2009 Vienna - European Society of Human Genetics

Statistical genetics, includes Mapping, linkage and association methods
revealed that single nucleotide polymorphisms (SNPs) of a novel gene,
PAX5, confer association with SLE (P < 5 x 10 -3 in basic allelic test).
Among all susceptibility SNPs, rs7859667, rs280025 and rs2812324
confer independent contribution upon logistic regression and conditional
haplotype-base analysis (P < 0.05), whose risk alleles constitute
a risk haplotype locating upstream of PAX5 (P = 2.05 x 10 -4 ). Further,
rs7859667 is selected for replication in 754 SLE samples and 1032
controls by TaqMan, and the association is validated (OR = 1.16, P =
0.012). The joint analysis of gene chip and replication data reveals SLE
association with an OR of 1.18 and P value of 5 x 10 -3 . Fine mapping
of PAX5 locus has been performed by selecting tag SNPs from 100kb
downstream to upstream of the gene and the genotyping results are
pending. PAX5 encodes a B-cell-specific activator protein that binds
to promoters of the CD19 gene, BLK, and to regulatory regions of the
immunoglobulin heavy chain locus, affecting B cell development and
proliferation. Thus genetic and biological evidence are both suggesting
a genuine association between PAX5 and SLE.
P08.61
tNF a (-308G/A) promoter polymorphism in systemic sclerosis
patients from Romania
R. Sfrent-Cornateanu1 , O. M. Popa1 , D. Opris2 , F. Berghea2 , C. Mihai2 , R.
Ionitescu2 , C. Bara1 , M. Dutescu3 , R. Ionescu2 ;
1Department of Immunology and Physiopathology, Carol Davila University of
Medicine and Pharmacy, Bucharest, Romania, 2Research Centre of Rheumatologic
Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest,
Romania, 3Prof C.T. Nicolau National Hematology Institute, Bucharest, Romania.
Background: It is shown that TNFα participates in activation of vascular
endothelium, regulation of immune response and metabolism of
the connective tissue by modulation of fibroblastic function. Systemic
sclerosis (SSc) patients exhibit a systemic and local rise of TNFα content.
This rise contributes to SSc progression development of fibrosing
alveolitis and skin fibrous alterations in Raynaud’s syndrome.
Objectives: The aim of this study was to investigate one of TNFα most
studied promoter polymorphism (-308 G/A) in SSc patients from Romania.
Methods: 37 unrelated patients with SSc diagnosed by a qualified
rheumatologist (35/2 F/M) and 67 healthy unrelated organ donors
(41/26 F/M) were typed for TNFα -308G/A polymorphism (rs 1800629)
by TaqMan SNP Genotyping Assay C_7514879_10 (Applied Biosystems,
USA).
Results: The observed genotypes for the TNFα-308G/A polymorphism
(2.70% AA, 13.51% GA, 83.78% GG in SSc patients, respectively
4.47%AA, 19.40%GA, 76.11%GG in controls) showed no departure
from Hardy-Weinberg equilibrium (HWE).
Conclusion: The present study shows no departure from HWE in SSc
patients from Romania and no potential association of investigated allele
with the susceptibility to this disease. In order to improve the statistical
power of this study, a larger number of patients may be required
to verify this conclusion.
P08.62
translocations and inversions in Finland
T. Reinikainen 1 , M. Pöyhönen 2,3 , K. O. J. Simola 4 , K. Aittomäki 3 , R. Salonen 5 , L.
Peltonen 1,6 , T. Varilo 1,2 ;
1 Institute for Molecular Medicine Finland FIMM, National Institute for Health and
Welfare and University of Helsinki, Helsinki, Finland, 2 Dept. of Medical Genetics,
University of Helsinki, Helsinki, Finland, 3 Dept. of Clinical Genetics, Helsinki
University Central Hospital, Helsinki, Finland, 4 Dept. of Pediatrics, Tampere
University Hospital, Tampere, Finland, 5 Dept. of Medical Genetics, Väestöliitto,
Helsinki, Finland, 6 Welcome Trust Sanger Institute, Hinxton, Cambridge, United
Kingdom.
Finland is acknowledged of its high standard of clinical medicine and in
the disease gene hunt of its founder populations. What is perhaps not
so well recognized is that Finland has probably the most comprehensive
health registers and records: hospitalizations, surgeries, chronic
diseases, and prescriptions etc. have been filed for decades.
