European Human Genetics Conference 2007 June 16 – 19, 2007 ...

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Genetic analysis, linkage, and association P1074. Polymorphism of nitric oxide synthases in preeclampsia G. S. Demin1,2 , I. Bouba3 , T. E. Ivashchenko1 , V. S. Baranov1,2 , I. A. Georgiou3 ; 1Ott’s Institute of Obstetrics & Gynecology, St.-Petersburg, Russian Federation, 2 3 Saint-Petersburg State University, Saint-Petersburg, Russian Federation, University of Ioannina, Ioannina, Greece. Preeclampsia is multifactorial disease of third trimester of pregnancy affecting up to 15% of women. The etiology of preeclampsia still remains unknown. Pathological changes lead to generalized endothelial dysfunction in mother and further complications of pregnancy. Nitric oxide plays an important role in regulating vascular processes, acting as a vasodilator and second messenger. Nitric oxide synthases (NOS) catalyze nitric oxide production. There are three types of NOS encoded by three different genes (NOS1, 2 and 3). Polymorphism of these genes correlates with NO level and thus certain genetic alleles may predispose to preeclampsia. DNA samples were obtained from the women with pure preeclampsia (n=39) and control group of women without any gynecologic complications and background disorders (n=98). Polymorphisms of NOS1 (AAT repeats), NOS2 (CCTTT repeats) and NOS3 (894G>T and 4a/4b) were studied by PCR-RFLP assay. The distribution of genotypes of all NOS genes was in agreement with the HWE law (p>0.05). There was no significant difference in frequency of genotypes of NOS1, NOS2 and NOS3 (894G>T) genes between studied groups (p>0.05). Although there were some tendencies for certain alleles of NOS2 (protective affect of allele 15) and NOS3 (894G) genes in patients but they were not significant. However the frequency of 4b/4b genotype of NOS3 gene was significantly higher in preeclamptic women (79.5%) than in controls (59.8%, p48) at physiological menopause collected in the same geographic areas. Among a number of candidate genes for POF, we started analysing genes involved by X/autosome balanced translocations. The analysis of the DIAPH2 gene gave us first evidence of its contribution as a susceptibility gene. Allelic frequencies at two polymorphic loci showed significant enrichment in the POF cohort and defined an associated haplotype spanning the proximal portion of the gene. Replication of the association results and functional studies are in progress to evaluate the prevalence of these variants in the etiology of POF. P1076. Genome-wide linkage analysis for familial primary cutaneous amyloidosis: a comparison between singlenucleotide polymorphisms and microsatellites assays M. Lin 1,2 , C. Lin 1 , Y. Su 1 , I. Chen 1 , D. Lee 2 , Y. Chang 1,2 , T. Liu 1 , C. Wong 2 , S. Tsai 1,3 ; 1 National Yang-Ming University, Taipei, Taiwan, 2 Taipei Veterans General Hospital, Taipei, Taiwan, 3 National Health Research Institutes, Zhunan Town, Miaoli 2 2 County, Taiwan. Primary cutaneous amyloidosis (PCA) is a relatively common skin disorder in South America and Southeast Asia. The pathogenesis of PCA remains unclear. Most cases of PCA are sporadic but familial aggregation has been reported from South America and Taiwan. The different susceptibility among ethnic groups suggests that genetic factor may play an important role in its pathogenesis. In this study, we performed genome-wide linkage analysis using both single-nucleotide polymorphisms (SNPs) and microsatellites (STRs) assays across nine families with familial primary cutaneous amyloidosis (FPCA) to map the disease gene(s) for FPCA. Multipoint linkage analysis of both SNPs and STRs assays identified significant lod scores (lod >3) with a peak lod score of 3.73 (NPL score = 5.39, p-value = 0.000057) produced by the SNPs assay on chromosome 5q region. However, the critical region of FPCA was further narrowed down from 7.25 cM to 2.37 cM by SNPs assay. The linkage peaks obtained by both SNPs and STRs sets had a high degree of correspondence in general, with SNPs consistently producing higher lod scores. Additional lod > 1 regions were observed on chromosome 2, 11, 15, and 16 with the SNPs set. There are 12 known genes in the candidate region of chromosome 5 identified by SNP linkage mapping. Re-sequencing of some of these genes are underway to identify the possible disease gene of FPCA. We conclude that genome-wide linkage analysis by using high-density SNP markers provided higher lod scores compared with the standard 10 cM microsatellite marker assays. P1077. Proopiomelanocortin gene variability and chronic heart failure: no association