2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
P09.118
Role of interlukin-10, interferon gamma and tumor necrosis
factor alpha genes polymorphisms in suicidal behaviour
M. Omrani, B. Bushehri, M. Bageri, A. Alipour, R. Massomi;
Uromieh Medical Science University, Uromieh, Islamic Republic of Iran.
Background: Suicide is a major and growing public health concern
throughout the world and yield significant number of morbidity and
mortality annually. Some researchers have shown that there is an imbalance
between pro-inflammatory and anti-inflammatory cytokines in
patient with suicidal behavior. But controversy still is high in this field
and further experiments among different population need to be carried
out.
Material and methods: To assess whether an association exists between
cytokine polymorphisms and suicide risk, 145 patients with
suicide attempts, and 160 (150-167) healthy individual genotyped for
IL-10, IFN-γ, TNF-α polymorphisms using ASO-PCR method.
Results: Our study showed the frequency of IL-10 A/A genotype
was significantly higher in the majority of the studied groups in comparison
to normal individuals (exception died male vs. normal male
(OR,CI:1.2(0.81, 1.59, 0.61)). IFN-γ +874 A/A and A/T genotypes was
significantly higher in male bedded vs. male control (OR, CI: 1.9(1.21,
2.59, 0.023)) and male died vs. male control (OR, CI: 1.63(1.22, 2.04,
0.037)), respectively. TNF-α -308 G/G genotype was significantly
higher in all studied patients groups vs. normal control, but TNF-α -
308 A/A genotype was significantly higher in only Died groups vs. control
groups (1.29(1.01, 1.57, 0.047)) and Female died vs. f. control
(1.76(1.16, 2.36, 0.014)).
Conclusion: Based on the finding of this study, it is possible to say,
IL-10, IFN-γ and TNF-α polymorphisms may play a role in suicidal behavior.
P09.119
Investigation of complement component C4 loci deficiencies in
Russian children with systemic Lupus Erythematosus (sLE)
I. Shagina 1 , N. Kuzmenko 2 , M. Kurnikova 1 , A. Shcherbina 2 , A. Prodeus 2 , D.
Shagin 1,3 ;
1 Evrogen Joint Stock Company, Moscow, Russian Federation, 2 Research and
Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow,
Russia, Moscow, Russian Federation, 3 Shemyakin and Ovchinnikov Institute of
Bioorganic Chemistry, RAS, Moscow, Russian Federation.
Systemic lupus erythematosus (SLE) is a multisystem, autoimmune
inflammatory disease, with both genetic and environmental causative
factors. A number of studies have shown that complement component
C4 loci (C4A and C4B) are among genes implicated in the pathogenesis
of SLE. Patients with C4A deficiency have been previously reported
as being susceptible to SLE in different ethnic groups. The aim
of our study was to examine the frequencies of homozygous C4A/B
deficiency, large deletion of C4A gene and CYP21A pseudogene and
2 bp insertion in exon 29 of C4A/B genes in Russian patients with
SLE. The patient group was comprised of 36 unrelated children who
fulfilled the American College of Rheumatology classification criteria
for SLE. Control group consisted of randomly selected unrelated 76
healthy individuals (50 children and 26 adults). The homozygous deficiency
of C4A was in one control child. The homozygous deficiency of
C4B was in one patient and in one control adult. The frequency of large
deletion of C4A gene and CYP21A pseudogene was 11.11% (4/36) in
patients compared to 18.00 % (9/50) in control children group, with no
significant difference between SLE patients and controls (p=0.379).
One patient had the 2 bp insertion in exon 29 of C4A gene as well as
one control adult. Thus, our results show lack of evidence of a specific
role for C4A/B deficiency in determining disease susceptibility among
children with SLE in Russian population.
P09.120
Evidence for genetic association and interaction between the
TYK and IRF genes in systemic lupus erythematosus
A. Hellquist 1 , T. M. Järvinen 2,3,4 , S. Koskenmies 3,2 , C. Orsmark-Pietras 1 , M.
Zucchelli 1 , L. Berglind 1 , J. Panelius 3 , T. Hasan 5 , H. Julkunen 6 , M. D’Amato 1 , U.
Saarialho-Kere 3,7 , J. Kere 1,2 ;
1 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden,
2 Department of Medical Genetics, University of Helsinki, and Folkhälsan
Institute of Genetics, Helsinki, Finland, 3 Department of Dermatology, Helsinki
University Central Hospital and Biomedicum Helsinki, University of Helsinki,
Helsinki, Finland, 4Helsinki Biomedical Graduate School LERU PhD Program in
Biomedicine, Helsinki, Finland, 5Department of Dermatology, University of Tampere
and Tampere University Hospital, Tampere, Finland, 6Department of Rheumatology,
Helsinki University Central Hospital, Peijas Hospital, Vantaa, Finland,
7Section of Dermatology, and Department of Clinical Science and Education,
Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden.
