2009 Vienna - European Society of Human Genetics

Statistical genetics, includes Mapping, linkage and association methods
entific Research Institute of Tuberculosis, Department of Health Care, Moscow,
Russian Federation.
The predictive diagnostics of socially significant diseases with a multifactorial
etiology becomes more significant due to worsening of ecological
conditions and increasing of the number of chronic pathologies.
We developed Pharmagen-biochip for the polymorphism analysis in
the candidate genes controlling the biotransformation system and
the NAT2-biochip for the analysis of all significant variants in NAT2
gene. Our analysis has revealed genetic risk factors for development
of several multifactorial pathologies: childhood acute leukemia (polymorphic
variants of genes GSTT1, GSTM1, NAT2 and MTRR), leukemia
and lymphoma in adults (polymorphic variants of genes CYP1A1,
GSTM1 and CYP2C9), and the lung diseases in children and adults
(polymorphic variants of genes CYP2C9, GSTT1, GSTM1 and NAT2).
The analysis of genes predisposing to cervical cancer has defined
risk factors of oncopathology development (polymorphic variants of
genes CYP1A1, GSTM1, MTHFR and NAT2). In addition, it has been
showed that polymorphic variants of CYP1A1, GSTT1, GSTM1 and
NAT2 genes may consider as predictive markers for risk of relapse
in childhood acute leukemia and could be used to individualize the
standard therapy.
Our results show the importance of the genetic risk factors analysis
in multifactorial diseases and the utility of biochips as genotyping instrument
in preclinical diagnostics and personalized medicine for individual
adjustment of drug dosage in clinic.
The work was supported by the Russian Foundation for Basic Research
(projects no. 06-04-49771 and 08-04-12225) and the Foundation
for Assistance to Small Innovative Enterprises (project no. 9194).
P08.53
Recurrent oncostatin m receptor gene mutations and haplotype
association in primary cutaneous amyloidosis in taiwan
M. Lin 1,2 , D. Lee 3 , T. Liu 4 , Y. Lin 5 , S. Chen 1 , Y. Chang 6 , J. A. McGrath 7 , S. Tsai 8,5 ;
1 Institute of Public Health, National Yang-Ming University, Taipei, Taiwan, 2 Department
of Medical Research & Education, Taipei Veterans General Hospital,
Taipei, Taiwan, 3 Department of Dermatology, Taipei Veterans General Hospital,
Taipei, Taiwan, 4 VYM Genome Research Center, National Yang-Ming University,
Taipei, Taiwan, 5 Department of Life Sciences and Institute of Genome
Sciences, National Yang-Ming University, Taipei, Taiwan, 6 Department of Dermatology,
Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan,
7 St John’s Institute of Dermatology, Division of Genetics and Molecular Medicine,
The Guy’s, King’s College and St Thomas’ School of Medicine, London,
United Kingdom, 8 Division of Molecular and Genomic Medicine, National Health
Research Institutes, Miaoli, Taiwan.
Primary cutaneous amyloidosis (PCA) is characterized by severe itching,
maculopapular lesions, pigmentation, and amyloid deposits in the
dermal papilla. The disease is relatively common in Southeast Asia
and South America. Previously, we reported familial clustering and genetic
heterogeneity of PCA and mapped the condition to 5p13.1-q11.2
in a subset of pedigrees from Taiwan. A gene within this region, OSMR,
has recently been found to harbor mutations in familial cases. Here,
we investigated 29 PCA pedigrees and found that 10 had heterozygous
missense mutations in OSMR, all of which occurred within the
fibronectin type III-like repeat domains of the encoded OSMRβ protein:
p.D647V (1 family), p.P694L (6 families), and p.K697T (3 families).
The mutation p.P694L was associated with the same haplotype in 5 of
6 families. This particular mutation and haplotype were also detected
in 2 sporadic cases of PCA, suggesting a common ancestral origin.
No mutations in OSMR were identified in the other 19 pedigrees with
familial PCA or in 89 sporadic cases of PCA, findings consistent with
other disease-associated genes or perhaps non-genetic causes in
some individuals. Our study provides insight about the complex genetic
etiology of PCA and shed light on cytokine receptors and PCA
pathogenesis.
P08.54
Functional variant of the PtPN22 gene associated with Graves‘
disease predisposition in slovenian population
A. Bicek, B. Krhin, S. Hojker;
University Medical Centre Ljubljana, Department of nuclear medicine, Zaloska
cesta 7, 1000 Ljubljana, Slovenia.