so far J. A. Bienertova Vasku 1,2 , L. Spinarova 1,3 , P. Bienert 1,2 , M. Forejt 1,4 , A. Vasku 1,2 ; 1 Masaryk University, Brno, Czech Republic, 2 Institute of Pathological Physiology, Masaryk University, Brno, Czech Republic, 3 1st Department of Cardioangiology, Masaryk University affiliated Hospital, Brno, Czech Republic, 4 Department of Preventive Medicine, Masaryk University, Brno, Czech Republic. Background: Chronic heart failure is characterized by persistent activation of the hypothalamic-pituitary-adrenocortical axis where proopiomelanocortin (POMC) plays a crucial role. In this study, we therefore aimed to investigate possible associations of the POMC RsaI (rs3754860) and C1032G (rs1009388) variants in the non-coding regions of proopiomelanocortin gene with chronic heart failure. Methods: The case-control study comprised a total of 374 patients of caucasian origin with chronic heart failure (functional classes NYHA II-IV, ejection fraction (EF) < 40%) and 202 age-matched healthy controls. They were genotyped for the POMC RsaI (5´-UTR) and C1032G variants (intron 1) by means of PCR-based methodology. Results: In univariable analyses, neither genotypes nor alleles of both examined polymorphisms were associated with BMI, older age, male sex, ejection fraction (EF), hypertension, left ventricular hypertrophy (LVH), diabetes mellitus (DM), and chronic kidney disease (CKD) (P≥0.05 for each); no case-control differerences in genotype distributions or allele frequencies were observed. We also constructed POMC RsaI/1032 C/G haplotypes and have not found a significant association with BMI, EF, LVH, DM or CKD. Conclusions: Our results do not clearly indicate that both the genotypes of alleles of RsaI and C1032G polymorphisms within the POMC genes are associated with chronic heart failure in the Czech cauacasian population. P1078. Novel associations of several polymorphisms and haplotypes in -alpha-reductase gene (SRD A2) in Czech prostate cancer patients M. Minarik 1 , A. Loukola 2 , L. Fantova 1 , M. Urban 3 , J. Heracek 3 , L. Benesova 1 ; 1 Genomac International, Prague, Czech Republic, 2 Finnish Genome Center, University of Helsinki, Helsinki, Finland, 3 Urology clinic, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic. Introduction & Objectives: SRD5A2 is a key member of androgen methabolic pathway converting testosterone to dihydrotestosterone and has been suggested to play a role in the transformation of prostate cells. Several SRD5A2 SNPs have previously been desribed as potential risk markers. The aim of this study was to evaluate potential SNP and haplotype association with prostate cancer. Material & Methods: The case-control study included 339 unrelated individuals with clinically verified prostate cancer and 231 unrelated
Genetic analysis, linkage, and association controls with clinically verified benign prostatic hyperplasia. DNA was extracted from venous blood and genotyping of a set of 17 SNPs at the SDR5A2 locus was carried out by PCR and cycling-gradient capillary electrophoresis (CGCE), a technique based on heteroduplex analysis in temperature gradient. Case-control association analyses were performed using PLINK (http://pngu.mgh.harvard.edu/~purcell/plink/data. shtml). Results: We have identified 5 SNPs showing significant allele frequency and genotype distribution differencies between cases and controls. The SNP markers with their respective p values are: rs4952219 (p=0.0186), rs413836 (p=0.0261), rs2300697 (p=0.0124), rs2208532 (p=0.0142) and a novel marker assigned as SRD5A2_SNP4 (p=0,0358). In addition we have identified 5 haplotypes showing strong association with p values between 0,001 and 0,005. Discussion: Many of the significant SNP markers are from noncoding regions, therefore the haplotype association may mostly be related to alternate gene regulation. Haplotype analyses on a larger patient cohorts is desirable in order to evaluate potential of the identified SNPs and haplotypes for identification of risk groups. This project was supported by Czech Ministry of Health grant no. 8039-3. P1079. Linkage to 13q in a novel autosomal dominant pseudoarthrogryposis-like syndrome S. A. Ugur 1 , D. Gul 2 , A. Tolun 1 ; 1 Bogazici University, Department of Molecular Biology and Genetics, Istanbul, Turkey, 2 Gülhane Military Medical Academy and Medical Faculty, Department of Medical Genetics, Ankara, Turkey. Distal Arthrogryposis (DA) Syndromes are characterized by nonprogressive, congenital contractures of two or more different body areas without primary neurological and/or muscle disease that affects limb function. Features common to all DA syndromes include