2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
several genes that code for ion channels have been implicated in the
LQTS which exists in two main forms: (i) Romano Ward syndrome
inherited as autosomal dominant, and (ii) Jervell and Lange-Nielsen
syndrome, an autosomal recessive disorder which is associated with
sensorineural deafness .
Here we present result of genetic linkage analysis on a family with a
history of sudden death in three children at the age of 7 to 8 years .
Screening the other four living children and their consanguineous parents
revealed that two sons were affected with prolonged QT intervals
with unremarkable hearing assessment . Whole genome scan using
Allegro software identified a locus on chromosome 5q31-34 with a
maximum positive LOD score of 2 .05 . This locus has not been described
in association with the LQTS . Further analysis of the region
with sequencing of potential candidate genes is in progress .
In this work, we report on the identification of a novel locus for the
LQTS . In the absence of hearing loss, the autosoml recessive pattern
of inheritance in our family suggests a new form of the LQTS . Furthermore,
identifying the causative gene on this locus may provide insight
into the genetic susceptibility to unexplained sudden death in general .
P06.161
LRP1, a candidate gene for risk modulation of premature
cardiovascular disease in heterozygous familial
hypercholesterolemia
R. Aledo 1 , V. Llorente-Cortés 1 , R. Alonso 2,3 , P. Mata 2,3 , L. Badimon 1,4 ;
1 Cardiovascular Research Institute, Barcelona, Spain, 2 Fundación Jiménez
Diaz, Madrid, Spain, 3 Fundación Hipercolesterolemia Familiar, Madrid, Spain,
4 CIBEROBN-Instituto Salud Carlos III, Barcelona, Spain.
Heterozygous familial hypercholesterolemia (hFH) is characterized by
severely elevated LDL-cholesterol levels and premature atherosclerosis
and cardiovascular disease (PCVD) . Genetic alterations of the
LDL-receptor gene are the main cause of this disease . However, there
is a substantial variation in the onset and severity of the disease . This
variability might be due to atherogenic risk factors of environmental,
metabolic and genetic origin modulating the phenotype of hFH disease
. LDL-receptor-related receptor (LRP1) is a multiligand binding
receptor that acts as a pivotal lipoprotein receptor for the atherotrombotic
transformation of the vascular wall . The aim of this study was
to analyse the association of LRP1 polymorphisms with premature
cardiovascular disease in 339 hFH-patients (262 PCVD and 77 non-
PCVD) from the Spanish FH Register . The polymorphisms c .1-25 C>G,
rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194,
rs1800181, rs1140648, rs1800164 distributed along the whole gene
were used in the study . The polymorphism rs1799986 showed a significant
association with PCVD in the codominant model for the heterozoygous
genotype CT (nominal P = 0 .0126, OR 2 .07 . CI 95 1 .14-3 .74)
.The functional effect of rs1799986, that apparently is a synonymous
mutation (Asp100Asp), was analyzed by the web interface http://pupasuite
.bioinfo .cipf .es . This polymorphism completely abolishes an
Exonic Splicing Enhancer sequence . This may results in splicing aberrations
as exon skipping and therefore in a deficient transcription of the
gene. Although further studies are needed to confirm the rs1799986
association with atherosclerosis and cardiovascular risk and to clarify
its physiological role, our results suggest that this polymorphism is a
biological plausible risk factor for PCVD .
P06.162
No association between polymorphic loci of the G gene and
major depressive disorder.
A. Gareeva, T. Noskova, E. Khusnutdinova;
Institute of Biochemistry and Genetics of Ufa Scientific center of Russian academy
of Sciences, Ufa, Russian Federation.
Major depressive disorder (MDD) is a common and highly heterogeneous
psychiatric disorder encompassing a spectrum of symptoms
involving deficits to a range of cognitive, psychomotor and emotional
processes. The flavoprotein D-amino acid oxidase (DAO) degrades the
gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type
glutamate receptors . A body of evidence suggests that DAO, together
with its activator, G72 protein, may play a key role in the pathophysiology
of MDD The present study tested the hypothesis that the M23
and M15 polymorphic loci of the G72 gene are associated with major
depressive disorder (MDD) . We studied M23 and M15 polymorphic
loci of the G72 gene in 163 MDD patients and in 268 normal controls
from Bashkortostan region (belonged to Russian and Tatars ethnic
groups). No significant differences were demonstrated for genotype or
allele frequency of the M23 and of M15 polymorphic loci of G72 gene
comparing the MDD and control group . The patient and the control
samples were not divided according ethnicity, because genotype and
allele frequencies were coincide in patient and control sample . Haplotype
analysis was conducted to assess the association between the
two markers within the G72 gene . The results showed that these two
markers are in no linkage disequilibrium (LD): D’ (patient sample) =
0.056, D’ (control sample) = 0.064. Our findings suggest that M23 and
M15 polymorphic loci of the G72 gene do not play a major role in the
susceptibility to MDD . However, further studies with a larger sample
are required to confirm the obtained results.
P06.163
search for genetic mechanisms involved in malaria infection in
Amazon
R. G. M. Ferreira 1 , L. M. Garrido 1 , C. E. M. Kawamata 1 , L. M. A. Camargo 2 , H.
Krieger 1 ;
1 Departmento de Parasitologia, Instituto de Ciências Biomédicas, Universidade
de São Paulo, Brazil, São Paulo, Brazil, 2 Universidade São Lucas, Porto Velho,
Brazil.
The biochemical pathways involved in the pathogenesis of the parasite
infection that causes malaria and the human host mechanisms of
defense against it are still not entirely know . Epidemiologic studies,
as well genetic studies, suggest the existence of genetic components
related to the host innate resistance or susceptibility to malaria (Hill
A .V .,2006) . Based on results obtained by our group in a genome-wide
scan in 182 individuals from Portuchuelo (8 o 37’S, 63 o 49’W), Rondonia
state, Brazil (Ferreira R .G .M . et al.,2007) . The following STRs markers
in the short arm of chromosome 4 spanning from 0 to 57cM where selected
to be genotyped in a distinct population, Monte Negro (10 o 15’S,
63 o 18’W), at the same Brazilian state .
The sample, 452 individuals from nuclear families, was genotyped using
7 SRTs markers (D4S412 - 4 .74cM, D4S2983 - 17 .5cM, D4S403
- 25cM, D4S419 - 30cM, D4S3022 - 36cM, D4S391 - 43 .6cM, D4S405
- 57cM) along short arm of chromosome 4, with a mean distance of
8 .74cM from each other . The software SimWalk2 (Sobel E . et al .,2002)
was used to check mendelian segregation of the alleles in the families
.
The reported number of malarial episodes, corrected by age and sex,
was used as the quantitative trait phenotype . This phenotype showed
expected association with Fy- individuals as well as familial aggregation
in conformity with genetic mechanisms, indicating its epidemiological
importance . Linkage analysis were conducted using the software
Solar 2 (Almasy L . et al .;1998) .
No evidence of linkage was found both in multi-point and two-point
analysis . (FAPESP,CNPq)
P06.164
matrix metalloproteinase-3 gene polymorphism and dilatative
pathology of ascending thoracic aorta
G. Sinkunaite, V. Lesauskaite, R. Benetis, A. Smalinskiene, S. Simonytë, G.
Jariene, V. Tatarunas, J. Petkeviciene, J. Klumbiene;
Institute of Cardiology, Kaunas University of Medicine, Kaunas, Lithuania.
The aim of the study was to identify whether the mutation in the promoter
region of MMP3 gene might be a determinant of dilatative pathology
of ascending thoracic aorta (DP ATA) .
Material and methods . We studied 76 (55 males, 21 females) patients
with DP ATA, the age ranged from 31 to 81 years (median, 64 years)
and a random sample of the population ((244 males and 366 females)
aged 25-64 yrs ., all from Lithuania . Analysis was done on DNA using
real-time polymerase chain reaction to genotype polymorphism 5A/6A
at a position -1171 of the MMP3 gene promoter .
Results . The prevalence of MMP-3 genotypes was similar between
group of DP ATA and random sample of population . The frequency of
5A allele did not differ between both groups and was 0 .506 and 0 .514,
respectively. Male patients carrying 5A/5A genotype were significantly
younger compared with those with the 6A/6A genotype .
In conclusion, the frequency of MMP-3 promoter 5A/6A genotypes did
not differ between the group of patients with DP ATA and the random
sample of population, but the males with DP ATA and 5A/5A genotype
required aortic reconstruction surgery at the younger age than the