2009 Vienna - European Society of Human Genetics

Genetic analysis, linkage ans association
was bimodal, based on previously studies we divided the alleles into 2
subclasses: class S included shorter ( or =27) repeats. Multivariate logistic regression models
including standard coronary risk factors revealed that the genotypes
were significantly related to CAD status . In this study, the patients with
shorter GT repeats were less likely to have CAD.
CONCLUSIONS: Length polymorphism in the HO-1 gene promoter is
related to CAD susceptibility in Iranian people who also have coronary
disease risk . This study confirm HO-1 antiatherogenic role in Iranian
patients with CAD.
P17.21
Genetic variations in nitric oxide synthase genes NOs1, NOs2A
and NOs3 and cerebral small vessel disease
J. Wang1 , M. Tscherner2 , R. Schmidt2 , F. Fazekas2 , H. Schmidt2 ;
1 2 Xinjiang Medical University, Xinjiang, China, Medical University Graz, Graz,
Austria.
Background: Cerebral small vessel disease (cSVD) is the second most
common endemic entity of the ageing brain following Alzheimer pathology.
Its hallmark lesions white matter lesions (WML) and lacunar
infarctions can be non-invasively depicted with brain MRI. Gait disturbances
and progressive cognitive impairment are frequent clinical consequences.
Major risk factors are hypertension and age. Its heritability
is in the range of 55-73%. Nitric oxide is an important regulator of blood
pressure and cerebral blood flow and has been implicated in ischemic
stroke. Here we studied genetic variations of nitric oxide synthetases,
NOS1, 2A and 3 in relation to cSVD.
Methods: The study was conducted in the Austrian Stroke Prevention
Study a prospective, cohort study in the normal elderly in Graz, Austria.
In total 787 participants underwent genotyping and MRI. Genotyping
was done by Illumina Human610-Quad BeadChip. Association
was tested by additive genetic model with 1-degree of freedom trend
test relating genotype dosage, 0 to 2 copies of the minor allele to WML
volume and lacunes. Adjustment was done for age and sex (model1)
and for age, sex and hypertension (model 2).
Results: We selected 9 tagging SNPs in NOS1, 17 in NOS2A and
12 SNPs in NOS3 gene. Several SNPs in NOS1 and NOS2A gene
showed significant associations in both models with WML but not with
lacunes. Association was no longer significant after adjustment for
multiple comparison.
Discussion: Our results do not support the role of SNPs at the NOS1,
2A and 3 genes in cerebral small vessel disease.
P17.22
NOtcH3 Gene and cerebral small Vessel Disease
M. Tscherner1 , R. Schmidt2 , F. Fazekas2 , H. Schmidt1 ;
1 2 Institute of Molecular Biology and Biochemistry, Graz, Austria, University
Clinic of Neurology, Graz, Austria.
Background: Cerebral small vessel disease (cSVD) is the second most
common entity of the ageing brain following Alzheimer pathology. Its
hallmarks are white matter lesions (WML) and lacunar infarctions, detected
by brain MRI. Gait disturbances and cognitive impairment are
the clinical consequences. Risk factors are hypertension and age. Its
heritability is in the range of 55-73%. In the present study we investigated
the role of NOTCH3 gene in cSVD. Mutations in NOTCH3 cause
CADASIL, a monogenetic form of cSVD.
Methods: The study population consisted of 923 participants of the
Austrian Stroke Prevention Study a population-based, prospective,
cohort study. cSVD was defined by MRI on T2 weighted images. Polymorphisms
in the NOTCH3 gene were screened in 88 persons with
and 82 persons without cSVD by denaturing HPLC or by sequencing.
SNPs (rs1043994, rs10423702, rs1043997) were genotyped in the
whole cohort by TaqMan assay.
Results: We detected 35 SNPs in the NOTCH3 gene, 10 SNPs were
not described previously. In total 23 SNPs were located in exons, 4 in
introns, 3 in the promoter and 2 in the 3`-UTR. There was a non significant
difference in the distribution of the SNPs rs1043994, rs10423702
and rs1043997 between cSVD positive and negative subjects.
