2009 Vienna - European Society of Human Genetics

Genetic analysis, linkage ans association
P17.37
Association of the ccttt repeat polymorphism in NOS (Nitric
oxide synthase 2 gene) promoter region with susceptibility to
pulmonary arterial hypertension
D. Valverde1 , T. Piñeiro-Gallego1 , I. Pereiro1 , C. Vilariño2 , A. Baloira2 ;
1 2 University of Vigo. Spain, Vigo, Spain, Servicio de Neumología. Complexo
Hospitalario de Pontevedra, Pontevedra, Spain.
Pulmonary arterial hypertension (PAH) is a progressive disease in
which the proportion of affected women is twice as men, with an incidence
of 1/100000-1000000. Familial cases cover 10% of cases and a
model of autosomal dominant inheritance with incomplete penetrance
and genetic anticipation has been proposed. Mutations in the gene
BMPR2 have been described as responsible for 90% of familial cases,
despite the fact that only 20% of the relatives of mutation carriers
develop the disease. For idiopathic pulmonary arterial hypertension,
mutations in the BMPR2 gene have been described in a 9-26% of
cases. These data support the hypothesis of the existence of other
genes involved and the environmental effect on the development of
this condition.
Vasodilators such as nitric oxide (NO) and prostacyclin, along with prolonged
overexpresion of vasoconstrictors such as endothelin (ET-1),
not only affect vascular tone but also promote vascular remodelling.
Both have been implicated in the pathogenesis of PAH.
NO is an endothelial-derived relaxing factor that is synthesized from
L-arginine by nitric oxide synthase. NOS2 is the major source of NO
production and polymorphisms in the NOS2 gene promoter are though
to regulate its transcription activity.
The aim of this work was to investigate the association between the
CCTTT polymorphism of the NOS2 gene and the susceptibility to
PAH.
We analysed that polymorphism in 30 patients of PAH and 50 controls.
The data reveals that the shorter forms of the CCTTT repeat were associated
with susceptibility of PAH.
P17.38
Vitamin D receptor gene polymorphism foki is associated
with severity of atherosclerosis and poor collateralization in
angiographically documented cAD patients
H. Saghafi 1 , A. Hossein-nezhad 1 , B. Larijani 2 ;
1 Bio & Nano Technology Unit of Endocrinology and Metabolism Research Center,
Tehran, Islamic Republic of Iran, 2 Endocrinology and Metabolism Research
Center of Tehran University of medical sciences, Tehran, Islamic Republic of
Iran.
Introduction:Recent studies found a relationship between Vitamin D
and atherosclerosis. The aim of this study was to evaluate severity of
coronary artery disease (CAD) and collateral development in different
genotypes of vitamin D receptor (VDR) gene.
Methods:In a case-control study 114 participants with angiographically
documented CAD and normal coronary were recruited. Severity of
CAD was defined by the numbers of involved coronary vessels. The
modified TIMI scoring was used to grade the collateral development.
Whole blood DNA extraction was performed and FokI polymorphism
(C27823T) was determined by PCR-RFLP method.
Results:The mean age of participants was 57.01±10.29 years. Single,
two and three-vessel were involved in 27.7, 16.9 and 34.5 percent of
participants, respectively. Prevalence of genotype FF, ff and Ff were
54.4%, 38.6% and 7% respectively. BMI, FBS, total cholesterol, triglyceride
and LDL were higher among ff though only significant about BMI
and triglyceride (p=0.03). Age and HDL were lower among ff though
only significant about age (p=0.003). in younger patients (age lower
than 55 years) with ff genotype compared with FF genotype had significantly
higher poor-developed (25% vs. 0%) and lower well-developed
collaterals (0% vs.4%) (p=0.03). Significantly higher severity of
CAD also was found among patients with ff genotype (66% of ff vs.
37.5% of FF had three-vessel involvement-p=0.01) in patients over
55 years old.