a consistent pattern of distal joint involvement, limited proximal joint involvement, an autosomal dominant inheritance pattern, and widely variable expressivity. Mutations in genes encoding the fast skeletal muscle regulatory proteins troponin T, troponin I, and beta-tropomyosin have been shown to cause DA syndromes. Pseudoarthrogryposis-like syndrome (PAG- L), a novel disorder, has been observed in a large Turkish kinship. Manifesting multiple contractures in patients, and an autosomal dominant mode of inheritance, the syndrome may be classified as a new form of DA. However, PAG-L is progressive with a preadolescence age of onset, which makes it distinct from DA syndromes. A genome-wide scan has identified a locus on chromosome 13q suggestive for linkage. Further genotyping in the candidate locus with additional family members is in progress. P1080. Genome-wide association studies for complex diseases using samples from the Quebec founder population: examples with psoriasis and ADHD B. Paquin, J. Raelson, P. Van Eerdewegh, V. Bruat, P. Croteau, J. Segal, S. Debrus, J. M. Vidal, M. Lapalme, S. Kebbache, J. W. Hooper, A. Belouchi, T. Keith; Genizon BioSciences, St. Laurent, PQ, Canada. Genizon is involved in the discovery of disease susceptibility genes in more than 20 diseases using samples from the Quebec founder population (QFP). We have successfully completed nine genome-wide association studies for complex diseases. To illustrate our process and the evolution of our strategy, examples from the psoriasis and ADHD studies are shown. The psoriasis study was performed using 500 trios and a custom marker map of 80,654 SNPs spaced according to the variation in the extent of local LD across the genome in the QFP. The ADHD study was performed using 459 trios with an upgraded custom marker map of 374,187 SNPs, consisting of the HAP300 chip from Illumina supplemented by 56,683 SNPs, optimizing the SNP selection to the QFP samples. For both studies, single-marker and haplotype association analyses were performed and genome-wide significance of the obtained P values was evaluated based on permutation tests. For both studies, regions with P-values that met the criteria of genomewide significance were identified. We describe the identified regions and the encoded genes. Many regions contained a single, druggable gene representing immediate opportunities for drug development and genes with biologically relevant function. Genes in novel pathways were identified in both studies. Additional disease genes were also found from conditional and sub-phenotype analyses. The disease genes were then used to infer a GeneMap that consists of a network of interacting disease genes and their biological pathways. The shown GeneMap reveals the genetic etiology of the disease and represents a comprehensive tool toward personalized medicine. P1081. Genetic refinement of PSORS4 and ATOD2 susceptibility loci in Italian samples C. Sinibaldi 1 , N. Paolillo 1 , E. Giardina 1 , C. Peconi 1 , L. Chini 2 , V. Moschese 2 , P. Rossi 2,3 , S. Chimenti 4 , S. Nisticò 4 , E. Galli 5 , G. Girolomoni 6 , G. Novelli 1,5,7 ; 1 Department of Biopathology, Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, School of Medicine, Tor Vergata University, Rome, Italy, 2 Department of Pediatrics, Tor Vergata University, Rome, Italy, 3 Division of Immunology and Infectious Disease, Department of Pediatrics, Children’s Hospital ‘Bambino Gesu, Rome, Italy, 4 Department of Dermatology, Tor Vergata University, Rome, Italy, 5 San Peter Hospital, Fatebenefratelli, Rome, Italy, 6 Department of Biomedical and Surgical Sciences, Section of Dermatology, University of Verona, Verona, Italy, 7 Department of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little rock, AR, United States. Psoriasis (PS) and atopic dermatitis (ATOD) are chronic inflammatory skin disorders triggered by both genetic and environmental factors. A susceptibility locus mapped on chromosome 1q21 have been identified in both the diseases (PSORS4-ATOD2). Recently we refined the PSORS4 and ATOD2 susceptibility loci by using a LD approach in two cohorts of 128 PS and 120 ATOD Italian trios. We showed that PS and ATOD shared a risk-haplotype defined by STRs markers MIDDLE and ENDAL16. We failed to reveal evidence of association for LOR gene located within the risk-haplotype although a differential gene expression has been observed in PS and ATOD. In order to reveal the identity of the susceptibility factor of PSORS4 and ATOD2 we newly refined the risk haplotype and its surrounding chromosomal regions (650 Kb) by typing a selection of 31 SNPs in our familial cohorts of