2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease 0
the parkin gene in patients with single heterozygous mutations . Our
results show a substantial number of sporadic EOPD patients carrying
single heterozygous mutations, suggesting that a second mutation
could be localized in the promoter . In our study the gene dosage of
core parkin promoter is still in progress .
P06.226
A functional G-463A polymorphism in the myeloperoxidase gene
promoter and Parkinson’s disease
F. E. Rocca1,2 , P. Tarantino1 , E. V. De Marco1 , D. Civitelli1 , I. C. Cirò Candiano1 ,
S. Carrideo1 , F. Annesi1 , G. Provenzano1 , V. Greco1 , G. Squillace1 , V. Scornaienchi1
, G. Nicoletti1,2 , G. Annesi1 ;
1 2 Institute of Neurological Sciences, Mangone (Cosenza), Italy, Institute of Neurology,
University Magna Graecia,, Catanzaro, Italy.
Epidemiological studies suggest that inflammation increases the risk of
developing Parkinson’s disease (PD) and experimental models of Pd
show that inflammatory oxidants modulate neuronal death. Myeloperoxidase
(MPO) is an antimicrobial enzyme involved in the inflammatory
process that produces reactive oxygen species . It is demonstrated
that the levels of catalytically active myeloperoxidase are elevated in
diseased brains and a functional G-463A polymorphism in the promoter
of the MPO gene is associated with the risk of developing neurodegenerative
disorders .There is biologic evidence implicating MPO
in PD neurodegeneration process, but no data are currently available
on the possible role of MPO polymorphism in the development of PD .
Our study is the first to examine the association between MPO genotype
and Pd risk . We investigated the G-463A polimorphism in 233
PD cases and 100 controls . All patients were screened for this SNP
by combination of PCR and RFLP analysis.We did not find significant
differences in allele or genotype distribution between PD cases and
controls (p=1).Genetic findings show that the less common A allele
decreases myeloperoxidase expression, apparently by destroying a
binding site for the transcription factor . The reactive oxygen species
play an important role in PD and individual susceptibility to PD may be
modulated by the G-463A SNP .This work will be completed by increasing
the number of the controls analysed to provide a more powered
study . Our preliminary data suggest that G-463A MPO polymorphism
is not a risk factor for PD neverthless further studies in other populations
are needed to confirm these results.
P06.227
characterization and replication of a novel locus for late-onset
Parkinson’s disease detected in a genome-wide association
study in an isolated population
Z. Bochdanovits1,2 , P. Rizzu1,2 , K. Rak1,2 , L. Pardo-Cortes1,2 , P. Heutink1,2 ;
1 2 VU Medical Center, Amsterdam, The Netherlands, Center for Neurogenomics
and Cognitive Research, Amsterdam, The Netherlands.
Genetically isolated populations have two major advantages above
general populations when conducting genome-wide association studies:
1- more extended LD allows for using less markers and 2- less
genetic heterogeneity, hence a higher relative risk of individual susceptibility
alleles . We have performed a genome-wide association
study in a young genetic isolate in Turkey for late onset Parkinson’s
disease (LOPD) . This isolate exhibits increased prevalence of the disease
suggesting that susceptibility alleles of relatively high risk are
segregating in this homogeneous population . We used the Affymetrix
10K SNPChip to genotype 31 LOPD disease patients and 27 unrelated
controls . Strong LD (r2>0 .8) was commonly found up to approximately
150kb, hence the 10K SNPChip is sufficient to cover the entire genome
in this isolate . Single SNP associations were carried out followed by a
permutation test to determine the genome wide significance threshold.
One SNP, rs1492592, was found to be significantly associated with
LOPD (p=4x10-6 ) . Finemapping a 1 .1 Mb region surrounding the initial
SNP has confirmed the association. Within 1.5 Mb of the locus, several
interesting candidate genes are located, most notably GRIN3A and
PPP3R2 . A known limitation of using genetic isolates is that the loci detected
in one population might not be of relevance in other isolates or
the general population . Therefore we screened two additional genetic
isolates and the general Dutch population for association with tagging
SNPs covering six candidate genes . We replicated our locus by showing
that multiple tagging SNPs are significantly associated with LOPD
in the additional populations .
