2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
Liverpool, United Kingdom, 6 University of Manchester, Manchester, United
Kingdom, 7 University of Nottingham, Nottingham, United Kingdom, 8 Salford
Royal Hospitals NHS Trust, Salford, United Kingdom.
Background: Deficiency of thiopurine methyltransferase (TPMT) has
been associated with severe neutropenia in individuals treated with
thiopurines. Adoption of TPMT testing into clinical practice has been
limited by insufficient robust prospective evidence regarding the added
value of testing.
Methods: A randomized controlled trial was undertaken. Individuals
with inflammatory disease requiring azathioprine treatment were randomized
(50:50) to receive standard prescribing or TPMT genotyping
to inform prescription. The primary endpoint was stopping azathioprine
secondary to adverse drug reactions (ADRs). Secondary endpoints
included reduction in severe neutropenia, prediction of other ADRs,
quality of life and drug efficacy. An economic evaluation was also conducted,
Results. Following ethical approval, 333 participants (167 intervention:
166 standard) were recruited from 19 centres in England over 24
months. Overall 111 (33%) patients stopped azathioprine by 4 months
due to any ADRs, with no difference in the likelihood of stopping by
treatment group (OR 0.91 p=0.71). The incidence of significant neutropenia
was lower than anticipated (2.7%). Only one individual (standard
arm), was homozygous for the TMPT*3A allele and presented
with severe neutropenia. Data on secondary clinical endpoints will be
presented.
Conclusion: Our findings support the assertion that TPMT testing is
specific (individuals homozygous for null alleles are at high risk of
neutropenia when treated with azathioprine), but has low sensitivity in
detecting individuals at risk of neutropenia. Therefore, TPMT testing is
valuable in identifying individuals at risk of neutropenia, but must be
performed in tandem with full blood count monitoring to detect individuals
at risk of non-TPMT related neutropenia.
P09.123
mutation detection of thyroid peroxidase gene in Persian
patients with thyroid dyshormonogenesis
S. Karimizare 1,2 , F. Soheilipour 3 , H. Khanahmad 1 , M. Karimipour 1 , S. Aminzadeh
1,2 , M. Hashemipour* 3 ;
1 Pasteur Institute of Iran, Molecular Medicine Department, Tehran, Islamic Republic
of Iran, 2 Science and Research Branch, Islamic Azad university, Tehran,
Islamic Republic of Iran, 3 Endocrine & Metabolism Research Center, Isfahan
University of Medical Sciences & Health Services, Isfahan, Islamic Republic of
Iran.
Congenital hypothyroidism (CH) is one of the most common endocrine
disorders in childhood. According to morphological findings, CH can be
subdivided into defects of thyroid development (dysgenesis), ranging
from hypoplasia to athyrosis, and defects of thyroid hormone biosynthesis
(dyshormonogenesis) with normal thyroid gland size. The most
prevalent cause of dyshormonogenesis is thyroid peroxidase (TPO)
gene deficiency. TPO encodes a membrane-bound glycoprotein. This
protein acts as an enzyme which plays a central role in iodide organification
and is important for thyroid function and pathogenesis. The
prevalence of CH is occurring one in 3000-4000 live births in North
America and Europe. The recent study in Isfahan province of Iran
Demonstrated a high frequency of congenital hypothyroidism with
1:370ratio in newborns. In this study DNA was extracted from peripheral
blood of 30 permanent congenital hypothyroidism Persian patients
of Isfahan province according to the salting out method. Diagnosis of
CH was based on elevated TSH and decreased T4 levels in 3 years
old children, who had normal thyroid scan. The 17 exonic region of
the TPO gene were amplified and PCR products were analyzed by
single strand conformation polymorphism (SSCP) and Sequencing.
No exonic mutation in TPO was identified In all patients with dyshormonogenesis
CH in this study. It remains possible that these patients’
disorder was caused by TPO gene defect in regulatory or intronic region.
In addition, other gene defects, such as in the pendrin, thyroid
oxidase and thyroglobulin genes, need to be considered and pursued
in further studies.
P09.124
tNF-alpha Gene 308 G/A and 850 c/t Polymorphisms in turkish
children with PANDAs
U. Luleyap, D. Onatoglu;
Department of Medical Biology and Genetics, Faculty of Medicine, University of
Cukurova, Adana, Turkey.
