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737 results on '"Syvanen, A"'

151. Trans-acting transposase mutant from Tn5

Author

Michael Syvanen and Alison DeLong

Subjects
Transposable element, Genotype, Restriction Mapping, Mutant, Transposases, chemical and pharmacologic phenomena, Biology, medicine.disease_cause, Transposition (music), Escherichia coli, medicine, Insertion sequence, Transposase, Mutation, Multidisciplinary, hemic and immune systems, Bacteriophage lambda, Nucleotidyltransferases, Molecular biology, eye diseases, Phenotype, Regulatory sequence, DNA Transposable Elements, Trans-acting, tissues, Plasmids, Research Article
Abstract

Transposition of Tn5 and of its component insertion sequence IS50R is regulated through the action of two proteins it encodes: a cis-acting transposase, Tnp, and a trans-acting inhibitor of transposition, Inh. The mechanism of the cis-acting Tnp and the relevance of inhibition to cis action have been addressed in the current study. A specific colony morphology assay for transposition of Tn5 was shown to be sensitive to Inh produced in trans and was used to screen for mutants in Inh and/or Tnp with altered regulation. A dominant mutant in IS50R that promotes transposition in trans was isolated and characterized. The mutant (449F) carries a Leu----Phe mutation at position 449 in Tnp. This mutation reduces the frequency of Tn5 or IS50R transposition in cis but allows Tnp-449F to act as efficiently in trans as it does in cis. Tnp-449F is sensitive to inhibition and, furthermore, Inh-449F is a competent inhibitor in trans. These results show that Tnp-449F is a trans-acting transposase, unlike wild-type Tnp, which is cis-acting.

Published
1991
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152. Membrane association of the Tnp and Inh proteins of IS50R

Author

A. DeLong and Michael Syvanen

Subjects
Mutant, Radioimmunoassay, Transposases, chemical and pharmacologic phenomena, medicine.disease_cause, Microbiology, Cell membrane, Bacterial Proteins, Escherichia coli, medicine, Inner membrane, heterocyclic compounds, Molecular Biology, chemistry.chemical_classification, biology, Cell Membrane, hemic and immune systems, bacterial infections and mycoses, biology.organism_classification, Nucleotidyltransferases, Enterobacteriaceae, Molecular biology, respiratory tract diseases, Enzyme, medicine.anatomical_structure, Biochemistry, chemistry, Genes, Bacterial, Cytoplasm, Mutation, DNA Transposable Elements, Electrophoresis, Polyacrylamide Gel, Research Article, Plasmids
Abstract

Using a radioimmunoassay for the IS50R proteins Tnp and Inh, we found that both proteins were present primarily in the cytoplasm, but 3 to 11% of Tnp and 3 to 5% of Inh were found in association with the inner membrane. The fractions of total Tnp and Inh that became membrane bound were unaffected by the amount of Tnp and Inh synthesized in whole cells, provided that the ratio of total Tnp to total Inh was not changed. In addition, Inh was not found in the membrane fraction in Tnp- IS50R mutants, indicating that Tnp is required for Inh localization.

Published
1990
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153. Integration of bacteriophage lambda into the cryptic lambdoid prophages of Escherichia coli

Author

A. Lichens-Park, Michael Syvanen, and Cassandra L. Smith

Subjects
Genes, Viral, Genotype, Restriction Mapping, Biology, medicine.disease_cause, Microbiology, Bacteriophage, Restriction map, Lysogenic cycle, Escherichia coli, medicine, Lysogeny, Molecular Biology, Prophage, Recombination, Genetic, Genetics, Chromosomes, Bacterial, Lambda phage, Provirus, biology.organism_classification, Bacteriophage lambda, Blotting, Southern, Rec A Recombinases, Restriction site, Research Article, Plasmids
Abstract

Bacteriophage lambda missing its chromosomal attachment site will integrate into recA+ Escherichia coli K-12 and C at the sites of cryptic prophages. The specific regions in which these recombination events occur were identified in both lambda and the bacterial chromosomes. A NotI restriction site on the prophage allowed its physical mapping. This allowed us to identify the locations of Rac, Qin, and Qsr' cryptic prophages on the NotI map of E. coli K-12 and, by analogy, to identify the cryptic prophage in E. coli C as Qin. No new cryptic prophages were detected in E. coli K-12.

Published
1990
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154. Identification and sequence of the drpA gene from Escherichia coli

Author

Michael Syvanen and Zonghan Zhou

Subjects
DNA, Bacterial, Transcription, Genetic, Molecular Sequence Data, Biology, Microbiology, Primer extension, Bacterial Proteins, Escherichia coli, Consensus sequence, Amino Acid Sequence, Promoter Regions, Genetic, Molecular Biology, Gene, Peptide sequence, Genetics, Base Sequence, Nucleic acid sequence, Chromosome Mapping, DNA-Directed RNA Polymerases, DnaA, RNA, Bacterial, Open reading frame, Terminator (genetics), Genes, Bacterial, Mutation, Research Article
Abstract

The drpA gene of Escherichia coli encodes a factor that is involved in global RNA synthesis. We establish that the drpA gene has been successfully cloned and describe the fine-structure map of three drpA-(Ts) mutations as well as the complete nucleotide sequence of the drpA gene. We identified a major sigma-70 promoter for the drpA gene on the bases of (i) its similarity to the consensus sequence and (ii) S1 protection and primer extension mapping data. In addition, the nucleotide sequence revealed a pair of dnaA boxes and a factor-independent terminator at the 5' end and 3' end of the gene, respectively. The deduced amino acid sequence of the DrpA protein showed a nucleotide-binding pocket found in some ATPases.

Published
1990
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156. Lasersko sintranje orodja za tlačno litje aluminija: Laser-sintered tools for the die-casting of aluminium

Author

Dolinšek, Slavko, Panjan, Peter, Ramovš, Jože, and Syvanen, Tatu

Abstract

In this paper some results from using a DMLS (direct metal laser sintering) rapid-tooling solution for aluminum die-casting are presented. The product chosen for the investigation was a car safety-belt strap winder (an application for the automotive industry), and according to the requirements ofthe prototype tools, we have adapted the construction of the classic tools and made some improvements to the material and the sintering process. The comparative-value analysis with classical tooling has shown that the time of production with the DMLS process is considerably shorter. The final investigation was focused on the industrial testing of the DMLS, followed by the tool analysis after die-casting to confirm the research goal, i.e., 5,000 practical parts produced. V prispevku so prikazani rezultati uporabe neposrednega laserskega sintranja kovinskih prahov (NLSK) kot postopka hitre izdelave orodij za tlačno litje aluminija. Za izvedbo raziskave smo izbrali za izdelek navijalnik varnostnega pasu (uporaba v avtomobilski industriji). Skladno z zahtevami glede izdelave prototipnih orodij smo sedanjo konstrukcijo običajnega orodja ustrezno prilagodili in naredili nekatere izboljšave materiala za sintranje kakor tudi postopka sintranja. Primerjalna vrednostna analiza med običajno izdelavo orodij in NLSK je pokazala, da je z NLSK čas izdelave dosti krajši. Končne raziskave so bile usmerjene v industrijsko testiranje orodja izdelanega z NLSK in analizo njegove obstojnosti za potrditev postavljenega raziskovalnega cilja, tj. izdelati 5.000 praktičnih izdelkov v industrijskem okolju.

Published
2006

157. Chromosome-wide pharmacogenetics: localisation and linkage disequilibrium of genes coding for ROS metabolism and signalling

Author

Arnoldo Frigessi, Anne Lise Børresen-Dale, V.N. Kristensen, Hege Edvardsen, A. C. Syvanen, GI Grenaker-Alnæs, and Bettina Kulle

Subjects
Genetics, Candidate gene, Linkage disequilibrium, Signalling, business.industry, Poster Presentation, Chromosome, Medicine, Metabolism, business, Bioinformatics, Gene, Pharmacogenetics
Published
2005
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158. DNA-Confirmed Taenia Solium Cysticercosis in Black Bears (Ursus Americanus) from California

Author

Michael Syvanen, Eileen Johnson, J. H. Theis, J. D. Banks, Arlette Gilson, Michael Cleary, and Pamela K. Swift

Subjects
Male, Veterinary medicine, Restriction Mapping, Cestoda, Helminthiasis, Zoology, Biology, Polymerase Chain Reaction, California, law.invention, Electron Transport Complex IV, law, Virology, parasitic diseases, Taenia solium, medicine, Animals, Helminths, Cestode infections, Ursus, Muscle, Skeletal, Polymerase chain reaction, DNA Primers, Cysticercosis, Heart, Cysticercus, DNA, Helminth, medicine.disease, biology.organism_classification, Mitochondria, medicine.drug_formulation_ingredient, Infectious Diseases, Parasitology, Ursidae
Abstract

Three cases of cysticercosis in black bears (Ursus americanus) in three northern California counties between 1990 and 1994 have been identified as due to the tapeworm Taenia solium. Both morphologic characteristics as well as the presence of T. solium mitochondria cytochrome oxidase I gene sequences, as detected by the polymerase chain reaction, confirmed the diagnosis. The number and geographic separation of the cases suggests that infection of the bears was not due to a single contamination. Humans infected with the definitive stage of T. solium are the probable source of cysticercosis for bears, as well as other humans. This is the first confirmation of cysticercosis due to T. solium in a black bear in North America.

Published
1996
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159. Transcription profile of Helicobacter pylori in the human stomach reflects its physiology in vivo

Author

Arun G. Suryaprasad, Jenni K. Boonjakuakul, Michael Syvanen, Jay V. Solnick, and Christopher L. Bowlus

Subjects
Adult, Male, Transcription, Genetic, Virulence, Physiology, Sensitivity and Specificity, Microbiology, Helicobacter Infections, Bacterial Proteins, In vivo, Gene expression, Gastric mucosa, medicine, Immunology and Allergy, CagA, Humans, RNA, Messenger, Gene, Aged, Aged, 80 and over, biology, Helicobacter pylori, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Stomach, Reproducibility of Results, Middle Aged, biology.organism_classification, Pathogenicity island, Molecular biology, Infectious Diseases, medicine.anatomical_structure, Gastric Mucosa, Female
Abstract

Background. Little is known about levels of expression of Helicobacter pylori genes in the human host. We therefore developed a quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) assay to measure transcript profiles of H. pylori in the human stomach. Methods. In vivo expression of 16 genes on the cag pathogenicity island and of 18 putative virulence genes was quantitated by isolation of total RNA directly from infected human gastric mucosa. The results were compared with in vitro expression determined from H. pylori cells grown in culture. Results. The highest levels of expression were found for cag1 and cag25 and for genes, such as urease and catalase, that may be important for bacterial homeostasis in the relatively hostile environment of the gastric mucosa. Transcript abundance, relative to 16S rRNA, was lower in vivo than in vitro, which suggests that H. pylori cells are in stationary phase in the gastric environment. This was particularly apparent for cagA. Since CagA is arguably of unique importance, in terms of interaction with the host, tight control of its in vivo expression might be particularly important. Conclusions. qRT-PCR is a powerful tool to measure gene expression in human or animal tissue that contains minute amounts of microbial mRNA, and the results reflect on the physiology of the pathogen in its natural host.

Published
2004

161. Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism

Author

Bruzelius, Maria, Strawbridge, Rona J., Tregouet, David-Alexandre, Wiggins, Kerri L., Gertow, Karl, Sabater-Lleal, Maria, Ohrvik, John, Bergendal, Annica, Silveira, Angela, Sundström, Anders, Kieler, Helle, Syvanen, Ann-Christine, Smith, Nicholas L., Morange, Pierre-Emmanuel, Odeberg, Jacob, Hamsten, Anders, Bruzelius, Maria, Strawbridge, Rona J., Tregouet, David-Alexandre, Wiggins, Kerri L., Gertow, Karl, Sabater-Lleal, Maria, Ohrvik, John, Bergendal, Annica, Silveira, Angela, Sundström, Anders, Kieler, Helle, Syvanen, Ann-Christine, Smith, Nicholas L., Morange, Pierre-Emmanuel, Odeberg, Jacob, and Hamsten, Anders

Abstract

Introduction: We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case-control study (n = 2753) from Sweden. Materials and Methods: 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. Results: Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181). Conclusions: It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE., QC 20141006

Published
2014
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164. DNA Methylation-Based Subtype Prediction for Pediatric Acute Lymphoblastic Leukemia (ALL)

Author

Nordlund, Jessica, Backlin, Christofer, Zachariadis, Vasilios, Cavelier, Lucia, Dahlberg, Johan, Ofverholm, Ingegerd, Barbany, Gisela, Nordgren, Ann, Overnas, Elin, Abrahamsson, Jonas, Flaegstad, Trond, Heyman, Mats, Jonsson, Olafur G., Kanerva, Jukka A., Larsson, Rolf, Palle, Josefine, Schmiegelow, Kjeld, Gustafsson, Mats G., Lonnerholm, Gudmar, Forestier, Erik, Syvanen, Ann-Christine, Nordlund, Jessica, Backlin, Christofer, Zachariadis, Vasilios, Cavelier, Lucia, Dahlberg, Johan, Ofverholm, Ingegerd, Barbany, Gisela, Nordgren, Ann, Overnas, Elin, Abrahamsson, Jonas, Flaegstad, Trond, Heyman, Mats, Jonsson, Olafur G., Kanerva, Jukka A., Larsson, Rolf, Palle, Josefine, Schmiegelow, Kjeld, Gustafsson, Mats G., Lonnerholm, Gudmar, Forestier, Erik, and Syvanen, Ann-Christine

Published
2014

165. Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes

Author

Madrigal, I., Alvarez-Mora, M.I., Karlberg, O., Rodriguez-Revenga, L., Martinez Elurbe, D., Rabionet, R., Mur, A., Pie, J., Ballesta, F., Sauer, S., Syvanen, A.C., Mila, M., Madrigal, I., Alvarez-Mora, M.I., Karlberg, O., Rodriguez-Revenga, L., Martinez Elurbe, D., Rabionet, R., Mur, A., Pie, J., Ballesta, F., Sauer, S., Syvanen, A.C., and Mila, M.

