 Universitat Autònoma de Barcelona and CIBERESP, Cerdanyola, Spain, Hospital
Josep Trueta, Girona, Spain.
Association studies to identify susceptibility genetic factors for thyroid
cancer have been appeared recently . Our initial case-control association
studies had shown that the rs2145418 and the rs4658973 markers
that map 377 kb apart on the 1p12 region have an independent
association with thyroid cancer susceptibility . Next we have expanded
these initial studies by genotype and haplotype analysis in the region
containing the two markers . Here we present the results related to the
rs2145418 region . Thus, the MassArray technique was used to genotype
136 control individuals and 201 thyroid patients . First we have
confirmed our previous results, by genotyping the rs2145418 SNP
along with two SNPs surrounding this marker . Only the rs2145418
polymorphism showed association with thyroid cancer . Consequently,
our hypothesis that rs2145418 could reside in a regulatory sequence
of casual genes mapping near or at certain distance of this marker
can not discarded . In addition, we have studied nine SNPs that cover
the TBX15 gene sequence, this gene maps 550 kb downstream of
rs2145418 . Four of these SNPs lying on the 5’-UTR region have shown
significant association with thyroid cancer (pT
of CD14 gene in 157 blood samples from children admitted in the Critical
Care Unit of the Hospital Niño Jesus (Madrid) with meningococcal
(Gram-negative) (n=55) or pneumococcal (Gram-positive) (n=102)
infections . Sixty six controls were genotyped in order to compare the
genotypic frequencies .
Genotypic frequencies of TLR2 polymorphisms were clearly different
in both groups of patients, when compared to control population, especially
for the p .R753Q polymorphism, being more frequent the p .753Q
allele (p=0 .0004 in meningococcal infections, and p=0 .0005 in pneumococcal
infections) .
Conversely, TLR4 polymorphism din not show different genotypic distribution
when compared to control population . Finally, the study of the
polymorphism of the CD14 showed different distribution when compared
to controls, with a p=0 .0113 in meningococcal infections and
p=0 .0353 in pneumococcal infections .
No differences were found among both groups of studied patients .
These results confirm the key role of the innate immunity system in predisposition
to severe infections . For both studied bacteria, the main risk
factor is the p .753Q allele followed by the CD14 promoter polymorphism .
TLR4 polymorphism did not influence the risk of suffering infections.