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

Genetic analysis, linkage, and association
took a 500k genome-wide scan in a larger sample of individuals.
Method: From the population-based KORA S3 survey 1,644 randomly
selected individuals were genotyped on Affymetrix 500k arrays. Association
was calculated using single and multi-marker tests under additive,
dominant and recessive models adjusting for covariates known to
explain parts of QT variance.
Results: In the 500k dataset the QTL at the NOS1AP gene gave a
clear unmistakably association signal. 60 SNPs throughout a 500kb
genomic region were associated with significance levels down to 1e-
7.5. In addition we identified 55 additional QTLs between 1 and 5
SNPs in size with significance levels smaller 1e-5. Five of these QTLs
were confirmed in a n=1.200 replication sample.
Conclusions: The QTL at the NOS1AP gene was confirmed as the
single most significant signal from a 500k-genomewide scan. Its strong
signal is due to its high allele frequency (MAF=0.35), 500kb long LD
relationship and relatively strong effect size. Newly identified QTLs display
a spectrum of different effect sizes, allele frequencies, surrounding
LD patterns and coverage by genotyping arrays, which in combination
decreased their detection probability and explains why they went
undetected in the previous association scan.
P0980. Gestational hypertensive disorders, newborn birth weight
and maternal IGF2/ApaI and H19/RsaI polymorphisms
F. M. Araujo1 , M. R. Soares1 , M. V. M. Gomes1 , G. Duarte1 , C. R. Marcondes1,2 ,
P. A. Vozzi1 , R. B. Lôbo1 , E. S. Ramos1 ;
1 2 University of São Paulo, Ribeirao Preto, Brazil, Empresa Brasileira de Pesquisa
Agropecuária, Belem, Brazil.
Gestational hypertensive disorders are among the leading causes of
maternal death. Genomic imprinting has an important role in fetoplacental
development. Polymorphism of the imprinted IGF2 gene has
been associated with obesity and cardiovascular risk predisposition.
The maternally expressed H19 gene does not code for a protein, but
the RNA has growth suppressing functions. In the present study, the
association among gestational hypertensive disorders, newborn birth
weight (NBW) and maternal IGF2/ApaI and H19/RsaI genotypes were
investigated. Blood samples of 235 pregnant women [56 with preeclampsia
or eclampsia (PE/E); 40 with gestational hypertension (GH);
34 with chronic arterial hypertension (CH); and 105 healthy controls]
were obtained for DNA extraction, PCR and genotyping. Statistical
analyses were performed by Qui-square, G, Kolmogorov-Smirnov and
Kruskal-Wallis Nonparametric Tests. There was no influence of „skin
color”. Around 80% of the patients presented at least one copy of the
alleles B (H19) and G (IGF2), concomitantly. Although the IGF2 and
H19 genotypes were not significantly associated with gestational hypertensive
disorders and/or NBW, a tendency for higher birth weight in
newborns of mothers with AA (IGF2) genotype [mean = 3176g versus
2939g (AG) and 2772g (GG)] was observed. To our knowledge, this
is the first study regarding the influence of H19/RsaI polymorphism in
hypertensive disorders of pregnancy.
P0981. GJB2 mutations in Croatian patients with non-syndromic
hearing loss
I. Sansović1 , I. Barišić1 , J. Pavelić2 ;
1 2 Children’s Hospital Zagreb, Department of Paediatrics, Zagreb, Croatia, Rudjer
Bošković Institute, Division of Molecular Medicine, Zagreb, Croatia.
Mutations in GJB2 (connexin 26) gene represent a major cause of prelingual
non-syndromic hearing loss (NSHL) worldwide. Among them,
35delG mutation accounts for approximately 70% of all GJB2 mutant
alleles in most European populations.
The aim of the study was to evaluate the frequency and type of mutations
in the exon 2 of GJB2 gene and frequency of (GJB6-D13S1830)del
in GJB6 gene in 48 patients with recessive NSHL from Croatia.
The coding region of the GJB2 gene was sequenced and the GJB6
deletion was analyzed by two specific PCR reactions.
A half (26/48 or 54%) of our patients presented with one or two mutations
in the GJB2 gene. Among 50 mutated chromosomes found in
patient with NSHL, 41 (82%) carried 35delG mutation. Other common
mutations - L90P, 313del14, V37I and W24X, accounted for 3.1% -
1.0% of analyzed chromosomes. We have also found a novel variant,
-24A>C, reported here for the first time. GJB6 deletion was not found
in our tested subjects. The high mutation rate (50/96 or 52%) in the
coding region of the GJB2 gene indicates the importance of the GJB2
gene testing in Croatian patients with recessive NSHL.