Abstract

Item does not contain fulltext, AIMS: The causes of intellectual disability, which affects 1%-3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases. METHODS: Whole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes. RESULTS: We present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose. CONCLUSIONS: The accessibility to next-generation sequencing allows clinicians to save much time and cost in identifying the aetiology of rare diseases. The presented cases are excellent examples that demonstrate the efficacy of next-generation sequencing in rare disease diagnosis.

Published
2014

166. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, Newton-Cheh, C. (Christopher), Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, and Newton-Cheh, C. (Christopher)

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Published
2014
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167. A Central Role for GRB10 in Regulation of Islet Function in Man

Author

University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Department of Environmental Sciences, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Prokopenko, Inga, Poon, Wenny, Maegi, Reedik, Prasad, Rashmi B., Salehi, S. Albert, Almgren, Peter, Osmark, Peter, Bouatia-Naji, Nabila, Wierup, Nils, Fall, Tove, Stancakova, Alena, Barker, Adam, Lagou, Vasiliki, Osmond, Clive, Xie, Weijia, Lahti, Jari, Jackson, Anne U., Cheng, Yu-Ching, Liu, Jie, O'Connell, Jeffrey R., Blomstedt, Paul A., Fadista, Joao, Alkayyali, Sami, Dayeh, Tasnim, Ahlqvist, Emma, Taneera, Jalal, Lecoeur, Cecile, Kumar, Ashish, Hansson, Ola, Hansson, Karin, Voight, Benjamin F., Kang, Hyun Min, Levy-Marchal, Claire, Vatin, Vincent, Palotie, Aarno, Syvanen, Ann-Christine, Mari, Andrea, Weedon, Michael N., Loos, Ruth J. F., Ong, Ken K., Nilsson, Peter, Isomaa, Bo, Tuomi, Tiinamaija, Wareham, Nicholas J., Stumvoll, Michael, Widen, Elisabeth, Lakka, Timo A., Langenberg, Claudia, Tonjes, Anke, Rauramaa, Rainer, Kuusisto, Johanna, Frayling, Timothy M., Froguel, Philippe, Walker, Mark, Eriksson, Johan G., Ling, Charlotte, Kovacs, Peter, Ingelsson, Erik, McCarthy, Mark I., Shuldiner, Alan R., Silver, Kristi D., Laakso, Markku, Groop, Leif, Lyssenko, Valeriya, University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Department of Environmental Sciences, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Prokopenko, Inga, Poon, Wenny, Maegi, Reedik, Prasad, Rashmi B., Salehi, S. Albert, Almgren, Peter, Osmark, Peter, Bouatia-Naji, Nabila, Wierup, Nils, Fall, Tove, Stancakova, Alena, Barker, Adam, Lagou, Vasiliki, Osmond, Clive, Xie, Weijia, Lahti, Jari, Jackson, Anne U., Cheng, Yu-Ching, Liu, Jie, O'Connell, Jeffrey R., Blomstedt, Paul A., Fadista, Joao, Alkayyali, Sami, Dayeh, Tasnim, Ahlqvist, Emma, Taneera, Jalal, Lecoeur, Cecile, Kumar, Ashish, Hansson, Ola, Hansson, Karin, Voight, Benjamin F., Kang, Hyun Min, Levy-Marchal, Claire, Vatin, Vincent, Palotie, Aarno, Syvanen, Ann-Christine, Mari, Andrea, Weedon, Michael N., Loos, Ruth J. F., Ong, Ken K., Nilsson, Peter, Isomaa, Bo, Tuomi, Tiinamaija, Wareham, Nicholas J., Stumvoll, Michael, Widen, Elisabeth, Lakka, Timo A., Langenberg, Claudia, Tonjes, Anke, Rauramaa, Rainer, Kuusisto, Johanna, Frayling, Timothy M., Froguel, Philippe, Walker, Mark, Eriksson, Johan G., Ling, Charlotte, Kovacs, Peter, Ingelsson, Erik, McCarthy, Mark I., Shuldiner, Alan R., Silver, Kristi D., Laakso, Markku, Groop, Leif, and Lyssenko, Valeriya

Published
2014

168. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author

Mahajan, A, Go, MJ, Zhang, W, Below, JE, Gaulton, KJ, Ferreira, T, Horikoshi, M, Johnson, AD, Ng, MCY, Prokopenko, I, Saleheen, D, Wang, X, Zeggini, E, Abecasis, GR, Adair, LS, Almgren, P, Atalay, M, Aung, T, Baldassarre, D, Balkau, B, Bao, Y, Barnett, AH, Barroso, I, Basit, A, Been, LF, Beilby, J, Bell, GI, Benediktsson, R, Bergman, RN, Boehm, BO, Boerwinkle, E, Bonnycastle, LL, Burtt, N, Cai, Q, Campbell, H, Carey, J, Cauchi, S, Caulfield, M, Chan, JCN, Chang, L-C, Chang, T-J, Chang, Y-C, Charpentier, G, Chen, C-H, Chen, H, Chen, Y-T, Chia, K-S, Chidambaram, M, Chines, PS, Cho, NH, Cho, YM, Chuang, L-M, Collins, FS, Cornelis, MC, Couper, DJ, Crenshaw, AT, van Dam, RM, Danesh, J, Das, D, de Faire, U, Dedoussis, G, Deloukas, P, Dimas, AS, Dina, C, Doney, ASF, Donnelly, PJ, Dorkhan, M, van Duijn, C, Dupuis, J, Edkins, S, Elliott, P, Emilsson, V, Erbel, R, Eriksson, JG, Escobedo, J, Esko, T, Eury, E, Florez, JC, Fontanillas, P, Forouhi, NG, Forsen, T, Fox, C, Fraser, RM, Frayling, TM, Froguel, P, Frossard, P, Gao, Y, Gertow, K, Gieger, C, Gigante, B, Grallert, H, Grant, GB, Groop, LC, Groves, CJ, Grundberg, E, Guiducci, C, Hamsten, A, Han, B-G, Hara, K, Hassanali, N, Hattersley, AT, Hayward, C, Hedman, AK, Herder, C, Hofman, A, Holmen, OL, Hovingh, K, Hreidarsson, AB, Hu, C, Hu, FB, Hui, J, Humphries, SE, Hunt, SE, Hunter, DJ, Hveem, K, Hydrie, ZI, Ikegami, H, Illig, T, Ingelsson, E, Islam, M, Isomaa, B, Jackson, AU, Jafar, T, James, A, Jia, W, Joeckel, K-H, Jonsson, A, Jowett, JBM, Kadowaki, T, Kang, HM, Kanoni, S, Kao, WHL, Kathiresan, S, Kato, N, Katulanda, P, Keinanen-Kiukaanniemi, SM, Kelly, AM, Khan, H, Khaw, K-T, Khor, C-C, Kim, H-L, Kim, S, Kim, YJ, Kinnunen, L, Klopp, N, Kong, A, Korpi-Hyovalti, E, Kowlessur, S, Kraft, P, Kravic, J, Kristensen, MM, Krithika, S, Kumar, A, Kumate, J, Kuusisto, J, Kwak, SH, Laakso, M, Lagou, V, Lakka, TA, Langenberg, C, Langford, C, Lawrence, R, Leander, K, Lee, J-M, Lee, NR, Li, M, Li, X, Li, Y, Liang, J, Liju, S, Lim, W-Y, Lind, L, Lindgren, CM, Lindholm, E, Liu, C-T, Liu, JJ, Lobbens, S, Long, J, Loos, RJF, Lu, W, Luan, J, Lyssenko, V, Ma, RCW, Maeda, S, Maegi, R, Mannisto, S, Matthews, DR, Meigs, JB, Melander, O, Metspalu, A, Meyer, J, Mirza, G, Mihailov, E, Moebus, S, Mohan, V, Mohlke, KL, Morris, AD, Muehleisen, TW, Mueller-Nurasyid, M, Musk, B, Nakamura, J, Nakashima, E, Navarro, P, Peng-Keat, N, Nica, AC, Nilsson, PM, Njolstad, I, Noethen, MM, Ohnaka, K, Ong, TH, Owen, KR, Palmer, CNA, Pankow, JS, Park, KS, Parkin, M, Pechlivanis, S, Pedersen, NL, Peltonen, L, Perry, JRB, Peters, A, Pinidiyapathirage, JM, Platou, CGP, Potter, S, Price, JF, Qi, L, Radha, V, Rallidis, L, Rasheed, A, Rathmann, W, Rauramaa, R, Raychaudhuri, S, Rayner, NW, Rees, SD, Rehnberg, E, Ripatti, S, Robertson, N, Roden, M, Rossin, EJ, Rudan, I, Rybin, D, Saaristo, TE, Salomaa, V, Saltevo, J, Samuel, M, Sanghera, DK, Saramies, J, Scott, J, Scott, LJ, Scott, RA, Segre, AV, Sehmi, J, Sennblad, B, Shah, N, Shah, S, Shera, AS, Shu, XO, Shuldiner, AR, Sigurdsson, G, Sijbrands, E, Silveira, A, Sim, X, Sivapalaratnam, S, Small, KS, So, WY, Stancakova, A, Stefansson, K, Steinbach, G, Steinthorsdottir, V, Stirrups, K, Strawbridge, RJ, Stringham, HM, Sun, Q, Suo, C, Syvanen, A-C, Takayanagi, R, Takeuchi, F, Tay, WT, Teslovich, TM, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Tikkanen, E, Trakalo, J, Tremoli, E, Trip, MD, Tsai, FJ, Tuomi, T, Tuomilehto, J, Uitterlinden, AG, Valladares-Salgado, A, Vedantam, S, Veglia, F, Voight, BF, Wang, C, Wareham, NJ, Wennauer, R, Wickremasinghe, AR, Wilsgaard, T, Wilson, JF, Wiltshire, S, Winckler, W, Wong, TY, Wood, AR, Wu, J-Y, Wu, Y, Yamamoto, K, Yamauchi, T, Yang, M, Yengo, L, Yokota, M, Young, R, Zabaneh, D, Zhang, F, Zhang, R, Zheng, W, Zimmet, PZ, Altshuler, D, Bowden, DW, Cho, YS, Cox, NJ, Cruz, M, Hanis, CL, Kooner, J, Lee, J-Y, Seielstad, M, Teo, YY, Boehnke, M, Parra, EJ, Chambers, JC, Tai, ES, McCarthy, MI, Morris, AP, Mahajan, A, Go, MJ, Zhang, W, Below, JE, Gaulton, KJ, Ferreira, T, Horikoshi, M, Johnson, AD, Ng, MCY, Prokopenko, I, Saleheen, D, Wang, X, Zeggini, E, Abecasis, GR, Adair, LS, Almgren, P, Atalay, M, Aung, T, Baldassarre, D, Balkau, B, Bao, Y, Barnett, AH, Barroso, I, Basit, A, Been, LF, Beilby, J, Bell, GI, Benediktsson, R, Bergman, RN, Boehm, BO, Boerwinkle, E, Bonnycastle, LL, Burtt, N, Cai, Q, Campbell, H, Carey, J, Cauchi, S, Caulfield, M, Chan, JCN, Chang, L-C, Chang, T-J, Chang, Y-C, Charpentier, G, Chen, C-H, Chen, H, Chen, Y-T, Chia, K-S, Chidambaram, M, Chines, PS, Cho, NH, Cho, YM, Chuang, L-M, Collins, FS, Cornelis, MC, Couper, DJ, Crenshaw, AT, van Dam, RM, Danesh, J, Das, D, de Faire, U, Dedoussis, G, Deloukas, P, Dimas, AS, Dina, C, Doney, ASF, Donnelly, PJ, Dorkhan, M, van Duijn, C, Dupuis, J, Edkins, S, Elliott, P, Emilsson, V, Erbel, R, Eriksson, JG, Escobedo, J, Esko, T, Eury, E, Florez, JC, Fontanillas, P, Forouhi, NG, Forsen, T, Fox, C, Fraser, RM, Frayling, TM, Froguel, P, Frossard, P, Gao, Y, Gertow, K, Gieger, C, Gigante, B, Grallert, H, Grant, GB, Groop, LC, Groves, CJ, Grundberg, E, Guiducci, C, Hamsten, A, Han, B-G, Hara, K, Hassanali, N, Hattersley, AT, Hayward, C, Hedman, AK, Herder, C, Hofman, A, Holmen, OL, Hovingh, K, Hreidarsson, AB, Hu, C, Hu, FB, Hui, J, Humphries, SE, Hunt, SE, Hunter, DJ, Hveem, K, Hydrie, ZI, Ikegami, H, Illig, T, Ingelsson, E, Islam, M, Isomaa, B, Jackson, AU, Jafar, T, James, A, Jia, W, Joeckel, K-H, Jonsson, A, Jowett, JBM, Kadowaki, T, Kang, HM, Kanoni, S, Kao, WHL, Kathiresan, S, Kato, N, Katulanda, P, Keinanen-Kiukaanniemi, SM, Kelly, AM, Khan, H, Khaw, K-T, Khor, C-C, Kim, H-L, Kim, S, Kim, YJ, Kinnunen, L, Klopp, N, Kong, A, Korpi-Hyovalti, E, Kowlessur, S, Kraft, P, Kravic, J, Kristensen, MM, Krithika, S, Kumar, A, Kumate, J, Kuusisto, J, Kwak, SH, Laakso, M, Lagou, V, Lakka, TA, Langenberg, C, Langford, C, Lawrence, R, Leander, K, Lee, J-M, Lee, NR, Li, M, Li, X, Li, Y, Liang, J, Liju, S, Lim, W-Y, Lind, L, Lindgren, CM, Lindholm, E, Liu, C-T, Liu, JJ, Lobbens, S, Long, J, Loos, RJF, Lu, W, Luan, J, Lyssenko, V, Ma, RCW, Maeda, S, Maegi, R, Mannisto, S, Matthews, DR, Meigs, JB, Melander, O, Metspalu, A, Meyer, J, Mirza, G, Mihailov, E, Moebus, S, Mohan, V, Mohlke, KL, Morris, AD, Muehleisen, TW, Mueller-Nurasyid, M, Musk, B, Nakamura, J, Nakashima, E, Navarro, P, Peng-Keat, N, Nica, AC, Nilsson, PM, Njolstad, I, Noethen, MM, Ohnaka, K, Ong, TH, Owen, KR, Palmer, CNA, Pankow, JS, Park, KS, Parkin, M, Pechlivanis, S, Pedersen, NL, Peltonen, L, Perry, JRB, Peters, A, Pinidiyapathirage, JM, Platou, CGP, Potter, S, Price, JF, Qi, L, Radha, V, Rallidis, L, Rasheed, A, Rathmann, W, Rauramaa, R, Raychaudhuri, S, Rayner, NW, Rees, SD, Rehnberg, E, Ripatti, S, Robertson, N, Roden, M, Rossin, EJ, Rudan, I, Rybin, D, Saaristo, TE, Salomaa, V, Saltevo, J, Samuel, M, Sanghera, DK, Saramies, J, Scott, J, Scott, LJ, Scott, RA, Segre, AV, Sehmi, J, Sennblad, B, Shah, N, Shah, S, Shera, AS, Shu, XO, Shuldiner, AR, Sigurdsson, G, Sijbrands, E, Silveira, A, Sim, X, Sivapalaratnam, S, Small, KS, So, WY, Stancakova, A, Stefansson, K, Steinbach, G, Steinthorsdottir, V, Stirrups, K, Strawbridge, RJ, Stringham, HM, Sun, Q, Suo, C, Syvanen, A-C, Takayanagi, R, Takeuchi, F, Tay, WT, Teslovich, TM, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Tikkanen, E, Trakalo, J, Tremoli, E, Trip, MD, Tsai, FJ, Tuomi, T, Tuomilehto, J, Uitterlinden, AG, Valladares-Salgado, A, Vedantam, S, Veglia, F, Voight, BF, Wang, C, Wareham, NJ, Wennauer, R, Wickremasinghe, AR, Wilsgaard, T, Wilson, JF, Wiltshire, S, Winckler, W, Wong, TY, Wood, AR, Wu, J-Y, Wu, Y, Yamamoto, K, Yamauchi, T, Yang, M, Yengo, L, Yokota, M, Young, R, Zabaneh, D, Zhang, F, Zhang, R, Zheng, W, Zimmet, PZ, Altshuler, D, Bowden, DW, Cho, YS, Cox, NJ, Cruz, M, Hanis, CL, Kooner, J, Lee, J-Y, Seielstad, M, Teo, YY, Boehnke, M, Parra, EJ, Chambers, JC, Tai, ES, McCarthy, MI, and Morris, AP

