2009 Vienna - European Society of Human Genetics

Statistical genetics, includes Mapping, linkage and association methods
ceptibility. These genes are located on chromosome 21q21.3-22.13,
and showed linkage for LOAD. Additionally, recent studies indicate that
variants in the promoter of the APP gene could up-regulate the APP
gene expression and that DYRK1A could be a key molecule bridging
between β -amyloid production and tau phosphorylation. Several
polymorphisms of these genes have been analyzed, however a
systematic meta-analysis of this SNPs in previous association studies,
suggested that only (APP=rs364048), (RUNX1=rs4816501) and
(DIRK1A= rs2835740) are true allele risk with OR>1.80. Materials and
Methods: A case-control study was design to evaluate the possible
association between these SNPs with LOAD in Mexican patients. We
studied 58 patients with LOAD and 70 sex and age-matched controls
subjects. We analyzed alleles and genotype distributions for APOE
(ε2/ε3/ε4), (-955A/G) of the APP promoter, (C/T) of the RUNX1, and
(T/C) of the DIRK1A. Results: We found different genotype frequencies
for all SNPs analyzed between cases and controls. Association
was observed for the APOE ε4 allele (OR =1.65), AA genotype of APP
(OR =1.67), TT genotype of RUNX1 (OR=1.24) and CC genotype of
DIRK1A (OR =1.24). Conclusions: These data suggest a genetic association
between these genotypes with LOAD in Mexican population.
Our results differ from studies performed in other populations.
Acknowledgements: This work was supported in part by CONACyT
(2004-C01-129) and UNAM (SDEI. PTID.05.5)
P08.05
Analysis of PiN1 genetic variation in Alzheimer’s disease
A. Maruszak 1 , K. Safranow 2 , K. Jakubowska 3 , M. Olszewska 2 , B. Kijanowska-
Haładyna 4 , K. Gustaw 5 , D. Chlubek 2 , M. Barcikowska 1 , C. Żekanowski 1 ;
1 Department of Neurodegenerative Disorders, Mossakowski Medical Research
Centre, Warsaw, Poland, 2 2. Department of Biochemistry and Medical Chemistry,
Pomeranian Medical University, Szczecin, Poland, 3 Department of Biochemistry
and Medical Chemistry, Pomeranian Medical University,, Szczecin,
Poland, 4 Institute of Psychiatry and Neurology, Warsaw, Poland, 5 4. Alzheimer’s
Research Unit, Institute of Agricultural Medicine, Lublin, Poland.
Background: Alzheimer’s disease (AD) is one of the most common
neurodegenerative disorders. As PIN1 plays a significant role in the
brain and the influence of PIN1 genetic variants in Alzheimer’s disease
remains unresolved, we performed an exhaustive analysis of PIN1 in
the Polish cohort.
Methods: 111 late onset (AAO: 73.2±5.0 years, range 66-88; 69.4%
females) and 49 early onset AD patients (AAO: 52.6±9.8 years; 57.1%
females) were recruited. The control group consisted of 104 healthy,
non-demented individuals (mean age: 75.1±5.2 years, range: 68-90;
71.15% females). We performed sequencing and/or dHPLC of PIN1
promoter and coding region in the studied groups and real-time PCE to
quantify PIN1 expression in the patient with c.58+64C>T substitution.
Results: Genotype, allele and haplogroup frequencies of common
PIN1 polymorphisms were similar in LOAD and EOAD patients in
comparison with the controls. However, we identified four novel PIN1
mutations (g.9805833T>C, c.24C>T, c.58+64C>T, c.382+105C>T) in
early-onset AD patients (EOAD). c.58+64C>T substitution was also
present in two late-onset AD patients (LOAD). None of the novel variants
was detected in the control group.
Conclusions: Although analyzed common polymorphisms are not associated
with AD in the Polish cohort, further studies are required to
resolve whether rare PIN1 mutations could contribute to AD etiology.
P08.06
Variations in two lipid metabolizing genes and susceptibility to
sporadic Alzheimer’s disease
V. Andreoli 1 , F. Trecroci 1 , A. La Russa 1 , R. Cittadella 1 , P. Spadafora 1 , G. Di
Palma 1 , M. Caracciolo 1 , A. Quattrone 1,2 ;
1 Institute of Neurological Sciences, National Research Council, Pianolago di
Mangone (CS), Italy, 2 Institute of Neurology, University Magna Graecia, Catanzaro,
Italy.