Conclusion: Our findings showed that sever CAD and poor collateralization
associated with ff genotype of VDR gene. VDR genotyping
may be useful as early predictor of poor prognosis of coronary artery
disease.
P17.39
Genetic variability in the AcE gene region surrounding the Alu
i/D polymorphism is maintained by balancing selection in human
populations
R. Cagliani 1 , M. Fumagalli 1,2 , S. Riva 1 , U. Pozzoli 1 , G. P. Comi 3 , N. Bresolin 1,3 ,
M. Sironi 1 ;
1 Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy, 2 Bioengineering Department,
Politecnico di Milano, Milan, Italy, 3 Dino Ferrari Centre, Department
of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico,
Mangiagalli and Regina Elena Foundation, Milan, Italy.
Angiotensin-converting enzyme (ACE) plays a critical role in the
maintenance of cardiovascular homeostasis. Extensive research has
aimed at identifying ACE genetic variants responsible for variation in
enzyme plasma concentrations and associated with human diseases.
These efforts have been hampered by the extensive linkage disequilibrium
across the gene and the identity an location of the functional
polymorphism(s) is at presently unknown.
Here, we characterize the sequence variation and haplotype structure
of the ACE gene region surrounding the Alu insertion/deletion (Alu I/
D) polymorphism in 4 human populations. We observed high levels
of nucleotide diversity, an excess of intermediate-frequency alleles
and, at least in African populations, a higher level of within-species
diversity compared to interspecific divergence. Analysis of haplotype
genealogy indicated the presence of two major clades separated by
deep branches with a coalescence time older than 1.5 million years. All
these features strongly suggest the action of balancing selection and
we verified that the selection signature is restricted to the gene region
surrounding the Alu I/D.
Our data therefore imply the presence of a functional polymorphism in
the Alu I/D region and illustrate the contribution of evolutionary models
to classic SNP-phenotype association approaches by providing information
about the localization of candidate functional variants.
P17.40
the effect of codon 71 polymorphism in the apolipoprotein B
gene on parameters of lipid metabolism in a serbian school-age
child population
T. M. Damnjanovic1 , I. Novakovic1 , B. Jekic1 , N. Maksimovic1 , M. Vukotic1 , S.
Nedeljkovic1 , S. Simeunovic2 , L. Lukovic1 ;
1 2 Institute of Biology and Human Genetics, Belgrade, Serbia, University Child
Hospital, Belgrade, Belgrade, Serbia.
Lipoproteins are vehicles for distribution of plasma lipids and polymorphism
in the genes encoding for apolipoproteins could influence the
amount of lipid in plasma. We examined the effect of single nucleotide
polymorphism in the codon 71 of the apolipoprotein B (apoB) gene on
levels of triglycerides and cholesterol in school-age child population.
Studied group included 530 Serbian children attending eight class of
elementary school. In all participants standard clinical examination
was performed. Levels of total cholesterol, LDL cholesterol, HDL cholesterol
and triglycerides were determined by standard biochemical
methods. Polymorphism in apoB codon 71 was genotyped by PCR
amplification of specific fragment of genomic DNA followed by digestion
with the Apa LI restriction enzyme. We found wild type genotype
CC in 265 (50%), heterozygous CT in 212 (40,0 %) and homozygous
mutant genotype TT in 53 (10,3%) children. Triglycerides level was
higher (p=0,0673) in TT than in two other genotype groups; this difference
was statistically significant (p=0,0305) in boys. Also, apolipoprotein
(a) level was significant higher (p=0,018) in TT group (boys
p=0,040). Among child with arterial blood pressure under p25 for age
carriers of T allele had statistically significant higher total cholesterol
(p=0,0078), LDL cholesterol (p=0,033) and triglyceride (p=0,0036)
levels comparing to the group without T allele. The increased arterial
blood pressure was associated with the significant decrease of HDL
cholesterol levels (p=0, 0249), especially in children with T allele. Our
study showed that apoB codon 71 polymorphism has effect on parameters
of lipid metabolism in school-age child.