Abstract

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Published
2014

169. Genetic variation in the CYP2B6 Gene is related to circulating 2,2 ',4,4 '-tetrabromodiphenyl ether (BDE-47) concentrations : an observational population-based study

Author

Penell, Johanna, Lind, Lars, Fall, Tove, Syvanen, Anne-Christine, Axelsson, Tomas, Lundmark, Per, Morris, Andrew P., Lindgren, Cecilia, Mahajan, Anubha, Salihovic, Samira, van Bavel, Bert, Ingelsson, Erik, Lind, P. Monica, Penell, Johanna, Lind, Lars, Fall, Tove, Syvanen, Anne-Christine, Axelsson, Tomas, Lundmark, Per, Morris, Andrew P., Lindgren, Cecilia, Mahajan, Anubha, Salihovic, Samira, van Bavel, Bert, Ingelsson, Erik, and Lind, P. Monica

Abstract

Background: Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample. Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Results: Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10(- 4) to 10(-9)). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals. Conclusion: Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population., Funding Agencies:Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning

Published
2014
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171. Search for Horizontal Gene Transfer from Transgenic Crops to Microbes

Author

Michael Syvanen

Subjects
biology, business.industry, Microorganism, Transgene, food and beverages, Genetically modified crops, biology.organism_classification, Coliform bacteria, Flavr Savr, Biotechnology, Horizontal gene transfer, business, Gene, Bacteria
Abstract

Publisher Summary A new era in farming technology began after the U.S. regulatory agencies approved Calgene's Flavr Savr tomato. Crops could be rationally designed by genetic engineering and by new advances in cell and molecular biology. The technology for making transgenic plants in 1986 required using genes that conferred resistance to antibiotics; these genes were actually normal bacterial genes adapted for expression in plant cells. The fear was raised that these antibiotic-resistance genes being released into the environment in large amounts could be taken up by native bacteria and pose public health risks. When transgenic plants were first approved, the US Food and Drug Administration (FDA) responded to the fears of the spread of antibiotic-resistance genes with the assertion that the genes from the plants would not be incorporated into bacteria. Stimulated by the challenging assertion from the FDA and some industry spokesmen that horizontal gene transfer from transgenic plants to microorganisms does not occur, a number of investigators have embarked on studies to show that this statement is false. Two types of experiments have been done. In the first, transgenic plant materials were fed to mice and the coliform bacteria isolated from their feces was screened for the presence of antibiotic-resistance genes originating from the plants. In the second approach, researchers in two labs looked at bacteria that cause spoilage of vegetables and examined whether, after growth on transgenic vegetables, the bacteria had taken up transgenic DNA.

Published
2002
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173. Temporal Patterns of Plant and Metazoan Evolution Suggest Extensive Polyphyly

Author

Michael Syvanen

Subjects
Monophyly, Molecular evolution, Evolutionary biology, Molecular sequence, Polyphyly, fungi, food and beverages, Zoology, Taxonomic rank, Biology, Molecular clock, Plant taxonomy, Clade
Abstract

Publisher Summary The temporal patterns of plant and metazoan evolution suggest extensive polyphyly. The difficulty in determining whether clades are monophyletic or polyphyletic is, especially problematic when attempting to reconstruct the evolutionary history of the modern flowering plants—the angiosperms—but is also seen in other higher taxonomic groups, such as the gymnosperms, ferns, and mosses. The introduction of molecular evolution studies was greeted with great expectations; it was assumed that the taxonomic ambiguities of plant classification would be resolved. It is documented in an earlier study of cytochrome c sequences and showed that the problem of homoplasy of the plant sequences was significantly different from homoplasy among animal sequences. Molecular sequence information has a potential advantage over morphological character arrays because of the possibility of inferring temporal relationships through the operation of the molecular clock.

Published
2002
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174. What's better, doing some manuever on a natural quarterpipe in a random park in Southwestern Spain, or doing that maneuver with a bunch of little Moroccan hooligans flipping you the bird while having fun doing that maneuver?

Author

Syvanen, Marius

Subjects
Skateboarders -- Beliefs, opinions and attitudes
Abstract

[ILLUSTRATION OMITTED] "What's better, doing some manuever on a natural quarterpipe in a random park in Southwestern Spain, or doing that maneuver with a bunch of little Moroccan hooligans flipping […]

Published
2010

175. Evaluation of the Effect of Interleukin 18 Associated Genetic Polymorphisms on Risk of Cardiovascular Events in Patients With Acute Coronary Syndrome

Author

Siegbahn, Agneta, Johansson, Åsa, Eriksson, Niclas, Hagström, Emil, Varenhorst, Christoph, Åkerblom, Axel, Bertilsson, Maria, Axelsson, Tomas, Barratt, Bryan J., Becker, Richard C., Himmelmann, Anders, James, Stefan K., Katus, Hugo A., Steg, Philippe G., Storey, Robert F., Syvanen, Ann-Christine, Wallentin, Lars, Siegbahn, Agneta, Johansson, Åsa, Eriksson, Niclas, Hagström, Emil, Varenhorst, Christoph, Åkerblom, Axel, Bertilsson, Maria, Axelsson, Tomas, Barratt, Bryan J., Becker, Richard C., Himmelmann, Anders, James, Stefan K., Katus, Hugo A., Steg, Philippe G., Storey, Robert F., Syvanen, Ann-Christine, and Wallentin, Lars

Published
2013

176. Coronary Heart Disease in Systemic Lupus Erythematosus is Associated with Interferon Regulatory Factor 8 Gene Variants

Author

Leonard, Dag, Svenungsson, E., Sandling, J. K., Berggren, Olof, Jonsen, A., Bengtsson, C., Wang, C., Jensen-Urstad, K., Granstam, Sven-Olof, Bengtsson, A. A., Gustafsson, J. T., Gunnarsson, I., Rantapaa-Dahlqvist, S., Nordmark, Gunnel, Eloranta, Maija-Leena, Syvanen, A-C, Ronnblom, Lars, Leonard, Dag, Svenungsson, E., Sandling, J. K., Berggren, Olof, Jonsen, A., Bengtsson, C., Wang, C., Jensen-Urstad, K., Granstam, Sven-Olof, Bengtsson, A. A., Gustafsson, J. T., Gunnarsson, I., Rantapaa-Dahlqvist, S., Nordmark, Gunnel, Eloranta, Maija-Leena, Syvanen, A-C, and Ronnblom, Lars

Published
2013
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177. Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia

Author

Nordlund, Jessica, Backlin, Christofer L., Wahlberg, Per, Busche, Stephan, Berglund, Eva C., Eloranta, Maija-Leena, Flaegstad, Trond, Forestier, Erik, Frost, Britt-Marie, Harila-Saari, Arja, Heyman, Mats, Jonsson, Olafur G., Larsson, Rolf, Palle, Josefine, Ronnblom, Lars, Schmiegelow, Kjeld, Sinnett, Daniel, Soderhall, Stefan, Pastinen, Tomi, Gustafsson, Mats G., Lonnerholm, Gudmar, Syvanen, Ann-Christine, Nordlund, Jessica, Backlin, Christofer L., Wahlberg, Per, Busche, Stephan, Berglund, Eva C., Eloranta, Maija-Leena, Flaegstad, Trond, Forestier, Erik, Frost, Britt-Marie, Harila-Saari, Arja, Heyman, Mats, Jonsson, Olafur G., Larsson, Rolf, Palle, Josefine, Ronnblom, Lars, Schmiegelow, Kjeld, Sinnett, Daniel, Soderhall, Stefan, Pastinen, Tomi, Gustafsson, Mats G., Lonnerholm, Gudmar, and Syvanen, Ann-Christine

Abstract

Background: Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood. Results: We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. Conclusions: Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.