Discussion: This is the first study investigating the whole NOTCH3
gene in healthy population and its role in cSVD. Our results show that
SNPs in NOTCH3 gene appear with a high frequency in the elderly. So
far our data do not support a role of NOTCH3 in cSVD.
P17.23
CYP C * allele modifies the activity of the renin-angiotensin
system in hypertensive men
K. M. Donner 1,2 , T. P. Hiltunen 1,2 , T. Suonsyrjä 1,2 , T. Hannila-Handelberg 1,2 , I.
Tikkanen 1 , M. Antikainen 3 , A. Hirvonen 3 , K. Kontula 1,2 ;
1 Department of Medicine, University of Helsinki, Helsinki, Finland, 2 Research
Program for Molecular Medicine, University of Helsinki, Helsinki, Finland, 3 Finnish
Institute of Occupational Health, Helsinki, Finland.
CYP2C9 catalyses the formation of epoxyeicosatrienoic acids (EETs)
that have been described to show antihypertensive action in kidneys
and vasculature. Two variants, CYP2C9*2 and *3, have reduced catalytic
activity. We studied the impact of these variants on the activity
of the renin-angiotensin-aldosterone system (RAAS) in two cohorts of
hypertensive subjects.
The GENRES Study consisted of 219 hypertensive Finnish men, aged
35 to 60 years, who were treated with four different antihypertensive
monotherapies for four weeks. Baseline laboratory values were measured
at the end of the first placebo period. The cohort with treatmentresistant
essential hypertension (TREH) consisted of 170 females and
145 males who completed a captopril challenge test (CCT) and had no
interfering medications.
Allele frequencies for CYP2C9*2 and *3 in both cohorts correspond to
reported Caucasian frequencies. In the GENRES group, CYP2C9*1*3
genotype was associated with lower baseline plasma renin activity
(PRA) and serum aldosterone levels compared with CYP2C9*1*1 genotype
(P=0.0008 and 0.009, respectively). In the TREH group, PRA
and aldosterone levels and their product were lower in male CYP2C9*3
allele carriers (P=0.09, 0.19, and 0.04, respectively), and these males
had a lower increase in PRA (P=0.24) and a lower reduction in serum
aldosterone (P=0.003) upon CCT. In addition, these males had higher
serum sodium levels (P=0.08).
In conclusion, this study carried out in two independent cohorts of hypertensive
men shows that CYP2C9*3 influences RAAS activity. These
findings might reflect variations in CYP2C9-mediated EET metabolism
and call for additional studies on the eicosanoid-related genetic effects
in human hypertension.
P17.24
Deletion allele in a tunisian healthy and myocardial infarction
population
S. Mehri 1 , B. Baudin 2 , S. Mahjoub 1 , B. Bénéteau-Burnat 2 , R. Mechmeche 3 , M.
Hammami 4 , S. Ben Arab 1 ;
1 Unité d`Epidémiologie Génétique et Moléculaire, Faculté de Médecine de
Tunis, Tunis, Tunisia, 2 Service de Biochimie A, Hôpital Saint-Antoine, Paris,
France, 3 Services des Explorations Fonctionnelles Cardiologiques, Hôpital La
Rabta de Tunis, Tunis, Tunisia, 4 Laboratoire de Biochimie, U.S.C.R de Spectrométrie
de Masse, la Faculté de Médecine de Monastir, Tunis, Tunisia.
Background: The role of the insertion/deletion polymorphism in the angiotensin-converting
enzyme gene (ACE I/D) on myocardial infarction
(MI) is controversial. Individuals homozygous for the deletion have a
higher level of circulating enzyme and therefore may predispose to
cardiovascular damage.
Aim: to assesses the effect of the ACE polymorphism on MI and its
relationship with serum ACE activity and to compare them with other
populations.
Patients and Methods: 119 patients with MI compared to 380 healthy
controls, originated from the same areas, and genotyped by PCR. Serum
ACE activity was measured by FAPGG as substrate.
Results: The ACE I/D was significantly associated with MI (p