2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology
P07.120
Prevalence of cAt-interruptions in (cAG)n-repeat region in the
gene for SCA in siberian populations.
L. A. Koneva1 , N. P. Babushkina1 , M. S. Kuharskiy1 , N. R. Maksimova2 , A. N.
Kucher1 ;
1 2 Institute of Medical Genetics, Tomsk, Russian Federation, Yakuts Scientific
Centre, Yakutsk, Russian Federation.
Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal-dominant
neurogical disorder caused by expansion of an unstable (CAG)-repeats
in gene for ataxin-1 (6p22-23) . Normal repeat tract (in healthy
people) consists of 6-37 triplets with 1-3 CAT-interruptions whereas
mutant alleles contain pure repeat tracts from 39-70 CAG . CAT-interruptions
are thought to serve as stabilizing factor .
We have studied frequency of alleles without CAT-interruptions among
normal size alleles from different Siberian populations (855 individuals):
Yakuts (the highest level of SCA1 accumulation) and Buryats, Tuvinians,
Russians, Tatars, Kirghiz, Altaians and Khantys (without SCA1
accumulation). It is the first estimation of prevalence of homogeneous
(CAG)n of normal length in SCA1 gene in different ethnic groups of
Siberia with distinct contribution of European and Asian components
in the their gene pools . SfaN I restriction method was used to identify
the interruptions . High frequency of chromosomes with normal homogeneous
CAG repeat in Yakuts (15 .66%), Tuvinians (17 .9%), Kirghiz
(13 .57%), Altaians (9 .56%), Buryats (9 .51%) and rather low prevalence
of such individuals among Tatars (7 .15%), Russians (3 .75%)
and Khantys (2 .83%) is revealed . Thus, high frequency of individuals
without CAT-interruptions in normal length alleles in the populations
without SCA1 accumulation has been shown. This finding puts a question
concerning role of CAT-interruptions in (CAG)n-expansion in the
gene ataxin-1 .
The study was supported by RFBR grant N 06-04-49086 .
P07.121
simulation of dynamic spread of triplet Repeat Expansion
Diseases in human populations on example of spinocerebellar
ataxia type i
L. Koneva, A. Konev, A. Kucher;
Institute of Medical Genetics, Siberian Branch of Russian Academy of Medical
Sciences, Tomsk, Russian Federation.
Spinocerebellar Ataxia Type I (SCA1) is an autosomal-dominant neurogenerative
disorder caused by expansion of unstable CAG codon
in Sca1 gene that leads to abnormally long polyglutamine chains in
nuclear matrix protein ataxin 1 . SCA1 is frequent in Yakut populations,
with 1 .2% and 0 .3% prevalence in Abyisky uluses (northern Yakutia)
and Ust-Aldansky uluses (central Yakutia), respectively, in 2003 . We
developed the computational model in RAD environment Borland Delphi
7 for simulation of dynamics of SCA1 in population, and verified it
with the epidemiological data from the two separate Yakutia regions .
The program is designed for simulation of SCA1 evolution in interactive
mode. The user defines the initial parameters, such as population size
and number of mutation carriers, as well as the interactive variables
(demographical coefficients) - birth rate, death rate, migration and
nuptiality, which can be adjusted during simulation . Other variables
include: threshold number of CAG repeats, probabilities to inherit the
mutation from mother/father, average expansion of trinucleotides tract
during inheritance and reduction in number of mutant progenies due
to genetic counseling . The model enables prediction of the length of
CAG repeats, age of onset and life expectancy in individual mutation
carriers in the lineage, and the prevalence of disease in population .
Comparison of the data produced in simulation with the real values
in existing populations was used to verify the computational model .
This program provides flexible and highly visual way to predict dynamic
changes in prevalence and spectrum of clinical characteristics of
SCA1 in population in different demographic scenario .
P07.122
Association analysis of tryptophan Hydroxylase-1 gene (tPH1)
and suicidal behavior in Russian population
Z. Khalilova1 , D. Gaysina2 , A. Kazantseva1 , E. Khusnutdinova1 ;
1 2 Russian Academy of Sciences, Ufa, Russian Federation, Institute of Psychiatry,
King’s College London, London, United Kingdom.
Suicide is an important public health problem, ranking among the top
10 causes of death for individuals of all ages . There is strong neurobiological
evidence showing that serotonergic system dysfunction
predisposes to suicidal behavior . Tryptophan hydroxylase, the rate
limiting enzyme in serotonin biosynthesis, is one of the most important
regulating factors in the serotonergic system . The aim of our study was
to examine the association of four single nucleotide polymorphisms (rs
4537731, rs211105, rs1800532 and rs7933505) of TPH1 gene and attempted
suicide . DNA samples of 312 cases (101- male, 152- female),
who had suicide attempts, and 346 control subjects (194- men, 152women)
from Bashkortostan (Russia) were genotyped using PCR-
RFLP technique . The distribution of allelic and genotype frequencies
was in accordance with the Hardy-Weinberg equilibrium. No significant
differences in either allele or genotype frequencies of rs1800532 and
rs7933505 polymorphisms of TPH1 gene were found between suicidal
and control groups . In a male group there was a tendency of underrepresentation
of the *G/*G genotype of rs 4537731 polymorphism in
suicide group compared to that in control group (11% vs 21%; X2 =
3 .81; p = 0 .05; df = 1) . For the females *G/*G genotype of rs211105
polymorphism was reported to be protective marker of suicidal behavior
(X2 = 5 .66; p = 0 .017; df = 1; OR = 0 .226; 95%CI 0 .06-0 .85) . The
results suggest sex-related differences in the contribution of the TPH1
gene to susceptibility for suicidal behavior .
The work was supported by RSCI grant 06-06-00163 .
P07.123
New candidate gene B GALNT is not associated with type 1
diabetes
T. Zemunik 1 , V. Torlak 2 , V. Škrabić 2 , Z. Kačić 3 , J. Jakšić 4 , G. Stipančić 5 , A.
Špehar 6 , A. Markotić 1 , V. Boraska 1 ;
1 School of Medicine, Split, Croatia, 2 Clinical hospital Split, Split, Croatia, 3 General
Hospital Dubrovnik, Dubrovnik, Croatia, 4 General Hospital Šibenik, Šibenik,
Croatia, 5 University Hospital “Sestre Milosrdnice”, Zagreb, Croatia, 6 University
Hospital Rebro, Zagreb, Croatia.
Monosialo-ganglioside (GM2-1) can be found on the pancreatic β-cell
membrane . GM2-1 has recently been shown to be a target for ICA and
GAD autoantibodies associated with type 1 diabetes mellitus (T1DM)
development . Beta-1,4-N acetyl-galactosaminyl transferase 1 (Gal-
NAc-T) is the enzyme involved in the biosynthesis of GM2 gangliosides .
GalNAc-T catalyzes the transfer of GalNAc into GM3 by beta-1,4 linkage
resulting in the synthesis of GM2 . Enzyme beta-1,4 GalNAc-T is
coded with B4GALNT1 gene located on chromosome 12 . The purpose
of this study was to examine the relation of B4GALNT1 gene tag single
nucleotide polymorphisms (tagSNP) with susceptibility to T1DM . Two
analyzed B4GALNT1 tagSNP-s, rs1008314 and rs715930, capture
100% of B4GALNT1 common variation at the r 2 =0 .8, based on the
HapMap data . We performed case-control (213 patients and 199 control
subjects) and family-based (202 families) studies in Croatian population
. Case-control study did not observe an association with T1DM
(rs1008314, p=0 .3001; rs715930, p=0 .5256) . Also, transmission disequilibrium
test did not detect any discrepancy from the expected minor
allele transmission (rs1008314, p=0 .6547; rs715930, p=0 .4986)
nor from the haplotype transmission from parents to affected child .
This is the first ever reported association study to examine B4GALNT1
gene polymorphisms with T1DM. We did not find any evidence to support
our hypothesis of B4GALNT1 T1DM association .
P07.124
Quantitative Epidemiology of the Haemoglobinopathies
suggests a molecular model of complex Disease Based on
Variability in the Assembly of Hetero-Dimeric molecules
A. E. Felice, R. Galdies, W. Cassar, M. Pizzuto, M. Farrugia, B. Cauchi, M. R.
Caruana, C. A. Scerri;
Laboratory of Molecular Genetics, Faculty of Medicine, University of Malta, and
Section of Molecular Genetics, Mater Dei Hospital., Msida, Malta.
Between 1998 and 2008 we conducted a comprehensive population
based Haemoglobin testing programme . Lately we integrated the