Published
2013
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178. Large-scale association analysis identifies new risk loci for coronary artery disease

Author

Deloukas, Panos, Kanoni, Stavroula, Willenborg, Christina, Farrall, Martin, Assimes, Themistocles L., Thompson, John R., Ingelsson, Erik, Saleheen, Danish, Erdmann, Jeanette, Goldstein, Benjamin A., Stirrups, Kathleen, Koenig, Inke R., Cazier, Jean-Baptiste, Johansson, Asa, Hall, Alistair S., Lee, Jong-Young, Willer, Cristen J., Chambers, John C., Esko, Tonu, Folkersen, Lasse, Goel, Anuj, Grundberg, Elin, Havulinna, Aki S., Ho, Weang K., Hopewell, Jemma C., Eriksson, Niclas, Kleber, Marcus E., Kristiansson, Kati, Lundmark, Per, Lyytikainen, Leo-Pekka, Rafelt, Suzanne, Shungin, Dmitry, Strawbridge, Rona J., Thorleifsson, Gudmar, Tikkanen, Emmi, Van Zuydam, Natalie, Voight, Benjamin F., Waite, Lindsay L., Zhang, Weihua, Ziegler, Andreas, Absher, Devin, Altshuler, David, Balmforth, Anthony J., Barroso, Ines, Braund, Peter S., Burgdorf, Christof, Claudi-Boehm, Simone, Cox, David, Dimitriou, Maria, Do, Ron, Doney, Alex S. F., El Mokhtari, NourEddine, Eriksson, Per, Fischer, Krista, Fontanillas, Pierre, Franco-Cereceda, Anders, Gigante, Bruna, Groop, Leif, Gustafsson, Stefan, Hager, Joerg, Hallmans, Göran, Han, Bok-Ghee, Hunt, Sarah E., Kang, Hyun M., Illig, Thomas, Kessler, Thorsten, Knowles, Joshua W., Kolovou, Genovefa, Kuusisto, Johanna, Langenberg, Claudia, Langford, Cordelia, Leander, Karin, Lokki, Marja-Liisa, Lundmark, Anders, McCarthy, Mark I., Meisinger, Christa, Melander, Olle, Mihailov, Evelin, Maouche, Seraya, Morris, Andrew D., Mueller-Nurasyid, Martina, Nikus, Kjell, Peden, John F., Rayner, N. William, Rasheed, Asif, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P., Schaefer, Arne, Sivananthan, Mohan, Song, Ci, Stewart, Alexandre F. R., Tan, Sian-Tsung, Thorgeirsson, Gudmundur, van der Schoot, C. Ellen, Wagner, Peter J., Wells, George A., Wild, Philipp S., Yang, Tsun-Po, Amouyel, Philippe, Arveiler, Dominique, Basart, Hanneke, Boehnke, Michael, Boerwinkle, Eric, Brambilla, Paolo, Cambien, Francois, Cupples, Adrienne L., de Faire, Ulf, Dehghan, Abbas, Diemert, Patrick, Epstein, Stephen E., Evans, Alun, Ferrario, Marco M., Ferrieres, Jean, Gauguier, Dominique, Go, Alan S., Goodall, Alison H., Gudnason, Villi, Hazen, Stanley L., Holm, Hilma, Iribarren, Carlos, Jang, Yangsoo, Kahonen, Mika, Kee, Frank, Kim, Hyo-Soo, Klopp, Norman, Koenig, Wolfgang, Kratzer, Wolfgang, Kuulasmaa, Kari, Laakso, Markku, Laaksonen, Reijo, Lee, Ji-Young, Lind, Lars, Ouwehand, Willem H., Parish, Sarah, Park, Jeong E., Pedersen, Nancy L., Peters, Annette, Quertermous, Thomas, Rader, Daniel J., Salomaa, Veikko, Schadt, Eric, Shah, Svati H., Sinisalo, Juha, Stark, Klaus, Stefansson, Kari, Tregouet, David-Alexandre, Virtamo, Jarmo, Wallentin, Lars, Wareham, Nicholas, Zimmermann, Martina E., Nieminen, Markku S., Hengstenberg, Christian, Sandhu, Manjinder S., Pastinen, Tomi, Syvanen, Ann-Christine, Hovingh, G. Kees, Dedoussis, George, Franks, Paul W., Lehtimaki, Terho, Metspalu, Andres, Zalloua, Pierre A., Siegbahn, Agneta, Schreiber, Stefan, Ripatti, Samuli, Blankenberg, Stefan S., Perola, Markus, Clarke, Robert, Boehm, Bernhard O., O'Donnell, Christopher, Reilly, Muredach P., Maerz, Winfried, Collins, Rory, Kathiresan, Sekar, Hamsten, Anders, Kooner, Jaspal S., Thorsteinsdottir, Unnur, Danesh, John, Palmer, Colin N. A., Roberts, Robert, Watkins, Hugh, Schunkert, Heribert, Samani, Nilesh J., Deloukas, Panos, Kanoni, Stavroula, Willenborg, Christina, Farrall, Martin, Assimes, Themistocles L., Thompson, John R., Ingelsson, Erik, Saleheen, Danish, Erdmann, Jeanette, Goldstein, Benjamin A., Stirrups, Kathleen, Koenig, Inke R., Cazier, Jean-Baptiste, Johansson, Asa, Hall, Alistair S., Lee, Jong-Young, Willer, Cristen J., Chambers, John C., Esko, Tonu, Folkersen, Lasse, Goel, Anuj, Grundberg, Elin, Havulinna, Aki S., Ho, Weang K., Hopewell, Jemma C., Eriksson, Niclas, Kleber, Marcus E., Kristiansson, Kati, Lundmark, Per, Lyytikainen, Leo-Pekka, Rafelt, Suzanne, Shungin, Dmitry, Strawbridge, Rona J., Thorleifsson, Gudmar, Tikkanen, Emmi, Van Zuydam, Natalie, Voight, Benjamin F., Waite, Lindsay L., Zhang, Weihua, Ziegler, Andreas, Absher, Devin, Altshuler, David, Balmforth, Anthony J., Barroso, Ines, Braund, Peter S., Burgdorf, Christof, Claudi-Boehm, Simone, Cox, David, Dimitriou, Maria, Do, Ron, Doney, Alex S. F., El Mokhtari, NourEddine, Eriksson, Per, Fischer, Krista, Fontanillas, Pierre, Franco-Cereceda, Anders, Gigante, Bruna, Groop, Leif, Gustafsson, Stefan, Hager, Joerg, Hallmans, Göran, Han, Bok-Ghee, Hunt, Sarah E., Kang, Hyun M., Illig, Thomas, Kessler, Thorsten, Knowles, Joshua W., Kolovou, Genovefa, Kuusisto, Johanna, Langenberg, Claudia, Langford, Cordelia, Leander, Karin, Lokki, Marja-Liisa, Lundmark, Anders, McCarthy, Mark I., Meisinger, Christa, Melander, Olle, Mihailov, Evelin, Maouche, Seraya, Morris, Andrew D., Mueller-Nurasyid, Martina, Nikus, Kjell, Peden, John F., Rayner, N. William, Rasheed, Asif, Rosinger, Silke, Rubin, Diana, Rumpf, Moritz P., Schaefer, Arne, Sivananthan, Mohan, Song, Ci, Stewart, Alexandre F. R., Tan, Sian-Tsung, Thorgeirsson, Gudmundur, van der Schoot, C. Ellen, Wagner, Peter J., Wells, George A., Wild, Philipp S., Yang, Tsun-Po, Amouyel, Philippe, Arveiler, Dominique, Basart, Hanneke, Boehnke, Michael, Boerwinkle, Eric, Brambilla, Paolo, Cambien, Francois, Cupples, Adrienne L., de Faire, Ulf, Dehghan, Abbas, Diemert, Patrick, Epstein, Stephen E., Evans, Alun, Ferrario, Marco M., Ferrieres, Jean, Gauguier, Dominique, Go, Alan S., Goodall, Alison H., Gudnason, Villi, Hazen, Stanley L., Holm, Hilma, Iribarren, Carlos, Jang, Yangsoo, Kahonen, Mika, Kee, Frank, Kim, Hyo-Soo, Klopp, Norman, Koenig, Wolfgang, Kratzer, Wolfgang, Kuulasmaa, Kari, Laakso, Markku, Laaksonen, Reijo, Lee, Ji-Young, Lind, Lars, Ouwehand, Willem H., Parish, Sarah, Park, Jeong E., Pedersen, Nancy L., Peters, Annette, Quertermous, Thomas, Rader, Daniel J., Salomaa, Veikko, Schadt, Eric, Shah, Svati H., Sinisalo, Juha, Stark, Klaus, Stefansson, Kari, Tregouet, David-Alexandre, Virtamo, Jarmo, Wallentin, Lars, Wareham, Nicholas, Zimmermann, Martina E., Nieminen, Markku S., Hengstenberg, Christian, Sandhu, Manjinder S., Pastinen, Tomi, Syvanen, Ann-Christine, Hovingh, G. Kees, Dedoussis, George, Franks, Paul W., Lehtimaki, Terho, Metspalu, Andres, Zalloua, Pierre A., Siegbahn, Agneta, Schreiber, Stefan, Ripatti, Samuli, Blankenberg, Stefan S., Perola, Markus, Clarke, Robert, Boehm, Bernhard O., O'Donnell, Christopher, Reilly, Muredach P., Maerz, Winfried, Collins, Rory, Kathiresan, Sekar, Hamsten, Anders, Kooner, Jaspal S., Thorsteinsdottir, Unnur, Danesh, John, Palmer, Colin N. A., Roberts, Robert, Watkins, Hugh, Schunkert, Heribert, and Samani, Nilesh J.

Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Published
2013
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179. Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies

Author

Hruby, Adela, Ngwa, Julius S., Renström, Frida, Wojczynski, Mary K., Ganna, Andrea, Hallmans, Göran, Houston, Denise K., Jacques, Paul F., Kanoni, Stavroula, Lehtimaki, Terho, Lemaitre, Rozenn N., Manichaikul, Ani, North, Kari E., Ntalla, Ioanna, Sonestedt, Emily, Tanaka, Toshiko, van Rooij, Frank J. A., Bandinelli, Stefania, Djousse, Luc, Grigoriou, Efi., Johansson, Ingegerd, Lohman, Kurt K., Pankow, James S., Raitakari, Olli T., Riserus, Ulf, Yannakoulia, Mary, Zillikens, M. Carola, Hassanali, Neelam, Liu, Yongmei, Mozaffarian, Dariush, Papoutsakis, Constantina, Syvanen, Ann-Christine, Uitterlinden, Andre G., Viikari, Jorma, Groves, Christopher J., Hofman, Albert, Lind, Lars, McCarthy, Mark I., Mikkila, Vera, Mukamal, Kenneth, Franco, Oscar H., Borecki, Ingrid B., Cupples, L. Adrienne, Dedoussis, George V., Ferrucci, Luigi, Hu, Frank B., Ingelsson, Erik, Kahonen, Mika, Kao, W. H. Linda, Kritchevsky, Stephen B., Orho-Melander, Marju, Prokopenko, Inga, Rotter, Jerome I., Siscovick, David S., Witteman, Jacqueline C. M., Franks, Paul W., Meigs, James B., McKeown, Nicola M., Nettleton, Jennifer A., Hruby, Adela, Ngwa, Julius S., Renström, Frida, Wojczynski, Mary K., Ganna, Andrea, Hallmans, Göran, Houston, Denise K., Jacques, Paul F., Kanoni, Stavroula, Lehtimaki, Terho, Lemaitre, Rozenn N., Manichaikul, Ani, North, Kari E., Ntalla, Ioanna, Sonestedt, Emily, Tanaka, Toshiko, van Rooij, Frank J. A., Bandinelli, Stefania, Djousse, Luc, Grigoriou, Efi., Johansson, Ingegerd, Lohman, Kurt K., Pankow, James S., Raitakari, Olli T., Riserus, Ulf, Yannakoulia, Mary, Zillikens, M. Carola, Hassanali, Neelam, Liu, Yongmei, Mozaffarian, Dariush, Papoutsakis, Constantina, Syvanen, Ann-Christine, Uitterlinden, Andre G., Viikari, Jorma, Groves, Christopher J., Hofman, Albert, Lind, Lars, McCarthy, Mark I., Mikkila, Vera, Mukamal, Kenneth, Franco, Oscar H., Borecki, Ingrid B., Cupples, L. Adrienne, Dedoussis, George V., Ferrucci, Luigi, Hu, Frank B., Ingelsson, Erik, Kahonen, Mika, Kao, W. H. Linda, Kritchevsky, Stephen B., Orho-Melander, Marju, Prokopenko, Inga, Rotter, Jerome I., Siscovick, David S., Witteman, Jacqueline C. M., Franks, Paul W., Meigs, James B., McKeown, Nicola M., and Nettleton, Jennifer A.

Abstract

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (In-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P< 0.0001] and insulin (-0.020 In-pmo/L (95% CI: -0.024, -0.017), P< 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P= 0.03) with glucose, and rs11558471 in SLC30A8and rs3740393 near CNNM2showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted. J. Nutr. 143: 345-353, 2013.