trios. Preliminary statistical analysis identified three distinct associated haplotypes within the selected region: the first, Hap1 (9.7 kb) generated significant association in both the diseases (PS p-value 0.0229; ATOD p-value 0.0077), the second, Hap2 (8.8 kb) is associated in the only ATOD cohort (p-value 0.0257); the third, Hap3 (38.5 kb) generated significant p-value in the only PS cohort ( p-value= 0.0270). The weakness of association data reported could reflect the low penetrance of PSORS4 and ATOD2 but need to be confirmed in additional samples. Threfore, an independent set of sporadic psoriatic patients (n=300) and further 60 ATOD trios are being typed at the moment. Acknowledgements: This work was supported by A.DI.PSO P1082. Detection of large deletion of 4.5 Mb in PTCH region in a Croatian Gorlin syndrome case by semi-quantitative fluorescent multiplex PCR V. Musani 1 , A. Basta-Juzbašić 2 , P. Gorry 3 , S. Levanat 1 ; 1 Department of molecular medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia, 2 Department of Dermatovenerology, University School of Medicine, University of Zagreb, 10000 Zagreb, Croatia, 3 Laboratoire de Génétique, Développement & Cancer, Université V. Ségalen, Bordeaux, France. Gorlin syndrome or Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities, cysts of the skin, jaws, and mesentery and cancer predisposition to basal cell carcinomas (BCC), medulloblastomas, meningiomas, fibromas of the ovaries and heart. The syndrome is caused by mutations in the human homolog of the Drosophila patched gene, PTCH. PTCH is a tumor supressor gene, located at 9q22.3, and encodes a 12 transmembrane glycoprotein that acts as an antagonist in the Hedgehog signaling pathway. We present a Gorlin syndrome patient with typical phenothypical features of widespread basal cell carcinomas, jaw malformations, strabismus and mental retardation, with family history that beside basal cell carcinomas includes lung cancer and gastrointestinal carcinomas. Since we found no mutations in exons of PTCH gene with conventional methods of SSCP, dHPLC screening and direct sequencing, we developed a new method of semi-quantitative fluorescent multiplex PCR with polymorphic markers surrounding PTCH gene. With this method we defined a deletion of 4.5 Mb in size between markers SHGC- 110746 and SHGC-132418 (9q22.3-9q31.1). 2
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Volume 15 Supplement 1 June 2007 ww
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Table of Contents Spoken Presentati
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Plenary Lectures Plenary Lectures P
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Plenary Lectures labile iron can be
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Concurrent Symposia S07. Vertebrate
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Concurrent Symposia S17. Towards a
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Concurrent Symposia 11 at E13.5 sim
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Concurrent Symposia 1 phomagenesis.
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cover cryptic mutations in Drosophi
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Concurrent Sessions first excluded
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Concurrent Sessions of 210 ancestry
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Concurrent Sessions C23. Literature
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Concurrent Sessions a boy with a ty
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Concurrent Sessions C40. Mutation o
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Concurrent Sessions C48. CHROMSCAN:
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Concurrent Sessions C57. RNAi-based
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Concurrent Sessions been replicated
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Concurrent Sessions involved in an
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Concurrent Sessions tion considers
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Clinical genetics lateral neurosens
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Clinical genetics apparently sporad
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Clinical genetics itar syndrome, wh
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Clinical genetics diseases, Foundat
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Clinical genetics P0041. The first
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Clinical genetics EFNB1 was found t
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Clinical genetics of the CSB gene.