Alzheimer’s disease (AD) is the most common form of dementia. Currently,
the apolipoprotein E (APOE) ε4 allele is the sole identified genetic
risk factor for sporadic AD (sAD) but the underlying mechanism
is not understood. One hypothesis to explain how the ε4 allele might
affect increase AD risk in humans relies on an interaction between
APOE and its receptors. Particularly, the low density lipoprotein receptor-related
protein (LRP1) is the main APOE receptor in the brain. LRP
mediates clearence of β-amiloid aggregates of which lead to the for-
mation of senile plaques, a pathological hallmark of AD. Consequently,
any variations in LRP gene will lead to a defect in clearance of LRP
high affinity ligands, as the LRP-associated protein gene (LRPAP1).
Taken together, these data suggest that LRPAP1 could be involved
in the clearance of β-amyloid, and genetic variation at this gene could
modulate the rate of plaque formation. The association of the C766T
polymorphism in exon 3 of the LRP gene with AD is discussed controversially.
Here, we analyzed this LRP variation and the association of
intron 5 LRPAP1 (37 bp insertion/deletion) polymorphism in a number
of sAD patients and controls from the same white population (Southern
Italy). No statistically significant differences were found in LRP1 and
LRPAP1 genotype and allele frequencies between the AD sample and
controls. Together, the findings do not support a strong correlation of
the exon 3 LRP and intron 5 LRPAP1 polymorphisms with AD, indicating
that these variations only represent a minor risk factor for AD.
P08.07
Detecting recessive loci using very distant consanguineous
relationships in a case study (AmRF)
M. Bahlo 1 , C. J. Bromhead 1 , M. A. Bayly 2 , L. M. Dibbens 2 , S. F. Berkovic 3 ;
1 Walter and Eliza Hall Institute of Medical Research, Parkville, Australia, 2 Women’s
and Children’s Hospital, Adelaide, Australia, 3 Austin Health and Northern
Health, Heidelberg, Australia.
We recently identified a novel epilepsy gene for Action Myoclonus Renal
Failure Syndrome using just three unrelated affecteds. Only one
affected was known to be the offspring of a consanguineous relationship.
We identified an additional consanguineous relationship, which
was not known, for one of the other affecteds. Since publication of this
gene we have identified mutations in a further ten patients displaying a
total of ten different mutations in this gene.
Simplified Hidden Markov Models (HMMs) to identify identity by descent
(IBD) sharing between distantly related individuals have recently
been proposed. These methods can be viewed as halfway points between
pedigree-free homozygosity by state sharing methods and full
multipoint mapping and can assess sharing in very deep consanguineous
loops due to the availability of the much higher density SNP chip
mapping data.
These new approaches are promising but have not been applied to
many case studies. We have applied these methods to our AMRF cohort
where we know that the mutations lie in the gene SCARB2. This
allows assessment of their potential in identifiying new susceptibility
loci for rare recessive diseases genome wide with just single cases
known, or inferred to be, the offspring of distant consanguineous relationships.
P08.08
AcE i/D polymorphism is associated with abdominal aortic
aneurysm
I. Novakovic1 , D. Cvetkovic2 , N. Maksimovic1 , S. Cvetkovic3 , L. Davidovic3 ;
1Institute of Human Genetics, School of Medicine, University of Belgrade, Belgrade,
Serbia, 2Faculty of Biology, University of Belgrade, Belgrade, Serbia,
3Vascular Surgery Clinic, Institute for Cardiovascular Diseases, Clinical Center
of Serbia, Belgrade, Serbia.
The purpose of this study was to examine the relationship between the
polymorphism in angiotensin converting enzyme gene (ACE, I/D) and
abdominal aortic aneurysm (AAA), a common vascular disease with
high fatality rate. Previous studies have already pointed out that the
genes of the RAS system may have a significant role in AAA formation.
The study included a total of 127 unrelated individuals: 63 patients with
AAA (56 males and 7 females, median age 69, range 32-84), and 64
healthy controles comparable for sex and age. Out of 63 patients who
underwent surgery, 33 were with ruptured aneurysms (RA) and 30 with
nonruptured, asymptomatic aneurysms (NRA). They were genotyped
for the ACE I/D polymorphism by standard PCR analysis. Allele and
genotype frequencies were compared between patients and controls
using Chi-square test, and Kruskal-Wallis test was used to examine
differences in aneurysm diameter between genotypes.
ACE D allele was significantly more frequent in AAA patients compared
to the healthy controls (0.722 vs. 0.578, p=0.016). The genotype
distribution of ACE I/D was significantly different between patients and
controls, but not between RA and NRA group. Significant association
was found between DD genotype and the presence of AAA (OR DD