Published
2013
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180. Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility

Author

Wang, C., Ahlford, A., Laxman, N., Nordmark, G., Eloranta, M-L, Gunnarsson, I., Svenungsson, E., Padyukov, L., Sturfelt, G., Jonsen, A., Bengtsson, A. A., Truedsson, L., Rantapää-Dahlqvist, Solbritt, Sjowall, C., Sandling, J. K., Ronnblom, L., Syvanen, A-C, Wang, C., Ahlford, A., Laxman, N., Nordmark, G., Eloranta, M-L, Gunnarsson, I., Svenungsson, E., Padyukov, L., Sturfelt, G., Jonsen, A., Bengtsson, A. A., Truedsson, L., Rantapää-Dahlqvist, Solbritt, Sjowall, C., Sandling, J. K., Ronnblom, L., and Syvanen, A-C

Abstract

The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value = 1.0 x 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio = 0.56; P-value = 6.6 x 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

Published
2013
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181. Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants

Author

Leonard, D, Svenungsson, E, Sandling, JK, Berggren, O, Jonsen, A, Bengtsson, Christine, Wang, C, Jensen-Urstad, K, Granstam, S-O, Bengtsson, AA, Gustafsson, JT, Gunnarsson, I, Rantapää-Dahlqvist, Solbritt, Nordmark, G, Eloranta, M-L, Syvanen, A-C, Rönnblom, L, Leonard, D, Svenungsson, E, Sandling, JK, Berggren, O, Jonsen, A, Bengtsson, Christine, Wang, C, Jensen-Urstad, K, Granstam, S-O, Bengtsson, AA, Gustafsson, JT, Gunnarsson, I, Rantapää-Dahlqvist, Solbritt, Nordmark, G, Eloranta, M-L, Syvanen, A-C, and Rönnblom, L

Published
2013

182. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations

Author

Wang, Chuan, Ahlford, Annika, Jarvinen, Tiina M., Nordmark, Gunnel, Eloranta, Maija-Leena, Gunnarsson, Iva, Svenungsson, Elisabet, Padyukov, Leonid, Sturfelt, Gunnar, Jonsen, Andreas, Bengtsson, Anders A., Truedsson, Lennart, Eriksson, Catharina, Rantapaa-Dahlqvist, Solbritt, Sjöwall, Christoffer, Julkunen, Heikki, Criswell, Lindsey A., Graham, Robert R., Behrens, Timothy W., Kere, Juha, Ronnblom, Lars, Syvanen, Ann-Christine, Sandling, Johanna K., Wang, Chuan, Ahlford, Annika, Jarvinen, Tiina M., Nordmark, Gunnel, Eloranta, Maija-Leena, Gunnarsson, Iva, Svenungsson, Elisabet, Padyukov, Leonid, Sturfelt, Gunnar, Jonsen, Andreas, Bengtsson, Anders A., Truedsson, Lennart, Eriksson, Catharina, Rantapaa-Dahlqvist, Solbritt, Sjöwall, Christoffer, Julkunen, Heikki, Criswell, Lindsey A., Graham, Robert R., Behrens, Timothy W., Kere, Juha, Ronnblom, Lars, Syvanen, Ann-Christine, and Sandling, Johanna K.

Abstract

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities., Funding Agencies|Knut and Alice Wallenberg Foundation|2011.0073|Swedish Research Council for Medicine and Health|A0280001A0258801A80741201|Swedish Research Council for Science and Technology|90559401|Swedish Rheumatism Association||Ragnar Soderbergs Foundation||King Gustaf V 80-year Foundation||COMBINE, the Swedish Heart-Lung Foundation||Stockholm County Council||Karolinska Institutet (ALF)||Foundation in memory of Clas Groschinsky||Swedish Society of Medicine||Alliance for Lupus Research||Kirkland Scholar Award||NIH|AR044804AR02175AR052300M01 RR-000079|Uppsala University, Uppsala University Hospital||Swedish Council for Research Infrastructures|8057680170374401

Published
2013
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183. Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis

Author

Bolin, Karin, Sandling, Johanna K., Zickert, Agneta, Jonsen, Andreas, Sjöwall, Christoffer, Svenungsson, Elisabet, Bengtsson, Anders A., Eloranta, Maija-Leena, Ronnblom, Lars, Syvanen, Ann-Christine, Gunnarsson, Iva, Nordmark, Gunnel, Bolin, Karin, Sandling, Johanna K., Zickert, Agneta, Jonsen, Andreas, Sjöwall, Christoffer, Svenungsson, Elisabet, Bengtsson, Anders A., Eloranta, Maija-Leena, Ronnblom, Lars, Syvanen, Ann-Christine, Gunnarsson, Iva, and Nordmark, Gunnel

Abstract

Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7x10(-9), OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (pless than0.0001). An additional six genes showed an association with lupus nephritis with pless than0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6x10(-3) and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

Published
2013
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184. A gene-centric study of common carotid artery remodelling

Author

Harrison, S.C., Zabaneh, D., Asselbergs, F.W., Drenos, F., Jones, G.T., Shah, S., Gertow, K., Sennblad, B., Strawbridge, R.J., Gigante, B., Holewijn, S., Graaf, J. de, Vermeulen, S., Folkersen, L., Rij, A.M. van, Baldassarre, D., Veglia, F., Talmud, P.J., Deanfield, J.E., Agu, O., Kivimäki, M., Kumari, M., Bown, M.J., Nyyssonen, K., Rauramaa, R., Smit, A.J., Franco-Cereceda, A., Giral, P., Mannarino, E., Silveira, A., Syvanen, A.C., Borst, G.J. de, Graaf, Y. van der, Faire, U. de, Baas, A.F., Blankensteijn, J.D., Wareham, N.J., Fowkes, G., Tzoulaki, I., Price, J.F., Tremoli, E., Hingorani, A.D., Eriksson, P., Hamsten, A., Humphries, S.E., Harrison, S.C., Zabaneh, D., Asselbergs, F.W., Drenos, F., Jones, G.T., Shah, S., Gertow, K., Sennblad, B., Strawbridge, R.J., Gigante, B., Holewijn, S., Graaf, J. de, Vermeulen, S., Folkersen, L., Rij, A.M. van, Baldassarre, D., Veglia, F., Talmud, P.J., Deanfield, J.E., Agu, O., Kivimäki, M., Kumari, M., Bown, M.J., Nyyssonen, K., Rauramaa, R., Smit, A.J., Franco-Cereceda, A., Giral, P., Mannarino, E., Silveira, A., Syvanen, A.C., Borst, G.J. de, Graaf, Y. van der, Faire, U. de, Baas, A.F., Blankensteijn, J.D., Wareham, N.J., Fowkes, G., Tzoulaki, I., Price, J.F., Tremoli, E., Hingorani, A.D., Eriksson, P., Hamsten, A., and Humphries, S.E.

Abstract

Item does not contain fulltext, BACKGROUND: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. METHODS: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). RESULTS: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 x 10(-8)). A proxy SNP (rs4916251, R(2) = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 x 10(-3), I(2) = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. CONCLUSIONS: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Published
2013

185. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Author

Fall, M. (Magnus), Hägg, S. (Sara), Mägi, R. (Reedik), Ploner, A. (Alexander), Fischer, K. (Krista), Horikoshi, M. (Momoko), Sarin, A.-P., Thorleifsson, G. (Gudmar), Ladenvall, C. (Claes), Kals, M. (Mart), Kuningas, M. (Maris), Draisma, G. (Gerrit), Ried, J.S. (Janina), Zuydam, N.R. (Natalie) van, Huikari, V. (Ville), Mangino, M. (Massimo), Sonestedt, E. (Emily), Benyamin, B. (Beben), Nelson, C.P. (Christopher P.), Rivera, N.V. (Natalia), Kristiansson, K. (Kati), Shen, H.-y. (Huei-yi), Havulinna, A.S. (Aki), Dehghan, A. (Abbas), Donnelly, L.A. (Louise), Kaakinen, M. (Marika), Nuotio, M.-L. (Marja-Liisa), Robertson, N. (Neil), Bruijn, R.F.A.G. (Renée) de, Ikram, M.A. (Arfan), Amin, N. (Najaf), Balmforth, A.J. (Anthony), Braund, P.S. (Peter), Doney, A.S.F. (Alex), Döring, A. (Angela), Elliott, P. (Paul), Esko, T. (Tõnu), Franco, O.H. (Oscar), Gretarsdottir, S. (Solveig), Hartikainen, A.L., Heikkilä, K. (Kauko), Herzig, K.H., Holm, H. (Hilma), Hottenga, J.J. (Jouke Jan), Hyppönen, E. (Elina), Illig, T. (Thomas), Isaacs, A.J. (Aaron), Isomaa, B. (Bo), Karssen, L.C. (Lennart), Kettunen, J. (Johannes), Koenig, W. (Wolfgang), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Laitinen, J. (Jaana), Lindgren, C. (Cecilia), Lyssenko, V. (Valeriya), Läärä, E. (Esa), Rayner, N.W. (Nigel William), Männistö, S. (Satu), Pouta, A. (Anneli), Rathmann, W. (Wolfgang), Rivadeneira Ramirez, F. (Fernando), Ruokonen, A. (Aimo), Savolainen, M.J. (Markku), Sijbrands, E.J.G. (Eric), Small, K.S. (Kerrin), Smit, J.H. (Jan), Steinthorsdottir, V. (Valgerdur), Syvanen, A.C., Taanila, A. (Anja), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), Perola, M. (Markus), Evans, A. (Andrew), Ferrières, J. (Jean), Virtamo, J. (Jarmo), Kee, F. (F.), Tregouet, D.-A. (David-Alexandre), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Ferrario, F. (Franco), Brambilla, P. (Paolo), Hall, A. (Anne), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Whitfield, J. (John), Jula, A. (Antti), Knekt, P., Oostra, B.A. (Ben), Duijn, C.M. (Cornelia) van, Penninx, B.W.J.H. (Brenda), Davey-Smith, G. (George), Kaprio, J. (Jaakko), Samani, N.J. (Nilesh), Gieger, C. (Christian), Peters, A. (Annette), Wichmann, H.E. (Heinz Erich), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Tuomi, T. (Tiinamaija), Power, C. (Christopher), Hammond, C.J. (Christopher), Spector, T.D. (Timothy), Lind, L. (Lars), Orho-Melander, M. (Marju), Palmer, C.N.A. (Colin), Morris, A.D. (Andrew), Groop, L. (Leif), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Vartiainen, E. (Erkki), Hofman, A. (Albert), Ripatti, S. (Samuli), Metspalu, A. (Andres), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Pedersen, N.L. (Nancy), McCarthy, M.I. (Mark), Ingelsson, E. (Erik), Prokopenko, I. (Inga), Fall, M. (Magnus), Hägg, S. (Sara), Mägi, R. (Reedik), Ploner, A. (Alexander), Fischer, K. (Krista), Horikoshi, M. (Momoko), Sarin, A.-P., Thorleifsson, G. (Gudmar), Ladenvall, C. (Claes), Kals, M. (Mart), Kuningas, M. (Maris), Draisma, G. (Gerrit), Ried, J.S. (Janina), Zuydam, N.R. (Natalie) van, Huikari, V. (Ville), Mangino, M. (Massimo), Sonestedt, E. (Emily), Benyamin, B. (Beben), Nelson, C.P. (Christopher P.), Rivera, N.V. (Natalia), Kristiansson, K. (Kati), Shen, H.-y. (Huei-yi), Havulinna, A.S. (Aki), Dehghan, A. (Abbas), Donnelly, L.A. (Louise), Kaakinen, M. (Marika), Nuotio, M.-L. (Marja-Liisa), Robertson, N. (Neil), Bruijn, R.F.A.G. (Renée) de, Ikram, M.A. (Arfan), Amin, N. (Najaf), Balmforth, A.J. (Anthony), Braund, P.S. (Peter), Doney, A.S.F. (Alex), Döring, A. (Angela), Elliott, P. (Paul), Esko, T. (Tõnu), Franco, O.H. (Oscar), Gretarsdottir, S. (Solveig), Hartikainen, A.L., Heikkilä, K. (Kauko), Herzig, K.H., Holm, H. (Hilma), Hottenga, J.J. (Jouke Jan), Hyppönen, E. (Elina), Illig, T. (Thomas), Isaacs, A.J. (Aaron), Isomaa, B. (Bo), Karssen, L.C. (Lennart), Kettunen, J. (Johannes), Koenig, W. (Wolfgang), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Laitinen, J. (Jaana), Lindgren, C. (Cecilia), Lyssenko, V. (Valeriya), Läärä, E. (Esa), Rayner, N.W. (Nigel William), Männistö, S. (Satu), Pouta, A. (Anneli), Rathmann, W. (Wolfgang), Rivadeneira Ramirez, F. (Fernando), Ruokonen, A. (Aimo), Savolainen, M.J. (Markku), Sijbrands, E.J.G. (Eric), Small, K.S. (Kerrin), Smit, J.H. (Jan), Steinthorsdottir, V. (Valgerdur), Syvanen, A.C., Taanila, A. (Anja), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), Perola, M. (Markus), Evans, A. (Andrew), Ferrières, J. (Jean), Virtamo, J. (Jarmo), Kee, F. (F.), Tregouet, D.-A. (David-Alexandre), Arveiler, D. (Dominique), Amouyel, P. (Philippe), Ferrario, F. (Franco), Brambilla, P. (Paolo), Hall, A. (Anne), Heath, A.C. (Andrew), Madden, P.A.F. (Pamela), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Whitfield, J. (John), Jula, A. (Antti), Knekt, P., Oostra, B.A. (Ben), Duijn, C.M. (Cornelia) van, Penninx, B.W.J.H. (Brenda), Davey-Smith, G. (George), Kaprio, J. (Jaakko), Samani, N.J. (Nilesh), Gieger, C. (Christian), Peters, A. (Annette), Wichmann, H.E. (Heinz Erich), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Tuomi, T. (Tiinamaija), Power, C. (Christopher), Hammond, C.J. (Christopher), Spector, T.D. (Timothy), Lind, L. (Lars), Orho-Melander, M. (Marju), Palmer, C.N.A. (Colin), Morris, A.D. (Andrew), Groop, L. (Leif), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Vartiainen, E. (Erkki), Hofman, A. (Albert), Ripatti, S. (Samuli), Metspalu, A. (Andres), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Pedersen, N.L. (Nancy), McCarthy, M.I. (Mark), Ingelsson, E. (Erik), and Prokopenko, I. (Inga)

Abstract

Background:The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and Findings:We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05).