P06.228
Parkscreen: a Linkage marker Panel for Parkinson’s Disease
A. De Grandi 1 , C. Béu Volpato 1 , E. Bedin 1 , C. Pattaro 1 , F. Marroni 1 , I. Pichler 1 ,
A. Hicks 1 , G. Casari 2 , P. P. Pramstaller 1,3,4 ;
1 European Academy, Institute of Genetic Medicine, Bolzano, Italy, 2 Department
of Neuroscience, Vita-Salute University and San Raffaele Scientific Institute,
Milan, Italy, 3 Department of Neurology, General Regional Hospital, Bolzano,
Italy, 4 Department of Neurology, University of Lübeck, Lübeck, Germany.
PURPOSE: Parkinson’s disease (PD) is a complex disease with both
genetic and environmental susceptibility factors . We set out to develop
a rapid inexpensive tool to aid in the characterization of known or novel
loci that may contribute to PD in families . METHODS: We developed
a genetic marker screening panel, ParkScreen, optimized for simultaneous
marker amplification, to test families for linkage to known PD
loci using only a few affected individuals . We also used ParkScreen
for screening patients within genetically isolated homogenous populations
. It was applied to three groups of apparently sporadic PD patients
originating from different Italian Alpine valleys . RESULTS: Panel
functionality was proven by detection of linkage to PARK2 in a family
with known Parkin mutations . Linkage to several known PD loci in the
examined pedigrees was excluded, and suggestive linkage to PARK8,
PARK3, and PARK11 was found . For one family, linkage was excluded
for all known loci, thus marking it as a candidate for further studies .
CONCLUSION: ParkScreen is a useful, rapid, and inexpensive tool
for assessing the involvement of known loci in familial PD . It allows the
selection of families suitable for clinical follow-up and genotyping in
order to identify specific mutations or novel genes.
P06.229
A genetic variant in Pc-1 gene is associated with susceptibility
to type 2 diabetes among Japanese population
P. Keshavarz1 , H. Inoue2 ;
1 2 Guilan university of medical science, Rasht, Islamic Republic of Iran, The
university of Tokushima, Tokushima, Japan.
Previous studies have demonstrated the K121Q polymorphisms in
the plasma cell membrane glycoprotein-1 (PC-1, recently known as
ENPP1) gene influences insulin resistance, obesity and risk of type 2
diabetes .However conflict association results are reported in different
population . We previously found no evidence for association of K121Q
polymorphisms with risk of type 2 diabetes in a Japanese population .
This study for first time was carried out in samples of Japanese to
explore the key role of other previously reported polymorphisms and
haplotypes containing K121Q variant with risk of type 2 diabetes . To
accomplish this, we genotyped the rs997509, rs1799774 (IVS20delT-
11) and rs7754561 (A/G_1044TGA) polymorphisms for association
analysis in 911 type 2 diabetic patients (459 female/452male) and
876 control subjects (430 female/446 male) using TaqMan assay . According
to single locus association test, in IVS20delT-11, we identified
a significant association of delT allele with type 2 diabetes in Japanese
(adjusted odds ratio, 1.50; 95% confidence interval, 1.15-1.99);
p=0.0002). In a haplotype association analysis, we failed to find any
significant association between Q-delT-G haplotype and type 2 diabetes
(p>0 .05) . A subanalysis of subjects depending their body mass index
(BMI) status revealed no significant impact of the 3 polymorphisms
and Q-delT-G haplotype on BMI . In conclusion our study indicated the
potential role of an intronic polymorphism IVS20delT-11 with type 2
diabetes in Japanese .
P06.230
searching for molecular markers of polycystic ovary syndrome
K. Wertheim 1 , A. Sobczynska-Tomaszewska 1 , J. Maciejewski 2 , P. Kubik 2 , U.
Szutkowska 3 , J. Bal 1 ;
1 Institute of Mother and Child, Department of Medical Genetics, Warsaw, Poland,
2 Institute of Mother and Child, Clinic of Obstetrics and Gynaecology, Warsaw,
Poland, 3 Department of Genetics and Biotechnology, Warsaw University,
Warsaw, Poland.
Polycystic ovary syndrome (PCOS) affects about 10% of women in
reproductive age . PCOS is recognized in the presence of at least two
of the following symptoms: oligomenorrhea, hiperandrogenism, polycystic
ovaries morphology . Disease results in infertility and increased
risk of diabetes type 2, cardiovascular disease, endometrial cancer .
Etiology of the syndrome remains unknown, although interaction of
genetic and environmental factors is mostly discussed . Several meta-