2009 Vienna - European Society of Human Genetics

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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- 0
Complex traits and polygenic disorders ported associations between “diabetoSNPs” and the patient metabolic phenotype. We assessed beta-cell function and insulin sensitivity in 343 consecutive GADA-negative, drug treatment naive patients with newly diagnosed type 2 diabetes by state-of-art methods. Both betacell function and insulin sensitivity of these patients were severely reduced (~60%, p
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Volume 17 Supplement 2 May 2009 www
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European Society of Human Genetics
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Table of Contents spoken Presentati
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Plenary Lectures PL2.2 massive para
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Concurrent Symposia s01.1 Genome va
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Concurrent Symposia Monogenic diabe
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Concurrent Symposia invariable in t
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Concurrent Symposia s11.2 clinical,
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Concurrent Symposia s13.2 A novel g
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Concurrent Sessions c01.1 mRNA-seq
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Concurrent Sessions velopmental del
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Concurrent Sessions development of
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Concurrent Sessions c04.6 Duplicati
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Concurrent Sessions genes to be rec
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Concurrent Sessions c07.5 Prenatal
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Concurrent Sessions with familial h
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Concurrent Sessions University of W
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Concurrent Sessions with this, we f
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Concurrent Sessions had immotile ci
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Concurrent Sessions abnormal glycos
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Concurrent Sessions showers’ and
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Concurrent Sessions partial gene de
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Concurrent Sessions leads to distre
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Genetic counseling Genetics educati
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Clinical genetics and Dysmorphology
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Cytogenetics P03. cytogenetics Recu
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Cytogenetics use of metaphase analy
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Cytogenetics 2: mother’s age < fa
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Cytogenetics P03.028 HLA B27 allele
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Cytogenetics karyotype revealed a p
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Cytogenetics drome is estimated at
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Cytogenetics P03.057 Pathological c
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Cytogenetics grandmother and 2 mate
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Cytogenetics method used to detect
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Cytogenetics P03.082 High-resolutio
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Cytogenetics All detected anomalies
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Cytogenetics somy for chromosome 2.
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Cytogenetics cially in chromosome 4
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Cytogenetics (59.390.122 to 62.021.
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Cytogenetics For further characteri
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Cytogenetics 9p duplication. This c
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Cytogenetics regions with mental /d
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Cytogenetics donation program of po
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Cytogenetics P03.165 interpretation
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Cytogenetics P03.174 Deletion of th
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Cytogenetics P03.183 An atypical 7q
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Cytogenetics spermia, 11 oligosperm
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Reproductive genetics and social fa
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Reproductive genetics mosomal chang
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Reproductive genetics two cohorts w
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Reproductive genetics the 147 SC ch
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Prenatal and perinatal genetics P05
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Prenatal and perinatal genetics and
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Prenatal and perinatal genetics fro
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Prenatal and perinatal genetics dev
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Prenatal and perinatal genetics in
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Prenatal and perinatal genetics obj
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Prenatal and perinatal genetics P05
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Cancer genetics P06.005 tiling reso
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Cancer genetics tient group in whic
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Cancer genetics chronic inflammatio
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Cancer genetics licular thyroid can
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Cancer genetics also studied. In 31
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Cancer genetics tile polyposis. We
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Cancer genetics Upon recombinant ex
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Cancer genetics variant allele was
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Cancer genetics from patients with
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Cancer genetics tion (PAX5 and GATA
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Cancer genetics scribed underexpres
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Cancer genetics of the ZIC gene fam
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Cancer genetics Materials and metho
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Cancer genetics the past and it is
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Cancer genetics P06.130 spectrum an
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Cancer genetics P06.139 the role of
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Cancer genetics and MSH2 germline m
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Cancer genetics P06.155 New roles f
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Cancer genetics screening was perfo
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Cancer genetics val (DFI) than pati
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Cancer genetics is hTERC gene ampli
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Page 221 and 222: Statistical genetics, includes Mapp
Page 235 and 236: Complex traits and polygenic disord
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Page 267 and 268: Evolutionary and population genetic
Page 285 and 286: Genomics, Genomic technology and Ep
Page 313 and 314: Molecular basis of Mendelian disord
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Molecular basis of Mendelian disord
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Metabolic disorders P12.167 Pattern
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Metabolic disorders PKU. BH4 challe
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Metabolic disorders catepe Universi
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Metabolic disorders respectively. G
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Metabolic disorders enzymaticaly co
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Metabolic disorders Normal Affected
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Therapy for genetic disorders in th
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Therapy for genetic disorders P14.0
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Therapy for genetic disorders of me
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Laboratory and quality management P
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Laboratory and quality management T
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Molecular and biochemical basis of
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Genetic analysis, linkage ans assoc
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Author Index Allanson, J.: P02.140
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Author Index 0 Barbacioru, C.: C01.
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Author Index 0 Bonneau, D.: C16.2,
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Author Index 0 Chakravarti, A.: C13
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Author Index 0 Dan, D.: P01.39, P14
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Author Index 0 Duskova, J.: P06.012
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Author Index Franke, A.: P09.056 Fr
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Author Index Grasso, R.: P02.025 Gr
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Author Index Holder-Espinasse, M.:
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Author Index Jurkiewicz, E.: C14.5
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Author Index Kooper, A. J. A.: P05.
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Author Index Li, K. J.: P11.086 Li,
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Author Index Martinet, D.: P03.095
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Author Index Moorman, A. F. M.: P16
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Author Index P10.57, P10.82 Oguzkan
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Author Index P09.054, P09.085, P09.
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Author Index P16.01 Renieri, A.: P0
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Author Index Santorelli, F.: P08.55
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Author Index Sinke, R. J.: P02.020
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Author Index Taheri, M.: P04.33, P0
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Author Index Valentino, P.: P02.064
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Author Index Wiemer-Kruel, A.: P14.
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Keyword Index 1 10q22 deletions: P0
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Keyword Index autosomal dominant re
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Keyword Index CLA: P06.073 CLCN1 ge
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Keyword Index DMD: P16.40, P16.41,
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Keyword Index gene networks: S12.2
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Keyword Index hydrocephaly: P05.11
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Keyword Index malignant hyperthermi
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Keyword Index NAT2: P12.118 natridi
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Keyword Index Polymalformations: P0
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Keyword Index Sardinia: C09.6 Sardi
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Keyword Index TNFalpha: P08.61, P09
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2009 Vienna - European Society of Human Genetics

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