Published
2013
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186. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hjelt Institute, University of Helsinki, Department of Medicine, Fall, Tove, Hagg, Sara, Maegi, Reedik, Ploner, Alexander, Fischer, Krista, Horikoshi, Momoko, Sarin, Antti-Pekka, Thorleifsson, Gudmar, Ladenvall, Claes, Kals, Mart, Kuningas, Maris, Draisma, Harmen H. M., Ried, Janina S., van Zuydam, Natalie R., Huikari, Ville, Mangino, Massimo, Sonestedt, Emily, Benyamin, Beben, Nelson, Christopher P., Rivera, Natalia V., Kristiansson, Kati, Shen, Huei-yi, Havulinna, Aki S., Dehghan, Abbas, Donnelly, Louise A., Kaakinen, Marika, Nuotio, Marja-Liisa, Robertson, Neil, de Bruijn, Renee F. A. G., Ikram, M. Arfan, Amin, Najaf, Balmforth, Anthony J., Braund, Peter S., Doney, Alexander S. F., Doering, Angela, Elliott, Paul, Esko, Tonu, Franco, Oscar H., Gretarsdottir, Solveig, Hartikainen, Anna-Liisa, Heikkilä, Kauko Veli, Herzig, Karl-Heinz, Holm, Hilma, Hottenga, Jouke Jan, Hypponen, Elina, Illig, Thomas, Isaacs, Aaron, Isomaa, Bo, Karssen, Lennart C., Kettunen, Johannes, Koenig, Wolfgang, Kuulasmaa, Kari, Laatikainen, Tiina, Laitinen, Jaana, Lindgren, Cecilia, Lyssenko, Valeriya, Laara, Esa, Rayner, Nigel W., Mannisto, Satu, Pouta, Anneli, Rathmann, Wolfgang, Rivadeneira, Fernando, Ruokonen, Aimo, Savolainen, Markku J., Sijbrands, Eric J. G., Small, Kerrin S., Smit, Jan H., Steinthorsdottir, Valgerdur, Syvanen, Ann-Christine, Taanila, Anja, Tobin, Martin D., Uitterlinden, Andre G., Willems, Sara M., Willemsen, Gonneke, Witteman, Jacqueline, Perola, Markus, Evans, Alun, Ferrieres, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Ferrario, Marco M., Brambilla, Paolo, Hall, Alistair S., Heath, AndrewC., Madden, Pamela A. F., Martin, Nicholas G., Montgomery, Grant W., Whitfield, John B., Jula, Antti, Knekt, Paul, Oostra, Ben, van Duijn, Cornelia M., Penninx, Brenda W. J. H., Smith, George Davey, Kaprio, Jaakko, Samani, Nilesh J., Gieger, Christian, Peters, Annette, Wichmann, H. -Erich, Boomsma, Dorret I., de Geus, Eco J. C., Tuomi, Tiinamaija, Power, Chris, Hammond, Christopher J., Spector, Tim D., Lind, Lars, Orho-Melander, Marju, Palmer, Colin Neil Alexander, Morris, Andrew D., Groop, Leif, Jarvelin, Marjo-Riitta, Salomaa, Veikko, Vartiainen, Erkki, Hofman, Albert, Ripatti, Samuli, Metspalu, Andres, Thorsteinsdottir, Unnur, Stefansson, Kari, Pedersen, Nancy L., McCarthy, Mark I., Ingelsson, Erik, Prokopenko, Inga, ENGAGE Consortium, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hjelt Institute, University of Helsinki, Department of Medicine, Fall, Tove, Hagg, Sara, Maegi, Reedik, Ploner, Alexander, Fischer, Krista, Horikoshi, Momoko, Sarin, Antti-Pekka, Thorleifsson, Gudmar, Ladenvall, Claes, Kals, Mart, Kuningas, Maris, Draisma, Harmen H. M., Ried, Janina S., van Zuydam, Natalie R., Huikari, Ville, Mangino, Massimo, Sonestedt, Emily, Benyamin, Beben, Nelson, Christopher P., Rivera, Natalia V., Kristiansson, Kati, Shen, Huei-yi, Havulinna, Aki S., Dehghan, Abbas, Donnelly, Louise A., Kaakinen, Marika, Nuotio, Marja-Liisa, Robertson, Neil, de Bruijn, Renee F. A. G., Ikram, M. Arfan, Amin, Najaf, Balmforth, Anthony J., Braund, Peter S., Doney, Alexander S. F., Doering, Angela, Elliott, Paul, Esko, Tonu, Franco, Oscar H., Gretarsdottir, Solveig, Hartikainen, Anna-Liisa, Heikkilä, Kauko Veli, Herzig, Karl-Heinz, Holm, Hilma, Hottenga, Jouke Jan, Hypponen, Elina, Illig, Thomas, Isaacs, Aaron, Isomaa, Bo, Karssen, Lennart C., Kettunen, Johannes, Koenig, Wolfgang, Kuulasmaa, Kari, Laatikainen, Tiina, Laitinen, Jaana, Lindgren, Cecilia, Lyssenko, Valeriya, Laara, Esa, Rayner, Nigel W., Mannisto, Satu, Pouta, Anneli, Rathmann, Wolfgang, Rivadeneira, Fernando, Ruokonen, Aimo, Savolainen, Markku J., Sijbrands, Eric J. G., Small, Kerrin S., Smit, Jan H., Steinthorsdottir, Valgerdur, Syvanen, Ann-Christine, Taanila, Anja, Tobin, Martin D., Uitterlinden, Andre G., Willems, Sara M., Willemsen, Gonneke, Witteman, Jacqueline, Perola, Markus, Evans, Alun, Ferrieres, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Ferrario, Marco M., Brambilla, Paolo, Hall, Alistair S., Heath, AndrewC., Madden, Pamela A. F., Martin, Nicholas G., Montgomery, Grant W., Whitfield, John B., Jula, Antti, Knekt, Paul, Oostra, Ben, van Duijn, Cornelia M., Penninx, Brenda W. J. H., Smith, George Davey, Kaprio, Jaakko, Samani, Nilesh J., Gieger, Christian, Peters, Annette, Wichmann, H. -Erich, Boomsma, Dorret I., de Geus, Eco J. C., Tuomi, Tiinamaija, Power, Chris, Hammond, Christopher J., Spector, Tim D., Lind, Lars, Orho-Melander, Marju, Palmer, Colin Neil Alexander, Morris, Andrew D., Groop, Leif, Jarvelin, Marjo-Riitta, Salomaa, Veikko, Vartiainen, Erkki, Hofman, Albert, Ripatti, Samuli, Metspalu, Andres, Thorsteinsdottir, Unnur, Stefansson, Kari, Pedersen, Nancy L., McCarthy, Mark I., Ingelsson, Erik, Prokopenko, Inga, and ENGAGE Consortium

Published
2013

187. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Author

Fall, T, Hagg, S, Magi, R, Ploner, A, Fischer, K (Kirsten), Horikoshi, M, Sarin, AP, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, Maris, Draisma, HHM, Ried, JS, van Zuydam, NR, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, CP, Rivera, NV, Kristiansson, K, Shen, HY, Havulinna, AS, Dehghan, Abbas, Donnelly, LA, Kaakinen, M, Nuotio, ML, Robertson, N, Bruijn, Renee, Ikram, Arfan, Amin, Najaf, Balmforth, AJ, Braund, PS, Doney, ASF, Doring, A, Elliott, P, Esko, T, Franco Duran, OH, Gretarsdottir, S, Hartikainen, AL, Heikkila, K, Herzig, KH, Holm, H, Hottenga, JJ (Jouke Jan), Hypponen, E, Illig, T, Isaacs, Aaron, Isomaa, B, Karssen, Lennart, Kettunen, J, Koenig, W, Kuulasmaa, K, Laatikainen, T, Laitinen, J, Lindgren, C, Lyssenko, V, Laara, E, Rayner, NW, Mannisto, S, Pouta, A, Rathmann, W, Rivadeneira, Fernando, Ruokonen, A, Savolainen, MJ, Sijbrands, E.J.G., Small, KS, Smit, JH, Steinthorsdottir, V, Syvanen, AC, Taanila, A, Tobin, MD, Uitterlinden, André, Willems, SM, Willemsen, G, Witteman, JCM, Perola, M, Evans, A, Ferrieres, J, Virtamo, J, Kee, F, Tregouet, DA, Arveiler, D, Amouyel, P, Ferrario, MM, Brambilla, P, Hall, AS, Heath, A, Madden, PAF, Martin, NG, Montgomery, GW, Whitfield, JB, Jula, A, Knekt, P, Oostra, Ben, Duijn, Cornelia, Penninx, BWJH, Smith, GD, Kaprio, J, Samani, NJ, Gieger, C, Peters, A, Wichmann, HE, Boomsma, DI, de Geus, EJC, Tuomi, T, Power, C, Hammond, CJ, Spector, TD, Lind, L, Orho-Melander, M, Palmer, CNA, Morris, AD, Groop, L, Jarvelin, MR, Salomaa, V, Vartiainen, E, Hofman, Bert, Ripatti, S, Metspalu, A, Thorsteinsdottir, U, Stefansson, K, Pedersen, NL, McCarthy, MI, Ingelsson, E, Prokopenko, I, Fall, T, Hagg, S, Magi, R, Ploner, A, Fischer, K (Kirsten), Horikoshi, M, Sarin, AP, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, Maris, Draisma, HHM, Ried, JS, van Zuydam, NR, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, CP, Rivera, NV, Kristiansson, K, Shen, HY, Havulinna, AS, Dehghan, Abbas, Donnelly, LA, Kaakinen, M, Nuotio, ML, Robertson, N, Bruijn, Renee, Ikram, Arfan, Amin, Najaf, Balmforth, AJ, Braund, PS, Doney, ASF, Doring, A, Elliott, P, Esko, T, Franco Duran, OH, Gretarsdottir, S, Hartikainen, AL, Heikkila, K, Herzig, KH, Holm, H, Hottenga, JJ (Jouke Jan), Hypponen, E, Illig, T, Isaacs, Aaron, Isomaa, B, Karssen, Lennart, Kettunen, J, Koenig, W, Kuulasmaa, K, Laatikainen, T, Laitinen, J, Lindgren, C, Lyssenko, V, Laara, E, Rayner, NW, Mannisto, S, Pouta, A, Rathmann, W, Rivadeneira, Fernando, Ruokonen, A, Savolainen, MJ, Sijbrands, E.J.G., Small, KS, Smit, JH, Steinthorsdottir, V, Syvanen, AC, Taanila, A, Tobin, MD, Uitterlinden, André, Willems, SM, Willemsen, G, Witteman, JCM, Perola, M, Evans, A, Ferrieres, J, Virtamo, J, Kee, F, Tregouet, DA, Arveiler, D, Amouyel, P, Ferrario, MM, Brambilla, P, Hall, AS, Heath, A, Madden, PAF, Martin, NG, Montgomery, GW, Whitfield, JB, Jula, A, Knekt, P, Oostra, Ben, Duijn, Cornelia, Penninx, BWJH, Smith, GD, Kaprio, J, Samani, NJ, Gieger, C, Peters, A, Wichmann, HE, Boomsma, DI, de Geus, EJC, Tuomi, T, Power, C, Hammond, CJ, Spector, TD, Lind, L, Orho-Melander, M, Palmer, CNA, Morris, AD, Groop, L, Jarvelin, MR, Salomaa, V, Vartiainen, E, Hofman, Bert, Ripatti, S, Metspalu, A, Thorsteinsdottir, U, Stefansson, K, Pedersen, NL, McCarthy, MI, Ingelsson, E, and Prokopenko, I

