2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
P09.040
DEFA1/DEFA3 G3400A variation in patients with vesico-ureteric
reflux
B. Zagradisnik, N. Marcun Varda, K. Zerjavic, S. Stangler Herodez, A. Gregoric,
N. Kokalj Vokac;
University Medical Centre Maribor, Maribor, Slovenia.
Primary congenital vesico-ureteric reflux (VUR) is a very common
urogenital tract disorder. It represents a major risk factor for recurrent
urinary tract infections. VUR is considered a complex trait and among
possibly many implicated genes may be several that influence infectious
agent defense. Therefore it may be plausible to assume an association
between VUR and genetic variations in genes with antimicrobial
functions, Such genetic variations may not necessary contribute to
the development of VUR but may affect the course of the disease. This
study analyzed DEFA1/DEfA3 G3400A variation in the alpha defensin
locus for possible association with VUR.
Genotyping was done in 178 children diagnosed with primary congenital
vesico-ureteric reflux and in 300 healthy controls with no medical
record of reflux. Genomic DNA was extracted from whole blood samples
using standard methods. The G3400A variation was detected with
PCR-RFLP (HaeIII) using agarose gel electrophoresis.
A statistically significant overrepresentation of patients with DEFA3
3400A variant was observed when compared with the control group.
However the frequencies of both variants did not differ significantly
between tested groups..
Our results indicate that G3400A variation in the DEFA1/A3 alpha-defensin
locus may be associated with VUR. Such variations in alpha
defensins may increase the susceptibility of patients with VUR to urinary
tract infections and are probably not involved in the development
of VUR itself. Further analysis that would include other elements of a
complex structured alpha defensin locus are needed to validate a possible
role for alpha defensins in patients with VUR.
P09.041
changes in gene expression after diabetogenic stimulation
analyzed by using DNA microarrays and pathway analysis
(GeneGo, metacore), a family case report
Z. Halbhuber 1 , M. Hubackova 2 , M. Krivjanska 1 , K. Stechova 2 ;
1 Central European Biosystems Ltd, Prague, Czech Republic, 2 Faculty of
Medicine of Charles University and University Hospital Motol, Prague, Czech
Republic.
Diabetes mellitus is a disorder of metabolism that manifests itself as
type I or type II. The Type I (T1D, the object of this study) is caused
by destruction of the insulin-producing beta-islet cells of the pancreas.
The aim of our study was to monitor in vitro changes in gene expression
in peripheral blood mononuclear cells (PBMCs) after stimulation
with diabetogenic autoantigens within one family related to different
manifestation of the T1D. The situation was very exciting due to family
structure which includes identical quadruplets. PBMCs were divided
into equal halves and one half was stimulated using derived syntetic
peptides. After RNA isolation, amplification and fluorescent labeling,
the samples were competitively hybridize on the high density wholegenome
microarray HOA (PhalanxBiotech). Hybridized slides were
scanned and analyzed using GeneSpring GX (Agilent) and Pathway
analasis software MetaCore (GeneGo). The microarray part was done
as a service in microarray facility of Central European Biosystems Ltd.
We identified genes differentially expressed in each group according
to T1D occurence and family status. In accordance with previously
published results we found out the similar expression pattern between
basal expression and expression in stimulated samples depending
on the diabetes development. It seems that the down or up regulation
hit different genes in almost the same metabolic pathways. The
study confirms that there can be find differential expression pattern
and markers which preveal risk of diabetes.
This work was supported by grant NPVII 2B06019 from The Ministry of
Education, Youth and Sports of the Czech Republic.
P09.042
Use of a Genetic isolate to identify Disease Variants: a new
multiple sclerosis locus on 17q21.1
V. Leppä 1,2 , E. Jakkula 1,3 , J. Saare 1 , S. Kallio 1 , P. Tienari 4 , K. Koivisto 5 , I.
Elovaara 6 , M. Reunanen 1 , T. Pirttilä 7 , S. Purcell 3,8 , P. De Jager 3,9 , D. Hafler 3,9 , A.
Palotie 1,10 , M. Daly 3,8 , L. Peltonen 1,10 ;
1 National Public Health Institute, Helsinki, Finland, 2 BGS, University of Helsinki,
Helsinki, Finland, 3 The Broad Institute of MIT and Harvard, Cambridge, MA,
United States, 4 Dept. of Neurology, Helsinki Univ. Central Hospital, Helsinki,
Finland, 5 Central Hospital of Seinajoki, Seinajoki, Finland, 6 Dept. of Neurology,
Tampere Univ. Central Hospital, Tampere, Finland, 7 Dept. of Neurology,
Kuopio University Central Hospital, Kuopio, Finland, 8 Center for Human Genetic
Research, Massachusetts General Hospital, Boston, MA, United States, 9 Dept.
of Neurology, Brigham & Women’s Hospital, Boston, MA, United States, 10 Wellcome
Trust Sanger Institute, Hinxton, Cambridge, MA, United States.
Prevalence of multiple sclerosis (MS) in the Southern Ostrobotnia (SO)
sub-isolate region of Finland is two-fold compared to other populations
of Northern European descent. We used genealogical information
reaching up to 15 generations back to construct two regional “megapedigrees”.
We hypothesize that one or more variants predisposing to
MS may be regionally enriched and these pedigrees can be used to
identify new MS loci using a genome wide SNP screen.
68 MS cases from Southern Ostrobotnia were genotyped using the
Illumina 317K HumanHap panel and 136 IBS matched population
samples were used as controls. A five SNP sliding window haplotype
analysis on a previously indentified 5p12-14 linkage region (Kuokkanen
et al. 1996) revealed three associated loci with p-value ≤10 -4 .
One of the regions identified, C7-FLJ40243 locus, showed association
in an independent replication set from the SO region (p