2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
control groups. Statistical analysis showed significant association between
A to G mutation and risk of atherosclerosis (P = 0.01). No significant
alteration in the level of total bilirubin was observed between case
and control groups (P = 0.6). This is the first report on the association
between HMOX2 and atherosclerosis among Iranian CAD patients .
This finding presences the importance of this mutation in development
of atherosclerosis . More study would show the importance of hemoxygenase
2 gene mutation in other populations .
P06.032
Large scale association study of gene-gene interaction within
the filaggrin pathway
E. Rodríguez 1 , H. Baurecht 1 , N. Novak 2 , N. Klopp 3 , T. Illig 3 , S. Wagenpfeil 1 , A.
D. Irvine 4 , S. Weidinger 1 ;
1 Technical University Munich, Munich, Germany, 2 University of Bonn, Bonn,
Germany, 3 Helmholtz Zentrum München, Neuherberg, Germany, 4 Our Lady’s
Children’s Hospital, Dublin, Ireland.
Filaggrin deficiency due to null mutations in the FLG gene has been
established as risk factor for atopic eczema (AE) . Processing of profilaggrin
to biologically active filaggrin monomers involves several dephosphorylation
and proteolytic steps, and their impairment might also
disturb skin barrier function . Among the proteases suggested to be
implicated in profilaggrin processing is the stratum corneum chymotryptic
enzyme (SCCE), which is possibly regulated by SPINK5-derived
serine proteinase inhibitor LEKTI. An insertion in the 3′ untranslated
region of the kallikrein 7 gene (KLK7) encoding SCCE as well as
a SPINK5 variant have been reported to be associated with AE, but
could not be replicated so far .
In our study we aimed at clarifying the role of these genetic variants for
AE. Considering the potential biological interactions between filaggrin,
SSCE and LEKTI, we also examined gene-gene interactions .
Association analysis was carried out in a cohort of 486 German families
as well as in a cohort of 773 cases and 2924 supernormal controls .
Whereas the strong effect of FLG polymorphisms was confirmed, no
association of the KLK7 insertion could be detected . Concerning the
SPINK5 polymorphism rs2303067 A-allele, weak association was observed
in the family collection only, with a strong maternal effect . There
was no evidence for epistatic effects between FLG, KLK7, and SPINK5
variants that significantly predict AE risk. Thus, our data confirm the
impact of filaggrin deficiency due to FLG loss-of-function mutations on
AE risk, but do not support the hypothesis that this effect is dependent
on KLK7 or SPINK5 .
P06.033
Linkage and linkage disequilibrium scan for autism in an
extended pedigree from Finland
H. Kilpinen 1 , T. Ylisaukko-oja 1,2 , K. Rehnström 1,2 , E. Gaál 1 , J. A. Turunen 1 , E.
Kempas 1 , L. von Wendt 3 , T. Varilo 1,2 , L. Peltonen 1,2,4 ;
1 Department of Molecular Medicine, National Public Health Institute, Helsinki,
Finland, 2 Department of Medical Genetics, University of Helsinki, Helsinki, Finland,
3 Unit of Child Neurology, Hospital for Children and Adolescents, Helsinki,
Finland, 4 Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
As a part of the genetic study of autism spectrum disorders (ASDs)
in the Finnish population, an extensive genealogical search was conducted
to find out whether a substantial fraction of the families would
share the same ancestral lineage . Based on this search back to the
17th century, 18 ASD families (33 affected) were merged into one extended
pedigree .
We hypothesized that this pedigree could expose rare ASD gene(s)
enriched to this internal subisolate, and performed a genome-wide
scan using 1107 STS-markers (intermarker spacing ~3 .4cM) . A joint
analysis of linkage and linkage disequilibrium was performed with
Pseudomarker statistics and a traditional multipoint linkage analysis
with Simwalk2 .
Nine loci exceeded the chosen significance level of -log(p)>2.5. Of
these, 1q21-23 (p=0 .00082) is one of the best loci in our previous genome-wide
scans for autism and Asperger syndrome in Finland, while
15q11-13 (p=0 .00081) is a well-recognized site for cytogenetic abnormalities
associated with autism . Best multipoint linkage was observed
at 19p13 [-log(p)=3 .57] .
Regional candidate genes were chosen from these best loci at 1q23,
15q12 and 19p13, and analyzed with SNPs using additional 126
families with ASDs (281 affected). Most significant association was
observed with five consecutive SNPs of ATP1A2 (1q23; p=0 .00055)
and with eight consecutive SNPs within a TLE-gene cluster (19p13;
p=0 .000078) . This association evidence was not detected using the
nationwide sample, suggesting enrichment of these loci to our pedigree
. We are currently performing a high-resolution analysis of the
extent of shared chromosomal regions among the members of the
pedigree with Illumina 317k platform .
P06.034
the BDNF receptor gene NTRK is a susceptibility gene for
autism
C. Correia 1,2 , I. Sousa 2 , I. Peixeiro 2 , L. Lourenço 2 , J. Almeida 3 , R. Lontro 3 , L.
Galllagher 4,5 , M. Gill 4,5 , S. Ennis 6 , G. Oliveira 3 , A. M. Vicente 1,2 ;
1 Instituto Nacional de Saúde Dr.Ricardo Jorge, Lisboa, Portugal, 2 Instituto
Gulbenkian de Ciência, Oeiras, Portugal, 3 Hospital Pediátrico de Coimbra,
Coimbra, Portugal, 4 Department of Genetics, Smurfit Institute, Trinity College,
Dublin, Ireland, 5 Department of Psychiatry, Trinity College, Dublin, Ireland,
6 School of Medicine and Medical Sciences, University College, Dublin, Ireland.
Autism is a complex neurodevelopmental disorder likely determined by
multiple genes . The NTRK2 gene encodes a receptor, TrkB, for neurotrophin
4/5 and Brain-Derived Neurotrophic Factor (BDNF), which
promotes neuronal differentiation and regulation of synaptic function
in the developing and adult nervous system . Intriguing observations,
such as increased BDNF levels in autistic children and NTRK2 mutations
in children with developmental delays, raise the hypothesis that
an abnormal function/expression of NTRK2 might be involved in autism
. 38 tag SNPs, spanning the NTRK2 gene, were tested for association
with autism in 323 Portuguese trios. We found significant
transmission disequilibrium of alleles at three markers in introns 5-6
and 15-16 (0 .011