Published
2013

188. The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Author

Fall, Tove, Hagg, Sara, Maegi, Reedik, Ploner, Alexander, Fischer, Krista, Horikoshi, Momoko, Sarin, Antti-Pekka, Thorleifsson, Gudmar, Ladenvall, Claes, Kals, Mart, Kuningas, Maris, Draisma, Harmen H. M., Ried, Janina S., van Zuydam, Natalie R., Huikari, Ville, Mangino, Massimo, Sonestedt, Emily, Benyamin, Beben, Nelson, Christopher P., Rivera, Natalia V., Kristiansson, Kati, Shen, Huei-yi, Havulinna, Aki S., Dehghan, Abbas, Donnelly, Louise A., Kaakinen, Marika, Nuotio, Marja-Liisa, Robertson, Neil, de Bruijn, Renee F. A. G., Ikram, M. Arfan, Amin, Najaf, Balmforth, Anthony J., Braund, Peter S., Doney, Alexander S. F., Doering, Angela, Elliott, Paul, Esko, Tonu, Franco, Oscar H., Gretarsdottir, Solveig, Hartikainen, Anna-Liisa, Heikkila, Kauko, Herzig, Karl-Heinz, Holm, Hilma, Hottenga, Jouke Jan, Hypponen, Elina, Illig, Thomas, Isaacs, Aaron, Isomaa, Bo, Karssen, Lennart C., Kettunen, Johannes, Koenig, Wolfgang, Kuulasmaa, Kari, Laatikainen, Tiina, Laitinen, Jaana, Lindgren, Cecilia, Lyssenko, Valeriya, Laara, Esa, Rayner, Nigel W., Mannisto, Satu, Pouta, Anneli, Rathmann, Wolfgang, Rivadeneira, Fernando, Ruokonen, Aimo, Savolainen, Markku J., Sijbrands, Eric J. G., Small, Kerrin S., Smit, Jan H., Steinthorsdottir, Valgerdur, Syvanen, Ann-Christine, Taanila, Anja, Tobin, Martin D., Uitterlinden, Andre G., Willems, Sara M., Willemsen, Gonneke, Witteman, Jacqueline, Perola, Markus, Evans, Alun, Ferrieres, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Ferrario, Marco M., Brambilla, Paolo, Hall, Alistair S., Heath, AndrewC., Madden, Pamela A. F., Martin, Nicholas G., Montgomery, Grant W., Whitfield, John B., Jula, Antti, Knekt, Paul, Oostra, Ben, van Duijn, Cornelia M., Penninx, Brenda W. J. H., Smith, George Davey, Kaprio, Jaakko, Samani, Nilesh J., Gieger, Christian, Peters, Annette, Wichmann, H. -Erich, Boomsma, Dorret I., de Geus, Eco J. C., Tuomi, TiinaMaija, Power, Chris, Hammond, Christopher J., Spector, Tim D., Lind, Lars, Orho-Melander, Marju, Palmer, Colin Neil Alexander, Morris, Andrew D., Groop, Leif, Jarvelin, Marjo-Riitta, Salomaa, Veikko, Vartiainen, Erkki, Hofman, Albert, Ripatti, Samuli, Metspalu, Andres, Thorsteinsdottir, Unnur, Stefansson, Kari, Pedersen, Nancy L., McCarthy, Mark I., Ingelsson, Erik, Prokopenko, Inga, Fall, Tove, Hagg, Sara, Maegi, Reedik, Ploner, Alexander, Fischer, Krista, Horikoshi, Momoko, Sarin, Antti-Pekka, Thorleifsson, Gudmar, Ladenvall, Claes, Kals, Mart, Kuningas, Maris, Draisma, Harmen H. M., Ried, Janina S., van Zuydam, Natalie R., Huikari, Ville, Mangino, Massimo, Sonestedt, Emily, Benyamin, Beben, Nelson, Christopher P., Rivera, Natalia V., Kristiansson, Kati, Shen, Huei-yi, Havulinna, Aki S., Dehghan, Abbas, Donnelly, Louise A., Kaakinen, Marika, Nuotio, Marja-Liisa, Robertson, Neil, de Bruijn, Renee F. A. G., Ikram, M. Arfan, Amin, Najaf, Balmforth, Anthony J., Braund, Peter S., Doney, Alexander S. F., Doering, Angela, Elliott, Paul, Esko, Tonu, Franco, Oscar H., Gretarsdottir, Solveig, Hartikainen, Anna-Liisa, Heikkila, Kauko, Herzig, Karl-Heinz, Holm, Hilma, Hottenga, Jouke Jan, Hypponen, Elina, Illig, Thomas, Isaacs, Aaron, Isomaa, Bo, Karssen, Lennart C., Kettunen, Johannes, Koenig, Wolfgang, Kuulasmaa, Kari, Laatikainen, Tiina, Laitinen, Jaana, Lindgren, Cecilia, Lyssenko, Valeriya, Laara, Esa, Rayner, Nigel W., Mannisto, Satu, Pouta, Anneli, Rathmann, Wolfgang, Rivadeneira, Fernando, Ruokonen, Aimo, Savolainen, Markku J., Sijbrands, Eric J. G., Small, Kerrin S., Smit, Jan H., Steinthorsdottir, Valgerdur, Syvanen, Ann-Christine, Taanila, Anja, Tobin, Martin D., Uitterlinden, Andre G., Willems, Sara M., Willemsen, Gonneke, Witteman, Jacqueline, Perola, Markus, Evans, Alun, Ferrieres, Jean, Virtamo, Jarmo, Kee, Frank, Tregouet, David-Alexandre, Arveiler, Dominique, Amouyel, Philippe, Ferrario, Marco M., Brambilla, Paolo, Hall, Alistair S., Heath, AndrewC., Madden, Pamela A. F., Martin, Nicholas G., Montgomery, Grant W., Whitfield, John B., Jula, Antti, Knekt, Paul, Oostra, Ben, van Duijn, Cornelia M., Penninx, Brenda W. J. H., Smith, George Davey, Kaprio, Jaakko, Samani, Nilesh J., Gieger, Christian, Peters, Annette, Wichmann, H. -Erich, Boomsma, Dorret I., de Geus, Eco J. C., Tuomi, TiinaMaija, Power, Chris, Hammond, Christopher J., Spector, Tim D., Lind, Lars, Orho-Melander, Marju, Palmer, Colin Neil Alexander, Morris, Andrew D., Groop, Leif, Jarvelin, Marjo-Riitta, Salomaa, Veikko, Vartiainen, Erkki, Hofman, Albert, Ripatti, Samuli, Metspalu, Andres, Thorsteinsdottir, Unnur, Stefansson, Kari, Pedersen, Nancy L., McCarthy, Mark I., Ingelsson, Erik, and Prokopenko, Inga

Abstract

Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p =

Published
2013

189. Identification and cloning of a key insecticide-metabolizing glutathione S-transferase (MdGST-6A) from a hyper insecticide-resistant strain of the housefly Musca domestica

Author

Michael Syvanen, S. H. Wei, and Alan G. Clark

Subjects
Insecticides, Sequence analysis, Molecular Sequence Data, Gene Expression, medicine.disease_cause, Biochemistry, Isozyme, Catalysis, Insecticide Resistance, chemistry.chemical_compound, Houseflies, medicine, Parathion methyl, Animals, Amino Acid Sequence, Housefly, Cloning, Molecular, Molecular Biology, Escherichia coli, Glutathione Transferase, biology, Sequence Homology, Amino Acid, Active site, Glutathione, Sequence Analysis, DNA, biology.organism_classification, Isoenzymes, Glutathione S-transferase, chemistry, Insect Science, biology.protein
Abstract

Strains of the housefly, Musca domestica, highly resistant to organophosphate (OP) and other insecticides are known because they overproduce glutathione S-transferases (GSTs). Previous work has shown that overproduction in these strains involved numerous isozymes with glutathione conjugating activities (Pesticide Biochem. Physiol., 25 (1986) 169; Mol. General Genetics, 227 (1991) 355; J. Biol. Chem., 267 (1992) 1840; Mol. General Genetics, 245 (1994) 236; J. Mol. Evol., 43 (1996) 236). The current work describes the purification and identification of a M. domestica GST isozyme (pI 7.1) broadly specific for substrates from a housefly strain, Cornell-HR, that is highly resistant against OP-insecticides, and the isolation of two new MdGST genes using the antibody made against it. This isozyme, which was identified from amongst more than 20 isoelectric forms of GSTs of the same subunit size, was highly active for conjugating GSH to the model substrate 3,4-dichloronitrobenzne (DCNB). When expressed in Escherichia coli, one of the cloned GSTs, MdGST-6A, produces an enzyme that conjugates glutathione to the insecticides methyl parathion and lindane. On indication that it was the most active isozyme toward several xenobiotics among several MdGSTs tested, we advance the notion that MdGST-6A probably plays an important role in M. domestica Cornell-HR's resistance towards OP-insecticides. MdGST-6A and a second closely related one found in this work, MdGST-6B, are members of the traditional insect class I family (theta-class) and share the greatest homologies with a cluster of Drosophila GSTs on locus 55. In addition to having the unusually broad substrate specificity, the sequence of the new group of enzymes reveals that it has a highly diverged hydrophobic motif in its active site as compared to other class I GSTs from insects.

Published
2001

190. On the occurrence of horizontal gene transfer among an arbitrarily chosen group of 26 genes

Author

Michael Syvanen

Subjects
Genetics, Bacteria, Gene Transfer, Horizontal, Sequence Homology, Amino Acid, Biology, Genetic code, Archaea, Phylogenetics, Acetyltransferases, Yeasts, Horizontal gene transfer, Aspartate Carbamoyltransferase, Tryptophan Synthase, ORFS, Clade, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Orthologous Gene, Ornithine Carbamoyltransferase, Phylogeny, Gram
Abstract

The deduced amino acid sequences from 1200 Haemophilus influenzae genes was compared to a data set that contained the orfs from yeast, two different Archaea and the Gram+ and Gramminus sign bacteria, Bacillus subtilis and Escherichia coli. The results of the comparison yielded a 26 orthologous gene set that had at least one representative from each of the four groups. A four taxa phylogenetic relationship for these 26 genes was determined. The statistical significance of each minimal tree was tested against the two alternative four taxa trees. The result was that four genes significantly supported the (Archaea, Eukaryota) (Gram+, Gramminus sign) topology, two genes supported the one where Gramminus sign and Eukaryota form a clade, and one gene supported the tree where Gram+ and Eukaryota define one clade. The remaining genes do not uniquely support any phylogeny, thereby collapsing the two central nodes into a single node. These are referred to as star phylogenies. I offer a new suggestion for the mechanism that gave rise to the star phylogenies. Namely, these are genes that are younger than the underlying lineages that currently harbor them. This hypothesis is examined with two proteins that display the star phylogeny; namely onithine transcarbamylase and tryptophan synthetase. It is shown, using the distance matrix rate test, that the rate of evolution of these two proteins is comparable to a control gene when rates are determined by comparing closely related species. This implies that the genes under comparison experience comparable functional constraint. However, when the genes from remotely related species are compared, a plateau is encountered. Since we see no unusual levels of functional constraint this plateau cannot be attributed to the divergence of the protein having reached saturation. The simplest explanation is that the genes displaying the star phylogenies were introduced after Archaea, Eukaryota, and Bacteria had diverged from one another. They presumably spread through life by horizontal gene transfer.

Published
2001

192. The DNA Methylation Landscape of Paediatric Acute Lymphoblastic Leukemia

Author

Nordlund, Jessica, Backlin, Carin, Wahlberg, Per, Forestier, E., Heyman, M., Soderhall, S., Schmiegelow, K., Lönnerholm, Gudmar, Gustafsson, Mats, Syvanen, Ann-Christine, Nordlund, Jessica, Backlin, Carin, Wahlberg, Per, Forestier, E., Heyman, M., Soderhall, S., Schmiegelow, K., Lönnerholm, Gudmar, Gustafsson, Mats, and Syvanen, Ann-Christine

Published
2012
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194. Digital gene expression profiling of primary acute lymphoblastic leukemia cells

Author

Nordlund, J., Kiialainen, A., Karlberg, O., Berglund, E. C., Goransson-Kultima, H., Sonderkaer, M., Nielsen, K. L., Gustafsson, M. G., Behrendtz, M., Forestier, Erik, Perkkio, M., Soderhall, S., Lonnerholm, G., Syvanen, A-C, Nordlund, J., Kiialainen, A., Karlberg, O., Berglund, E. C., Goransson-Kultima, H., Sonderkaer, M., Nielsen, K. L., Gustafsson, M. G., Behrendtz, M., Forestier, Erik, Perkkio, M., Soderhall, S., Lonnerholm, G., and Syvanen, A-C

Abstract

We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of `second-generation' sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of similar to 50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (P<1 x 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.

Published
2012
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195. The DNA Methylation Landscape of Paediatric Acute Lymphoblastic Leukemia

Author

Nordlund, J., Backlin, C., Wahlberg, P., Forestier, Erik, Heyman, M., Soderhall, S., Schmiegelow, K., Lonnerholm, G., Gustafsson, M., Syvanen, A. C., Nordlund, J., Backlin, C., Wahlberg, P., Forestier, Erik, Heyman, M., Soderhall, S., Schmiegelow, K., Lonnerholm, G., Gustafsson, M., and Syvanen, A. C.