Recent findings have demonstrated that the single nucleotide polymorphism
1858C>T in the PTPN22 (protein tyrosine phosphatase
nonreceptor 22) gene has functional relevance and is associated with
a variety of autoimmune diseases. The aim of this study was to assess
the role of the PTPN22 1858C>T polymorphism in the genetic
predisposition to Graves’ disease (GD) in Slovenian population. We
analyzed a case-control cohort composed by 100 patients with Graves’
disease and 100 healthy controls. The PTPN22 1858C>T genotyping
was performed by TaqMan 5′ allelic discrimination assay. The allele
distributions followed the Hardy-Weinberg equilibrium. CC genotype
was found in 71 patients and 88 controls, CT genotype in 27 patients
and 11 controls, and TT genotype in 2 patients and 1 control. Results
were further analyzed by Fisher’s exact test. Allele and genotype frequencies
of the PTPN22 1858C>T polymorphism between patients
and controls were compared. Significantly different allele and genotype
distribution was observed. The p-value for GD susceptibility was
0.0046 for patients carrying T allele (CT+TT) compared to controls. As
allelic variation of 1858C>T polymorphism could alter T - cell signalization
we believe that PTPN22 gene holds a disease-predisposing allele
that contributes to development of GD. Therefore, our data suggest
that the PTPN22 1858C>T single nucleotide polymorphism has an effect
on GD susceptibility in Slovenian population.
P08.55
molecular diagnosis of known recessive ataxias by
homozygosity mapping with sNP arrays
D. H’Mida-Ben Brahim 1 , A. M’Zahem 2 , M. Assoum 1 , Y. Bouhlal 3 , F. Fattori 4 ,
M. Anheim 1 , L. Ali-Pacha 5 , C. Lagier-Tourenne 1 , N. Drouot 1 , C. Thibaut 1 , T.
Benhassine 6 , Y. Sifi 2 , J. Poujet 7 , A. Hamri 2 , F. Hentati 3 , R. Amouri 3 , F. Santorelli 4 ,
M. Tazir 5 , M. Koenig 1 ;
1 IGBMC, Strasbourg, France, 2 Centre Hospitalo-Universitaire Ben Badis, Constantine,
Algeria, 3 Institut de Neurologie, Tunis, Tunisia, 4 Molecular Medicine &
Dept. of Neurosciences IRCCS Ospidale. Bambino Gesù, Roma, Italy, 5 Service
de Neurologie, Centre Hospitalo-Universitaire Mustapha, Alger, Algeria, 6 Institut
Pasteur, Alger, Algeria, 7 Hopitaux Universitaires de Marseille, Marseille, France.
The diagnosis of rare inherited diseases is becoming increasingly difficult
as an increasing number of affections appears to have multigenic
inheritance. Multigenic inheritance applies for the recessive progressive
ataxias, for which 12 genes have been identified. We used homozygosity
mapping of patients with recessive ataxia and born from
consanguineous parents, as a guide for identification of the defective
locus. Patients from 97 families were analysed with GeneChip Mapping
10K or 50K SNP Affymetrix microarrays. We identified six families
homozygous for regions containing the ARSACS gene, two families
homozygous for the ataxia-telangiectasia gene, two families homozygous
for the AOA1 gene, and one family homozygous for the AOA2
gene. A mutation was identified in all families homozygous for the AR-
SACS, AOA1 or AOA2 loci, and in only one of the two families homozygous
for the A-T locus. The family without a mutation in the ATM
gene was not reminiscent of A-T, as alpha-foetoprotein was normal in
all 4 patients who had onset of ataxia at 8 years and absent reflexes.
However, the LOD score in favor of linkage for the 11q22.1-q23.1 region
was 3.2 and no other region of the genome was consistent with
linkage for this family, suggesting that a second ataxia gene is present
in this interval. While the use of homozygosity mapping was very effective
at pointing to the correct ataxia gene, it also suggests that the
majority of recessive ataxia cases are caused by mutations either in
the recently identified genes or in genes yet to be identified.
P08.56
Pharmacogenomic study of drug transporters CYP A , CYP A
and ABCB on cyclosporine A and tacrolimus with allograft
rejection in renal transplant recipients of north india
R. Singh, A. Srivastava, R. D. Mittal;
Sanjay Gandhi PGI, Lucknow, India.
Background: Calcineurin inhibitors cyclosporine (CsA) and tacrolimus
(Tac), substrates of cytochrome P-450 3A (CYP3A) subfamily and ATP