Objective. Several candidate genes have been implicated in susceptibility
for systemic lupus erythematosus (SLE), a complex autoimmune
disease. The proposed genes include members of the type I interferon
(IFN) pathway and genes involved in immunological defense functions.
The aim of this study was to systematically replicate six such genes,
TYK2, IRF5, CTLA4, PDCD1, FCGR2A and NOD2.
Methods. Single nucleotide polymorphisms in TYK2, IRF5, CTLA4,
PDCD1, FCGR2A and NOD2 were genotyped in 277 SLE patients
and 356 healthy controls from Finland, giving a power of 42-70% for
different genes at published allele frequencies.
Results. Significant association was seen for rs2304256 (p=0.0001)
and rs12720270 (p=0.0031) in TYK2 and rs10954213 (p=0.0043) in
IRF5 in our samples, but not for the other genes. We found evidence
for genetic interaction (p=0.014) between rs2304256 in TYK2 and
rs10954213 in IRF5, both members of the type I IFN pathway, further
strengthening the role of the type I IFN pathway in SLE pathogenesis.
Conclusion. We conclude that the interferon pathway genes IRF5 and
TYK2 may act synergistically in increasing risk for SLE, but our lack of
replication does not exclude effects of the other studied genes.
P09.121
Classification of low and high risk group of Type 2 Diabetes
mellitus in maltese and Libyan patients by quantitative
expression profiling of SNPlotypes
A. A. Al Ashtar 1 , J. Vassallo 2,3 , J. Azzopardi 3 , J. Borg 1 , M. Debono 2,3 , C. Scerri 1 ,
G. Grech 4 , A. E. Felice 1 ;
1 Laboratory of Molecular Genetics, Msida, Malta, 2 Diabetes and Endocrine
Centre, Mater Dei Hospital, Msida, Malta, 3 Department of Medicine, University
of Malta, Medical School, Msida, Malta, 4 Department of Pathology, Mater Dei
Hospital, Malta.
T2DM is related to interplay between multiple genes with quantitative
effect. Twenty SNPs were studied in the Diabetic patients of Malta and
Libya, together with a random number of neonatal controls. Seven
SNPs (ADRABβ2 [nt46 A->G], FABP2 [codon 54 G->A], UCP1 [nt3826
A->G], LEPTIN [nt -2549 C->A], IPF1 [codon 18 T->C], IL-6 [-174 G-
>C], TCF7L2 [IVS3 T->G]) were found to be more frequent among
Diabetic patients over the reference pool of neonates, and were selected
for SNPlotyping analysis, i.e accounting for the total mutant allele
number per SNPlotype per person. The log of risk ratio increased
with increasing SNP score from -0.7 to 1.08 in Maltese and in Libyan
-1.23 to 0.85. The response to Insulin, Metformin and Glibenclamide
in T2DM patients representing the different SNPlotypes was measured
as a function of differential allele expression on mRNA extracted
from monocytes. Only β2 adrenergic receptor (ADRABβ2) transcripts
were detected in the untreated and treated monocytes. The expression
of ADRABβ2 indicated a relation between the response to the
drug and the SNPlotype of the patient. The expression of ADRABβ2
was downregulated in response to Insulin and Metformin in patients
with SNPlotypes lacking the ADRABβ2 mutation and upregulated in
the other SNPlotypes. The outcome of ADRABβ2 mRNA was dependent
on patient SNPlotype, when ranked by wildtype and mutant UCP1
and ADRABβ2 polymorphisms. Quantitative mRNA data from selected
genes that made up common and rare SNPlotypes, reflect a risk for
T2DM due to SNPlotype scoring perhaps useful to classify patients
into potentially therapeutic groups.
P09.122
the tARGEt study: A randomised controllled trial of tPmt
testing
K. J. Tricker 1 , K. Payne 2 , S. A. Roberts 2,3 , E. A. Fargher 4 , S. Pushpakom 5 ,
J. Alder 5 , K. Poulton 1 , J. Andrews 2 , J. B. Houston 6 , R. A. Elliott 7 , R. Elles 1 , D.
Ray 1,2 , J. Shaffer 8 , C. Griffiths 2,8 , I. Bruce 1,2 , F. Qasim 1 , W. E. R. Ollier 2 , W. G.
Newman 2,1 ;
1 Central Manchester University Hospitals Foundation Trust, Manchester, United
Kingdom, 2 University of Manchester, Manchester, United Kingdom, 3 Central
Manchester University Hospitals Foundation Trust,, Manchester, United Kingdom,
4 Bangor University, Bangor, United Kingdom, 5 University of Liverpool,