Published
2012

196. Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples

Author

Isine Bolstad, Anne, Le Hellard, Stephanie, Kristjansdottir, Gudlaug, Vasaitis, Lilian, Kvarnstrom, Marika, Sjöwall, Christoffer, Joar Auglaend Johnsen, Svein, Eriksson, Per, Omdal, Roald, Brun, Johan G, Wahren-Herlenius, Marie, Theander, Elke, Syvanen, Ann-Christine, Ronnblom, Lars, Nordmark, Gunnel, Jonsson, Roland, Isine Bolstad, Anne, Le Hellard, Stephanie, Kristjansdottir, Gudlaug, Vasaitis, Lilian, Kvarnstrom, Marika, Sjöwall, Christoffer, Joar Auglaend Johnsen, Svein, Eriksson, Per, Omdal, Roald, Brun, Johan G, Wahren-Herlenius, Marie, Theander, Elke, Syvanen, Ann-Christine, Ronnblom, Lars, Nordmark, Gunnel, and Jonsson, Roland

Abstract

Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogrens syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin alpha (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. less thanbrgreater than less thanbrgreater thanMethods 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. less thanbrgreater than less thanbrgreater thanResults Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. less thanbrgreater than less thanbrgreater thanConclusions A strong association was found between several SNP in the LTA/LTB/TNF alpha locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS., Funding Agencies|Western Norway Regional Health Authority||Research Council of Norway||Strategic Research Program at Helse Bergen||Broegelmann Foundation||University of Bergen||Bergens forskningsstiftelse||Swedish Research Council||Stockholm County Council||Goran Gustafsson Foundation||Torsten and Ragnar Soderberg Foundation||King Gustaf the Vth 80-year Foundation||Anna-Greta Crafoord Foundation||Malmo University Hospital Cancer Research Foundation||Vinnova||Vardalstiftelsen||Swedish Foundation for Strategic Research||Swedish Rheumatism Association||Invest in Sweden Agency||KK-stiftelsen

Published
2012
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197. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author

Huang, J. (Jian), Sabater-Lleal, M. (Maria), Asselbergs, F.W. (Folkert), Tregouet, D.-A. (David-Alexandre), Shin, S.-Y., Ding, J. (Jingzhong), Baumert, J. (Jens), Oudot-Mellakh, T. (Tiphaine), Folkersen, L. (Lasse), Johnson, A.D. (Andrew), Smith, N.L. (Nicholas), Williams, S.M. (Scott), Ikram, M.A. (Arfan), Kleber, M.E. (Marcus), Becker, D.M. (Diane), Truong, V. (Vinh), Mychaleckyj, J.C. (Josyf), Tang, W. (Weihong), Yang, Q. (Qiong Fang), Sennblad, B. (Bengt), Moore, J.H. (Jason), Williams, F.M. (Frances), Dehghan, A. (Abbas), Silbernagel, G. (Günther), Schrijvers, E.M.C. (Elisabeth M. C.), Smith, S. (Sarah), Karakas, M. (Mahir), Tofler, G.H. (Geoffrey), Silveira, A. (Angela), Navis, G. (Gerjan), Lohman, K. (Kurt), Chen, M-H. (Ming-Huei), Peters, A. (Annette), Goel, A. (Anuj), Hopewell, J., Chambers, J.C. (John), Saleheen, D., Lundmark, P. (Per), Psaty, B.M. (Bruce), Strawbridge, R.J. (Rona), Boehm, B.O. (Bernhard), Carter, A.M. (Angela M.), Meisinger, C. (Christa), Peden, J. (John), Bis, J.C. (Joshua), McKnight, B. (Barbara), Öhrvik, J. (John), Taylor, K.D. (Kent), Franzosi, M., Seedorf, U. (Udo), Collins, R. (Rory), Franco-Cereceda, A. (Anders), Syvanen, A.C., Goodall, A.H. (Alison), Yanek, L.R. (Lisa), Cushman, M. (Mary Ann), Müller-Nurasyid, M. (Martina), Folsom, A.R. (Aaron), Basu, S. (Saonli), Aleksic, N. (Nena), Gilst, W.H. (Wiek) van, Kooner, J.S. (Jaspal), Hofman, A. (Albert), Danesh, J. (John), Clarke, R. (Robert), Meigs, J.B. (James), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Klopp, N. (Norman), Harris, T.B. (Tamara), Winkelmann, B., Grant, P.J. (Peter J.), Hillege, H.L. (Hans), Watkins, H. (Hugh), Spector, T.D. (Timothy), Becker, L.C. (Lewis), Tracy, R.P. (Russell), März, W. (Winfried), Uitterlinden, A.G. (André), Eriksson, P. (Per), Cambien, F. (François), Morange, P.-E. (P.), Koenig, W. (Wolfgang), Soranzo, N. (Nicole), Harst, P. (Pim) van der, Liu, Y. (YongMei), O'Donnell, C.J. (Christopher), Hamsten, A. (Anders), Huang, J. (Jian), Sabater-Lleal, M. (Maria), Asselbergs, F.W. (Folkert), Tregouet, D.-A. (David-Alexandre), Shin, S.-Y., Ding, J. (Jingzhong), Baumert, J. (Jens), Oudot-Mellakh, T. (Tiphaine), Folkersen, L. (Lasse), Johnson, A.D. (Andrew), Smith, N.L. (Nicholas), Williams, S.M. (Scott), Ikram, M.A. (Arfan), Kleber, M.E. (Marcus), Becker, D.M. (Diane), Truong, V. (Vinh), Mychaleckyj, J.C. (Josyf), Tang, W. (Weihong), Yang, Q. (Qiong Fang), Sennblad, B. (Bengt), Moore, J.H. (Jason), Williams, F.M. (Frances), Dehghan, A. (Abbas), Silbernagel, G. (Günther), Schrijvers, E.M.C. (Elisabeth M. C.), Smith, S. (Sarah), Karakas, M. (Mahir), Tofler, G.H. (Geoffrey), Silveira, A. (Angela), Navis, G. (Gerjan), Lohman, K. (Kurt), Chen, M-H. (Ming-Huei), Peters, A. (Annette), Goel, A. (Anuj), Hopewell, J., Chambers, J.C. (John), Saleheen, D., Lundmark, P. (Per), Psaty, B.M. (Bruce), Strawbridge, R.J. (Rona), Boehm, B.O. (Bernhard), Carter, A.M. (Angela M.), Meisinger, C. (Christa), Peden, J. (John), Bis, J.C. (Joshua), McKnight, B. (Barbara), Öhrvik, J. (John), Taylor, K.D. (Kent), Franzosi, M., Seedorf, U. (Udo), Collins, R. (Rory), Franco-Cereceda, A. (Anders), Syvanen, A.C., Goodall, A.H. (Alison), Yanek, L.R. (Lisa), Cushman, M. (Mary Ann), Müller-Nurasyid, M. (Martina), Folsom, A.R. (Aaron), Basu, S. (Saonli), Aleksic, N. (Nena), Gilst, W.H. (Wiek) van, Kooner, J.S. (Jaspal), Hofman, A. (Albert), Danesh, J. (John), Clarke, R. (Robert), Meigs, J.B. (James), Kathiresan, S. (Sekar), Reilly, M.P. (Muredach), Klopp, N. (Norman), Harris, T.B. (Tamara), Winkelmann, B., Grant, P.J. (Peter J.), Hillege, H.L. (Hans), Watkins, H. (Hugh), Spector, T.D. (Timothy), Becker, L.C. (Lewis), Tracy, R.P. (Russell), März, W. (Winfried), Uitterlinden, A.G. (André), Eriksson, P. (Per), Cambien, F. (François), Morange, P.-E. (P.), Koenig, W. (Wolfgang), Soranzo, N. (Nicole), Harst, P. (Pim) van der, Liu, Y. (YongMei), O'Donnell, C.J. (Christopher), and Hamsten, A. (Anders)

Published
2012
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198. Molecular tracking of mountain lions in the Yosemite valley region in California: genetic analysis using microsatellites and faecal DNA

Author

Walter M. Boyce, Holly B. Ernest, Michael Syvanen, Bernie May, and Maria Cecilia T. Penedo

Subjects
Lions, Food Chain, Population, Zoology, Biology, Genetic analysis, Polymerase Chain Reaction, California, law.invention, Predation, Feces, Dogs, law, Mountain lion, Genotype, Genetics, Animals, Humans, education, Ecology, Evolution, Behavior and Systematics, Polymerase chain reaction, Probability, education.field_of_study, Polymorphism, Genetic, Ecology, Sequence Analysis, DNA, biology.organism_classification, Microsatellite, Cattle, human activities, Microsatellite Repeats
Abstract

Twelve microsatellite loci were characterized in California mountain lions (Puma concolor) and sufficient polymorphism was found to uniquely genotype 62 animals sampled at necropsy. Microsatellite genotypes obtained using mountain lion faecal DNA matched those from muscle for all of 15 individuals examined. DNA from potential prey species and animals whose faeces could be misidentified as mountain lion faeces were reliably distinguished from mountain lions using this microsatellite panel. In a field application of this technique, 32 faecal samples were collected from hiking trails in the Yosemite Valley region where seven mountain lions previously had been captured, sampled, and released. Twelve samples yielded characteristic mountain lion genotypes, three displayed bobcat-type genotypes, and 17 did not amplify. The genotype of one of the 12 mountain lion faecal samples was identical to one of the mountain lions that previously had been captured. Three of the 12 faecal samples yielded identical genotypes, and eight new genotypes were detected in the remaining samples. This analysis provided a minimum estimate of 16 mountain lions (seven identified by capture and nine identified by faecal DNA) living in or travelling through Yosemite Valley from March 1997 to August 1998. Match probabilities (probabilities that identical DNA genotypes would be drawn at random a second time from the population) indicated that the samples with identical genotypes probably came from the same mountain lion. Our results demonstrate that faecal DNA analysis is an effective method for detecting and identifying individual mountain lions.

Published
2000

199. The origin of prokaryotic C2H2 zinc finger regulators

Author

Clarence I. Kado, Michael Syvanen, and Naima Bouhouche

Subjects
Microbiology (medical), Molecular Sequence Data, Biology, Microbiology, DNA-binding protein, Evolution, Molecular, Bacterial Proteins, Virology, Animals, Humans, Amino Acid Sequence, Phylogeny, LIM domain, Zinc finger, Genetics, Recombination, Genetic, Sp1 transcription factor, C2H2 Zinc Finger, Bacteria, Eukaryotic transcription, Promoter, Zinc Fingers, Cell biology, RING finger domain, DNA-Binding Proteins, Repressor Proteins, Infectious Diseases, Gene Expression Regulation
Abstract

C2H2 zinc finger bearing proteins are a large superfamily of nucleic acid binding proteins, which constitute a major subset of eukaryotic transcription factors. Although originally thought to occur only in eukaryotes, a novel C2H2 zinc finger transcription factor, Ros, which regulates both prokaryotic and eukaryotic promoters has been found in bacteria. Phylogenically, Ros is distantly related to eukaryotic zinc finger regulators.

Published
2000

200. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J.R., Travers, M.E., Bouatia-Naji, N., Dimas, A.S., Nica, A., Wheeler, E., Chen, H., Voight, B.F., Taneera, J., Kanoni, S., Peden, J.F., Turrini, F., Gustafsson, S., Zabena, C., Almgren, P., Barker, D.J., Barnes, D., Dennison, E.M., Eriksson, J.G., Eriksson, P., Eury, E., Folkersen, L., Fox, C.S., Frayling, T.M., Goel, A., Gu, H.F., Horikoshi, M., Isomaa, B., Jackson, A.U., Jameson, K.A., Kajantie, E., Kerr-Conte, J., Kuulasmaa, T., Kuusisto, J., Loos, R.J., Luan, J., Makrilakis, K., Manning, A.K., Martinez-Larrad, M.T., Narisu, N., Nastase Mannila, M., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A.A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A.J., Syvanen, A.C., Tuomi, T., Hooft, F. van 't, Walker, M., Weedon, M.N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J.C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C.G., Lind, L., Cooper, C.C., Serrano-Rios, M., Ferrannini, E., Forsen, T.J., Clarke, R., Franzosi, M.G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F.S., Laakso, M., Dermitzakis, E.T., Boehnke, M., McCarthy, M.I., Wareham, N.J., Groop, L., Pattou, F., Gloyn, A.L., Dedoussis, G.V., Lyssenko, V., Meigs, J.B., Barroso, I., Watanabe, R.M., Heijer, M. den, Kiemeney, L.A.L.M., et al., Strawbridge, R.J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J.R., Travers, M.E., Bouatia-Naji, N., Dimas, A.S., Nica, A., Wheeler, E., Chen, H., Voight, B.F., Taneera, J., Kanoni, S., Peden, J.F., Turrini, F., Gustafsson, S., Zabena, C., Almgren, P., Barker, D.J., Barnes, D., Dennison, E.M., Eriksson, J.G., Eriksson, P., Eury, E., Folkersen, L., Fox, C.S., Frayling, T.M., Goel, A., Gu, H.F., Horikoshi, M., Isomaa, B., Jackson, A.U., Jameson, K.A., Kajantie, E., Kerr-Conte, J., Kuulasmaa, T., Kuusisto, J., Loos, R.J., Luan, J., Makrilakis, K., Manning, A.K., Martinez-Larrad, M.T., Narisu, N., Nastase Mannila, M., Ohrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A.A., Sennblad, B., Silveira, A., Stancakova, A., Stirrups, K., Swift, A.J., Syvanen, A.C., Tuomi, T., Hooft, F. van 't, Walker, M., Weedon, M.N., Xie, W., Zethelius, B., Ongen, H., Malarstig, A., Hopewell, J.C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Ostenson, C.G., Lind, L., Cooper, C.C., Serrano-Rios, M., Ferrannini, E., Forsen, T.J., Clarke, R., Franzosi, M.G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F.S., Laakso, M., Dermitzakis, E.T., Boehnke, M., McCarthy, M.I., Wareham, N.J., Groop, L., Pattou, F., Gloyn, A.L., Dedoussis, G.V., Lyssenko, V., Meigs, J.B., Barroso, I., Watanabe, R.M., Heijer, M. den, Kiemeney, L.A.L.M., and et al.

Abstract

Contains fulltext : 95931.pdf (publisher's version ) (Closed access), OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of approximately 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

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