Relying on this infrastructure we are gathering information on ~ 3000
known reciprocal balanced translocations and inversions to a national
database (www.fintransloc.org). By analyses of the medical records
and by searches of national registers, we are obtaining novel information
of not only monogenic traits with unidentified mutations, but also of
multifactorial traits associated with any given chromosomal abnormality.
Moreover, such a database will greatly assist genetic counseling
efforts.
To date, we have surveyed 1529 hospital contacts involving translocations
or inversions consisting of 395 families plus singletons. We are
already breakpoint mapping three families providing potential shortcuts
in the identification of disease genes.
Some interesting families
Family Chromosomal
abnormality
5 t(1;12) Specific delay in development 6
29 t(2;18)
Dyspractic developmental
speech disorder
82 t(5;12) Fibroma molle in palate 3
Trait Carriers Traits of the carriers
2 with specific delay, 1 with dyslexia, 2 with learning
difficulty
7 3 with speech difficulty, 1 with dyslexia
3 with fibroma molle (+ 1 patient with chromosome
status unknown)
107 inv 8 Borderline mentalretardation 16 11 with borderline mental retardation
128 t(10;11) Aortic dilatation 2
1 aortic dilation (+ 2 patients with chromosome status
unknown )
207 t(4;12) Height 2
2 with growth disturbance (+ 1 individual with chromosome
status unknown)
P08.63
Polymorphisms in KLF11 gene and development of type 2
diabetes in Japanese
A. Abbaspour1 , T. Tanahashi2 , P. Keshavarz1 ;
1 2 Guilan University of Medical Science, Rasht, Islamic Republic of Iran, Institute
for Genome Research, The University of Tokushima, Tokushima, Japan.
Kru¨ ppel-like factor 11 is a pancreatic transcription factor whose activity
induces the insulin gene. In North European populations, its common
functional variant Q62R (rs35927125) is a strong genetic factor
for Type 2 diabetes (P=0.00033, odds ratio for G allele=1.29, 95% CI
1.12-1.49). We examined the contribution of KLF11 variants to the
susceptibility to Type 2 diabetes in a Japanese population. By re-sequencing
Japanese individuals (n=24, partly 96), we screened all four
exons,exon/intron boundaries and flanking regions of KLF11 Verified
single nucleotide polymorphisms (SNPs) were genotyped in 731 initial
samples (369 control and 362 case subjects). Subsequently, we
tested for association in 1087 samples (524 control and 563 case subjects),
which were collected in different districts of Japan from the initial
samples. We identified eight variants, including a novel A/C variant
on intron 3, but no mis-sense mutations. In an association study, we
failed to find any significant result of SNPs (minor allele frequency 8.2-
46.2%) after correcting for multiple testing. Similarly, no haplotypes
were associated with Type 2 diabetes. It is notable that the G allele
in rs35927125 was completely absent in 1818 Japanese individuals.
Genetic variants in KLF11 are unlikely to have a major effect of Type 2
diabetes in the Japanese population, although they were significantly
associated in North European populations. These observations might
help to determine the role of KLF11 variants in Type 2 diabetes in different
populations.
P08.64
Identification of genetic susceptibility markers of the TPH1 gene
for unipolar depression
T. Noskova, E. Khusnutdinova;
1Institute of Biochemistry and Genetics Ufa Scientific Centre RAS, Ufa, Russian
Federation.
The tryptophan hydroxylase isoform 1 (TPH1) gene is of interest with
respect to the risk of unipolar depression (UD) as it expresses a biosynthetic
enzyme for serotonin in the brain during development. Previous
studies showed that the TPH1 gene to be associated with suicidal
behavior, bipolar disorder. This study examined association of the polymorphisms
A218C in intron 7 and A-6526G in the promoter region of
TPH1 gene with UD in patients from Russian. Samples of 201 patients
and 270 healthy volunteers were investigated using PCR method and
subsequent enzyme digestion. We found significant differences in the
genotype frequencies distribution (χ2=11.43,P=0.003) of the A218C
polymorphism between patients and control groups. An increase of the
*A/*A genotype (OR=1.91,95%CI1.18-3.1) frequency and decrease of
the *A/*C genotype (OR=0.55,95%CI0.38-0.81) frequency were registered
in the depressive group compared to those in the control one.
There were no statistical differences registered between UD patients
and healthy controls in the genotypic and allelic distribution of the A-
6526G polymorphism investigated. Maximum likelihood analysis of
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