Objectives: PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders
Associated with Streptococcal Infections) is a newly defined
pediatric disorder in neuropsychiatry. This disorder occurs with an
autoimmune mechanism after Grup A Beta Haemolytic Streptococcus
infection. Streptococcus infection may causes OCD (Obsessive Compulsive
Disorder) or tic disorders and PANDAS. The aim of the current
study was to investigate whether there is an association between TNFalpha
gene 308 G/A and 850 C/T polymorphisms and PANDAS.
Methods: In this study, 92 cases of PANDAS and 58 control cases
were genotyped for TNF-alpha-308 G/A and TNF-alpha-850 C/T polymorphisms
with PCR-RFLP method.
Results: All 92 PANDAS cases had mutant genotype for 308 G/A polymorphism.
In control group, however, cases had 8,62% GA mutant
genotype and 91,38% GG genotype.
As for 850 C/T polymorphism, we found 34,78% CC genotype, and
65,22% mutant genotype in PANDAS cases. In control group, however,
46,55% mutant genotype and 53,45% CC genotype was observed.
In our study, we observed remarkable effects of these two polymorphisms
particularly on phenotype-genotype relations. In different parts
of the world, studies conducted for different OCD patients have variable
results. Moreover, there have not been any study revealing an
association between PANDAS and TNF-alpha gene polymorphisms
reported yet.
Conclusion: Here, we have demonstrated an association between
TNF-alpha 308 G/A and 850 C/T polymorphisms and PANDAS susceptibility.
In light of our findings, we propose that these two polymorphisms
can be used as a molecular indicators of PANDAS which needs
to be verified by further research on PANDAS.
P09.125
Association of candidate genes for type 1 diabetes with
parameters of vasoactive and proteolytic systems
N. V. Tarasenko1 , E. I. Kondratieva2 , L. V. Spirina2 , G. A. Suchanova2 , A. A.
Rudko1 , V. P. Puzyrev1 ;
1State Research Institute of Medical Genetics, Tomsk, Russian Federation,
2Siberian Medical University, Tomsk, Russian Federation.
Associations of polymorphisms in genes NOS1 (C3392T), NOS3 (C-
691T, VNTR, C774T, G894T), TNFA (G-308A), IL1A (+3953 A1/A2),
IL1RN (VNTR), IL4 (G717C) and IL4RA (A148G) with parameters of
vasoactive and proteolytic systems at children and the adolescents
with type 1 diabetes (T1D) were studied. 119 children and the adolescents
with T1D have been surveyed. Biochemical research included
definition of: kallikrein (KK), kallikreinogen (KKG), angiotensin converting
enzyme (ACE), α1-proteinase inhibitor (α1-PI), α2-macroglobulin
(α2-MG). At T1D group, there was an increase in activity of KK, and
development of diabetic neuropathy (DN) was accompanied by hyperactivity
of ACE and decrease in activity of α1-PI in blood. Children
and adolescents who were carriers of C allele of C774T (NOS3) had
lower values of KKG than TT homozygotes (p=0,043). Carriers of G allele
of G894T (NOS3) had lower values of α1-PI than TT homozygotes
(p=0,008). For polymorphism A148G in IL4RA we found that activity
of ACE was increased in carriers of A allele (p=0,008). The obtained
associations of investigated polymorphisms with parameters of vasoactive
and proteolytic systems confirm participation of these genes in
development of endothelial dysfunction at diabetes.
P09.126
“Genetic Load” of diabetes risk alleles affects beta-cell function
in patients with newly diagnosed type 2 diabetes
S. Bonetti 1 , G. Malerba 2 , E. Trabetti 2 , L. Xumerle 2 , M. Trombetta 1 , L. Boselli 1 , M.
Muggeo 1 , E. Bonora 1 , R. C. Bonadonna 1 , P. F. Pignatti 2 ;
1 Dept of Biomedical and Surgical Sciences, University of Verona, Verona, Italy,
2 DMIBG, Sect of Biology and Genetics, University of Verona, Verona, Italy.
Genetic variation in a number of SNPs has been demonstrated to affect
the risk of type 2 diabetes mostly by genome wide association studies.
Some of these “diabetoSNPs” have been associated to prediabetic
phenotypes in nondiabetic individuals. However, no studies have re-
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