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Clinical genetics growth retardatio
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Clinical genetics PCR with a modifi
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Clinical genetics pound heterozygou
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Clinical genetics plicated: two cou
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Clinical genetics P0105. APC gene m
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Clinical genetics an indication of
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Clinical genetics great importance
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Clinical genetics P0133. Hidrotic e
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Clinical genetics eight patients as
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Clinical genetics P0152. Kabuki syn
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Clinical genetics P0161. Intrafamil
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Clinical genetics matter and normal
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Clinical genetics type at 550 bands
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Clinical genetics will be confirmed
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Clinical genetics nosed. Accurate r
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Clinical genetics which has not bee
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Clinical genetics P0217. Partial mo
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Clinical genetics fested progeroid
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Clinical genetics A 29 years old ma
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Clinical genetics ing loss (HHL). I
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Clinical genetics dació Son Llatze
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Clinical genetics These preliminary
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Clinical genetics P0272. Williams S
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Cytogenetics Po02. Cytogenetics P02
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Cytogenetics to reports from Saudi
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Cytogenetics P0298. Female-specific
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Cytogenetics P0306. Lipoatrophic pa
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Cytogenetics 22 leading to the form
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Cytogenetics somal sperm and that o
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Cytogenetics University of Belgrade
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Cytogenetics Within the same metaph
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Cytogenetics Less than 10 cases of
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Cytogenetics lar markers taken from
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Cytogenetics Brain Unaffected Schiz
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Cytogenetics ability with no speech
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Cytogenetics P0389. An age based cy
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Cytogenetics P0399. Molecular Chara
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Cytogenetics ing of complex examina
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Cytogenetics letion in 5q33 in all
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Cytogenetics and his son carried th
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Prenatal diagnosis tion about famil
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Prenatal diagnosis P0443. The risk
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Prenatal diagnosis in house PCR pro
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Prenatal diagnosis P0462. Increased
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Prenatal diagnosis P0471. Preimplan
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Prenatal diagnosis agreement with w
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Prenatal diagnosis of Turner Syndro
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Cancer genetics ously defined for d
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Cancer genetics Their frequencies w
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Cancer genetics tion Clinic-Portugu
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Cancer genetics tric carcinogenesis
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Cancer genetics P0532. Secondary ch
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Cancer genetics P0542. Differential
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Cancer genetics gastric cancer risk
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Cancer genetics ania, 3 The Institu
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Cancer genetics low: 8% (8/98 sampl
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Cancer genetics P0578. Somatic mito
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Cancer genetics P0587. Differential
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Cancer genetics cinoma (ESCC), whic
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Cancer genetics method to measure t
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Cancer genetics pression (compared
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Cancer genetics to available biolog
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Molecular and biochemical basis of
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Genomics, technology, bioinformatic
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Genetic counselling, education, gen
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Therapy for genetic disease Po10. T
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Therapy for genetic disease P1405.
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Therapy for genetic disease exon 7
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Author Index 1 Arslan-Krichner, M.:
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Author Index Borkowska, A.: P1089 B
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Author Index Coviello, D.: P0078, P
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Author Index Estivill, X.: P1216, P
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Author Index Graf, S. A.: P0021 Gra
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Author Index 1 Josifiova, D.: PL07
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Author Index Laurier, V.: C03 Lauri
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Author Index Melo, D. G.: P0260, P0
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Author Index Osorio, P.: P0218 Osta
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Author Index Reese, T.: C06 Regal,
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Author Index 1 Shaposhnikov, S.: P0
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Author Index Touitou, I.: P0733 Tou
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Author Index Xiao, C.: P1241 Xie, G
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Keyword Index ARMR: P0907 array CGH
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Keyword Index Consanguineous marria
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Keyword Index 1 Fronto-temporal dem
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Keyword Index IRF5: P1086 IRF6: P07
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Keyword Index NBS1 gene: P0567 NBS-
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Keyword Index P1085 Rep1: P1104 rep
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Keyword Index vision: P0632 Vitamin
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Notes 1
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A natural choice in Fabry Disease P
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