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154. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis

Author

Dreger, Abaa, P., Brand, R. C., Milligan, D. D., Corradini, P. E., Finke, J. F., Lambertenghi Deliliers, G. G., Martino, R. H., Russell, N. I., Biezen, V. A. N., Michallet, A. C., Niederwieser, M. J., Herrmann, D. K., Greinix, R. P. L., Ferrant, H. M., Koza, A. N., Vitek, V. O., Vindelöv, A. P., Ruutu, L. Q., Remes, T. R., Milpied, K. S., Varet, N. T., Gorin, B. U., Sutton, N. C. V., Kroger, L. W., Hertenstein, N. X., Trumper, B. Y., Beelen, L. Z., Derigs, D. Z., Ab, G., Casper, Ac, J., Stilgenbauer, Ad, S., Bunjes, Ad, D., Majolino, Ae, I., Bacigalupo, Af, A., Meloni, Giovanna, Ag, G., Willemze, Ah, R., Witte, D. E., Ai, T., Cornelissen, J. J., Aj, Verdonck, Ak, L., Hansz, Al, J., Morgenstern, Am, G., Hows, An, J., Goldstone, Ao, A., Aschan, Ap, J., Oberg, Aq, G., Esteve, Ar, J., Caballero, As, D., Iriondo, At, A., and University of Groningen

Subjects
Male, Oncology, Cancer Research, Transplantation Conditioning, BLOOD, Chronic lymphocytic leukemia, DONORS, DISEASE, Recurrence, Risk Factors, allogeneic stem cell transplantation, hemic and lymphatic diseases, Registries, education.field_of_study, ALEMTUZUMAB, Incidence, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Fludarabine, PCR, treatment-related mortality, SURVIVAL, Alemtuzumab, cll, reduced-intensity conditioning, Female, FLUDARABINE, medicine.drug, Adult, EXPRESSION, medicine.medical_specialty, Population, MARROW TRANSPLANTATION, Internal medicine, medicine, Humans, Transplantation, Homologous, Risk factor, education, Aged, Proportional Hazards Models, Proportional hazards model, business.industry, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Transplantation, Immunology, business, Settore MED/15 - Malattie del Sangue, CLL
Abstract

To elucidate whether reduced-intensity conditioning (RIC) decreases treatment-related mortality (TRM) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL), we retrospectively compared 73 RIC cases from a recent EBMT survey with 82 patients from the EBMT database who had undergone standard myeloablative conditioning ( MC) for CLL during the same time period. The two populations were matched by adjusting the primary risk factor, the conditioning regimen, in a series of Cox models for age, sex, donor type, remission status at transplant and analyzed for its effect on TRM, relapse incidence, event-free (EFS) and overall survival ( OS). After adjustment, a significant reduction of TRM became evident for the RIC population ( hazard ratio (HR) 0.4 (95% confidence interval 0.18-0.9); P=0.03). On the other hand, RIC was associated with an increased relapse incidence (HR 2.65 (0.98-7.12); P=0.054). There was no significant difference between RIC and MC in terms of EFS (HR 0.69 (0.38-1.25); P=0.22) and OS (HR 0.65 (0.33-1.28); P=0.21). We conclude that RIC appears to favorably influence TRM after allo-SCT for CLL. This observation, as well as possible detrimental effects of RIC on relapse risk, should be confirmed by prospective studies.

Published
2005

157. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

Author

Guigas, B, de Leeuw van Weenen, J E, van Leeuwen, N, Simonis-Bik, A M, van Haeften, T W, Nijpels, G, Houwing-Duistermaat, J J, Beekman, M, Deelen, J, Havekes, L M, Penninx, B W J H, Vogelzangs, N, van 't Riet, E, Dehghan, A, Hofman, A, Witteman, J C, Uitterlinden, A G, Grarup, Niels, Jørgensen, Torben, Witte, D R, Lauritzen, T, Hansen, Torben, Pedersen, O, Hottenga, J, Romijn, J A, Diamant, M, Kramer, M H H, Heine, R J, Willemsen, G, Dekker, J M, Eekhoff, E M, Pijl, H, de Geus, E J, Slagboom, P E, 't Hart, L M, Guigas, B, de Leeuw van Weenen, J E, van Leeuwen, N, Simonis-Bik, A M, van Haeften, T W, Nijpels, G, Houwing-Duistermaat, J J, Beekman, M, Deelen, J, Havekes, L M, Penninx, B W J H, Vogelzangs, N, van 't Riet, E, Dehghan, A, Hofman, A, Witteman, J C, Uitterlinden, A G, Grarup, Niels, Jørgensen, Torben, Witte, D R, Lauritzen, T, Hansen, Torben, Pedersen, O, Hottenga, J, Romijn, J A, Diamant, M, Kramer, M H H, Heine, R J, Willemsen, G, Dekker, J M, Eekhoff, E M, Pijl, H, de Geus, E J, Slagboom, P E, and 't Hart, L M

Abstract

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans.METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis.RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*10(-4) ) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*10(-4) ) but again not in men (P = 0.34).CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene.

Published
2014

158. Quality control and conduct of genome-wide association meta-analyses

Author

Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis, G, Absher, D, Alavere, H, Albrecht, E, Allen, H, Almgren, P, Amin, N, Amouyel, P, Anderson, D, Arnold, A, Arveiler, D, Aspelund, T, Asselbergs, F, Assimes, T, Atalay, M, Attwood, A, Atwood, L, Bakker, S, Balkau, B, Balmforth, A, Barlassina, C, Barroso, I, Basart, H, Bauer, S, Beckmann, J, Beilby, J, Bennett, A, Ben Shlomo, Y, Bergman, R, Bergmann, S, Berndt, S, Biffar, R, Di Blasio, A, Boehm, B, Boehnke, M, Boeing, H, Boerwinkle, E, Bolton, J, Bonnefond, A, Bonnycastle, L, Boomsma, D, Borecki, I, Bornstein, S, Bouatia Naji, N, Boucher, G, Bragg Gresham, J, Brambilla, P, Bruinenberg, M, Buchanan, T, Buechler, C, Cadby, G, Campbell, H, Caulfield, M, Cavalcanti Proença, C, Cesana, G, Chanock, S, Chasman, D, Chen, Y, Chines, P, Clegg, D, Coin, L, Collins, F, Connell, J, Cookson, W, Cooper, M, Cupples, L, Cusi, D, Day, I, Dedoussis, G, Dei, M, Deloukas, P, Dermitzakis, E, Dimas, A, Dimitriou, M, Dixon, A, Dörr, M, van Duijn, C, Ebrahim, S, Edkins, S, Eiriksdottir, G, Eisinger, K, Eklund, N, Elliott, P, Erbel, R, Erdmann, J, Erdos, M, Eriksson, J, Estrada, K, Evans, D, de Faire, U, Farrall, M, Feitosa, M, Ferrario, M, Ferrières, J, Fischer, K, Fisher, E, Fowkes, G, Fox, C, Franke, L, Franks, P, Fraser, R, Frau, F, Frayling, T, Freimer, N, Froguel, P, Fu, M, Gaget, S, Ganna, A, Gejman, P, Gentilini, D, Geus, E, Gieger, C, Gigante, B, Gjesing, A, Glazer, N, Goddard, M, Goel, A, Grallert, H, Gräßler, J, Grönberg, H, Groop, L, Groves, C, Gudnason, V, Guiducci, C, Gyllensten, U, Hall, A, Hall, P, Hallmans, G, Hamsten, A, Hansen, T, Haritunians, T, Harris, T, van der Harst, P, Hartikainen, A, Hassanali, N, Hattersley, A, Havulinna, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, den Heijer, M, Hengstenberg, C, Herzig, K, Hicks, A, Hingorani, A, Hinney, A, Hirschhorn, J, Hofman, A, Holmes, C, Homuth, G, Hottenga, J, Hovingh, K, Hu, F, Hu, Y, Huffman, J, Hui, J, Huikuri, H, Humphries, S, Hung, J, Hunt, S, Hunter, D, Hveem, K, Hyppönen, E, Igl, W, Illig, T, Ingelsson, E, Iribarren, C, Isomaa, B, Jackson, A, Jacobs, K, James, A, Jansson, J, Jarick, I, Jarvelin, M, Jöckel, K, Johansson, Å, Johnson, T, Jolley, J, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kähönen, M, Kajantie, E, Kanoni, S, Kao, W, Kaplan, L, Kaplan, R, Kaprio, J, Kapur, K, Karpe, F, Kathiresan, S, Kee, F, Keinanen Kiukaanniemi, S, Ketkar, S, Kettunen, J, Khaw, K, Kiemeney, L, Kinnunen, L, Kivimaki, M, Kivmaki, M, Van der Klauw, M, Kleber, M, Knowles, J, Koenig, W, Kolcic, I, Kolovou, G, König, I, Koskinen, S, Kovacs, P, Kraft, P, Kraja, A, Kristiansson, K, Krjutåjkov, K, Kroemer, H, Krohn, J, Krzelj, V, Kuh, D, Kulzer, J, Kumari, M, Kuulasmaa, K, Kuusisto, J, Kvaloy, K, Laakso, M, Laitinen, J, Lakka, T, Lamina, C, Langenberg, C, Lantieri, O, Lathrop, G, Launer, L, Lawlor, D, Lawrence, R, Leach, I, Lecoeur, C, Lee, S, Lehtimäki, T, Leitzmann, M, Lettre, G, Levinson, D, Li, G, Li, S, Liang, L, Lin, D, Lind, L, Lindgren, C, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Loley, C, Lorentzon, M, Luben, R, Ludwig, B, Madden, P, Magnusson, P, Mangino, M, Manunta, P, Marek, D, Marre, M, Martin, N, März, W, Maschio, A, Mathieson, I, Mcardle, W, Mccaroll, S, Mccarthy, A, Mccarthy, M, Mcknight, B, Medina Gomez, C, Medland, S, Meitinger, T, Metspalu, A, van Meurs, J, Meyre, D, Midthjell, K, Mihailov, E, Milani, L, Min, J, Moebus, S, Moffatt, M, Mohlke, K, Molony, C, Monda, K, Montgomery, G, Mooser, V, Morken, M, Morris, A, Mühleisen, T, Müller Nurasyid, M, Munroe, P, Musk, A, Narisu, N, Navis, G, Neale, B, Nelis, M, Nemesh, J, Neville, M, Ngwa, J, Nicholson, G, Nieminen, M, Njølstad, I, Nohr, E, Nolte, I, North, K, Nöthen, M, Nyholt, D, O'Connell, J, Ohlsson, C, Oldehinkel, A, van Ommen, G, Ong, K, Oostra, B, Ouwehand, W, Palmer, C, Palmer, L, Palotie, A, Paré, G, Parker, A, Paternoster, L, Pawitan, Y, Pechlivanis, S, Peden, J, Pedersen, N, Pedersen, O, Pellikka, N, Peltonen, L, Penninx, B, Perola, M, Perry, J, Person, T, Peters, A, Peters, M, Pichler, I, Pietiläinen, K, Platou, C, Polasek, O, Pouta, A, Power, C, Pramstaller, P, Preuss, M, Price, J, Prokopenko, I, Province, M, Psaty, B, Purcell, S, Pütter, C, Qi, L, Quertermous, T, Radhakrishnan, A, Raitakari, O, Rauramaa, R, Rayner, N, Rehnberg, E, Rendon, A, Ridderstråle, M, Ridker, P, Ripatti, S, Rissanen, A, Rivadeneira, F, Rivolta, C, Robertson, N, Rose, L, Rudan, I, Saaristo, T, Sager, H, Salomaa, V, Samani, N, Sambrook, J, Sanders, A, Sandholt, C, Sanna, S, Saramies, J, Schadt, E, Schipf, S, Schlessinger, D, Schreiber, S, Schunkert, H, Schwarz, P, Scott, L, Shi, J, Shin, S, Shuldiner, A, Shungin, D, Signorini, S, Silander, K, Sinisalo, J, Skrobek, B, Smit, J, Smith, A, Smith, G, Snieder, H, Soranzo, N, Sørensen, T, Sovio, U, Spector, T, Speliotes, E, Stančáková, A, Stark, K, Stefansson, K, Steinthorsdottir, V, Stephens, J, Stirrups, K, Stolk, R, Strachan, D, Strawbridge, R, Stringham, H, Stumvoll, M, Surakka, I, Swift, A, Syvanen, A, Tammesoo, M, Teder Laving, M, Teslovich, T, Teumer, A, Theodoraki, E, Thomson, B, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Timpson, N, Tönjes, A, Tregouet, D, Tremoli, E, Trip, M, Tuomi, T, Tuomilehto, J, Tyrer, J, Uda, M, Uitterlinden, A, Usala, G, Uusitupa, M, Valle, T, Vandenput, L, Vatin, V, de Vegt, F, Vermeulen, S, Viikari, J, Virtamo, J, Visscher, P, Vitart, V, Van Vliet Ostaptchouk, J, Voight, B, