2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
Polymorphisms C677T and A1298C in MTHFR gene have been associated
with a varying risk of cervical dysplasia . We evaluated the
association of C677T and A1298C polymorphisms at the MTHFR
locus with cervical intraepithelial neoplasia (CIN) or cervical cancer
(CC) in Yucatan, Mexico, where CC is the first most common cancer.
A case-control study was performed . Cases were 84 DNA samples of
women with CIN or CC (47 CIN I, 14 CIN II, 7 CIN III, 9 invasive cervix
cancer and 7 cervical cancer) and controls were 127 DNA samples of
women who were negative to PAP . Polymorphisms were determined
by PCR-RFLPs . Allele and genotype frequencies were compared between
cases and controls in EpiInfo software (OR, IC 95%) . Genotype
frequencies in cases and controls were according to Hardy-Weinberg
expectations (p>0 .33) for both polymorphisms . For C677T-MTHFR
polymorphism, allele and genotype frequencies were not significantly
different between cases and controls (p>0 .05), whereas for A1298C
polymorphism, frequency of allele C was significantly different between
cases and controls (P=0 .0325), suggesting an association of
1298C allele with a reduced risk to CIN or CC (OR 0 .51, IC 0 .25-0 .98) .
Stratification according to phenotype showed that heterozygous genotype
AC and allele C were associated only with CIN I, p= 0 .023 and p=
0 .0180, respectively . Our results suggest that polymorphism A1298C
in MTHFR gene is associated to CIN I as a protective factor to develop
more severe dysplasias in Yucatan population .
P06.187
mtHFR gene polymorphisms and neural tube defects - the
incidence in slovak population.
J. Behunova 1 , L. Klimcakova 2 , D. Potocekova 3 , L. Podracka 1 ;
1 I. Department of Pediatrics, Safarik University Children Hospital, Kosice, Slovakia,
2 Department of Medical Biology, Safarik University School of Medicine,
Kosice, Slovakia, 3 Department of Informatics, Safarik University School of
Medicine, Kosice, Slovakia.
Neural tube defects (NTD) belong to the most debilitating birth anomalies
. The geographical & historical differences in NTD incidence vary
tremendously - from 8/1000 till 0,21/1000 . Discovery of folic acid´s preventive
effect influenced the research of NTD genetic background focusing
to the genes whose products take part in the folate metabolism .
One of the most important enzymes involved is MTHFR - methylenetetrahydrofolate
reductase whose common termolabile variant C677T
in homozygote state reduces MTHFR activity to 30-40% of norm . Lowered
activity might play a crucial role in early embryonic development .
That is why this polymorphism has been investigated in various NTD
populations and in some of them the mutant variant has been proven
to be a risk factor for failure of neural tube closure .
In Slovakia with average natality about 50 000 liveborn per year, there
are anually 10-20 children born with NTD (0,28/1000) - mostly with
meningomyelocele . When including stillborn and selective abortions,
the number of NTD pregnancies is even higher (0,35-0,52/1000) . To
evaluate genetic risk of folate metabolism variations in our population,
we investigated MTHFR gene polymorphisms C677T and A1298C in
91 Slovak children with NTD . The obtained results of genetic analyses
are being compared with those from 300 newborns from Slovak population
. Currently we got the results of C677T polymorphism analysis,
which, however, did not show any significant difference in the prevalence
of TT genotype or T allele between the patients and controls (OR
= 1,22 [95% CI 0,5-2,9]; OR = 1,16 [CI 0,8-1,7] respectively) .
P06.188
Use of a Genetic isolate to identify Rare ms Variants
S. P. Kallio 1 , E. Jakkula 1,2 , S. Purcell 2,3 , M. Suvela 1 , K. Koivisto 4 , P. J. Tienari 5 ,
M. L. Sumelahti 6 , I. Elovaara 7 , T. Pirttilä 8 , M. Reunanen 9 , D. Bronnikov 1 , M.
Viander 10 , J. Hillert 11 , F. Lundmark 11 , H. F. Harbo 12 , Å. R. Lorentzen 13,14 , P. L. De
Jager 2,15 , M. J. Daly 2,3 , D. A. Hafler 2,15 , A. Palotie 1,2 , L. Peltonen 1,16 , J. Saarela 1 ;
1 National Public Health Institution, University of Helsinki and FIMM, Helsinki,
Finland, 2 The Broad Institute of Harvard and MIT, Cambridge, MA, United
States, 3 Center for Human Genetic Research, Massachusetts General Hospital
and Harvard Medical School, Boston, MA, United States, 4 Central Hospital of
Seinäjoki, Seinäjoki, Finland, 5 Department of Neurology, University of Helsinki,
Helsinki, Finland, 6 School of Public Health, University of Tampere, Tampere,
Finland, 7 Department of Neurology, Tampere University Hospital, Tampere,
Finland, 8 Department of Neurology and Neuroscience, Kuopio University Hospital,
Kuopio, Finland, 9 Department of Neurology, Oulu University Hospital, Oulu,
Finland, 10 Department of Medical Microbiology and Immunology, University of
Turku, Turku, Finland, 11 Department of Clinical Neuroscience, Karolinska Institutet
at Karolinska University Hospital-Huddinge, Stockholm, Sweden, 12 Department
of Neurology, Ullevål University Hospital, Oslo, Norway, 13 Institute of
Immunology, Rikshospitalet University Hospital, Oslo, Norway, 14 Department of
Neurology, Faculty Division Ullevål University Hospital, University of Oslo, Oslo,
Norway, 15 Department of Neurology, Center for Neurologic Diseases, Brigham
and Women’s Hospital and Harvard Medical School, Boston, MA, United
States, 16 Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
MS is a chronic inflammatory disease of the CNS with complex inheritance
. The etiology of MS is poorly understood . Large case-control association
studies primarily aim to identify common variants contributing
to pathogenesis of common traits . To tackle rare alleles contributing to
the molecular background of MS, alternative strategies are needed .
One approach is to use special populations with a founder effect and
isolation, where one could hypothesize allelic enrichment . Such a
unique high-risk region for MS is the Southern Ostrobothnia in Finland,
where both the prevalence and familial occurrence are exceptionally
high . We have performed a high-resolution genome-wide SNP study
using the Illumina HumanHap300 panel to monitor, which alleles are
shared by 72 familial MS cases from this high-risk isolate . Genealogical
studies showed that majority of these patients are distantly related .
Genotype data of 68 IBS-matched Finns was used as controls . We
first focused on the 45Mb region on 5p, for which we have shown linkage
in Finnish MS-families . The haplotype analysis over this region
revealed association with one haplotype, and the finding was validated
in a larger study set from the high-risk region (OR 2 .73, p=3 .2x10 -6 ) .
The identified risk-haplotype flanks two genes, C7 (complement component)
and FLJ40243 (predicted protein) . Suggestive association
with C7-FLJ40243 alleles and MS was also seen in more heterogeneous
populations . Interestingly, plasma C7 protein levels and total
complement activity were observed to correlate with the risk-haplotype
identified. Sequencing of the 31kb C7 region did not reveal an obvious
causative variant . Sequencing of FLJ40243 is in progress .
P06.189
Genetic polymorphysms of iL12B and VDR in association with
multiple sclerosis in russians
S. Babenko1 , J. Orlova2 , V. Alifirova2 , V. Pusyrev1,2 ;
1 2 Institute of Medical Genetics, Tomsk, Russian Federation, Siberian State
Medical University, Tomsk, Russian Federation.
We investigated genotypes and haplotypes frequencies for VDR and
IL12B polymorphisms in case-control studies of MS in 92 Russian
inhabitants of Tomsk region. Our results show significant differences
of alleles and genotypes frequencies in the distribution of the polymorphism
1188A>C IL12B between MS patients and controls (p