2 1
P0982. No modifier effect of the Glu298Asp polymorphism of
ENOS gene in autosomal dominant polycystic kidney disease
N. Stefanakis1 , E. Tsaliki1 , M. Vasilakou1 , P. Zirogiannis2 , S. Trigonis2 , K. M.
Lamnissou1 ;
1 2 Department of Biology, Athens, Greece, Department of Nephrology,
“G.Gennimatas” Hospital, Athens, Greece.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the
most common monogenic hereditary diseases. It is characterized by
a substantial variability in the severity of renal phenotype, primary assessed
by the age at end - stage renal disease (ESRD). The role of
modifier genes has been shown in different hereditary diseases, including
ADPKD. ENOS, the gene coding for the endothelial nitric oxide
synthase is considered to have modifier effect in ADPKD. In this study
we investigated the influence of one of the most studied polymorphisms
of ENOS gene, the Glu298Asp polymorphism, on the age at
ESRD. We analysed a total of 100 ADPKD unrelated patients and 104
healthy cohorts from Greece. The frequencies of the three genotypes
GG, GT, TT of the Glu298Asp polymorphism were 0.48, 0.38, 0.14,
respectively in the group of patients and 0.47, 0.46, 0.075, respectively,
in the control group. Analysis of the dada regarding progression
to ESRD within 5 years or after more than 5 years following clinical
diagnosis of ADPKD provided no evidence of statistical difference. In
contrast to some earlier studies our results do not support that the
frequent of Glu298Asp polymorphism of ENOS is associated with a 5
year lower mean age at ESRD in this subset of ADPKD patients.
P0983. Glucocerebrosidase gene mutations are associated to
Parkinson’s disease in a population from Southern Italy
E. V. De Marco, F. E. Rocca, P. Tarantino, G. Provenzano, D. Civitelli, S. Carrideo,
I. C. Cirò candiano, I. C. Cirò Candiano, F. Annesi, G. Nicoletti, G. Annesi;
Institute of Neurological Sciences, National Research Council, Mangone (CS),
Italy.
Recent studies have reported clinical, neuropathological and genetic
associations between Parkinson’s disease PD) and Gaucher’s disease
(GD), an autosomal recessive disorder caused by mutations in
the GBA gene, coding for the lysosomal enzyme glucocerebrosidase.
Screenings for GBA mutations in PD subjects belonging to different
populations have suggested that heterozygosity may be a susceptibility
factor predisposing to PD.
In order to elucidate the role of the GBA gene in PD in our population
we screened 401 PD patients coming from Calabria (Southern Italy)
for the two most frequent mutations, N370S and L444P. Forty-nine patients
(12,2%) were familial. A control group consisting of 495 subjects
originating from the same geographical area of the patients was used
to determine the mutation frequency in the general population. Genotyping
was performed by using PCR amplification followed by restriction
enzyme digestion with XhoI for the N370S substitution and NciI
for the L444P substitution. Mutation frequencies in cases and controls
were compared using Fisher’s exact test.
We found 11 patients (2.7%) carried a heterozygous mutant GBA allele:
three of them had the N370S mutation and eight had the L444P
mutation. In the control group 1 subject (0.5%) carried a heterozygous
L444P mutation. These distributions are significantly different
(p=0.0018).
This study was performed on the most consistent PD group so far investigated
for GBA mutations, revealing a significant association with
the disease. Our results thus contribute to identify genetic factors influencing
PD susceptibility in our population.
P0984. Growth hormone receptor codon 440 G/T polymorphism
is associated with first-year growth response in patients with
GHD
F. Tsai 1,2 , L. Wan 1 , C. Tsai 3 , C. Lee 4 ;
1 Department of Medical Genetics ,China Medical University Hospital, Taichung,
Taiwan, 2 College of Chinese Medicine,China Medical University, Taichung,
Taiwan, 3 Department of Biotechnology and Bioinformatics, Asia University,
Taichung, Taiwan, 4 Department of Neurology,China Medical University Hospital,
Taichung, Taiwan.
Context: GH replacement is an effective therapy for GH deficient (GHD)
children. However, growth velocity post-GH replacement therapy varies
between individuals.
Objective: To investigate possible influences of gene polymorphisms
on the growth response to GH in GHD children.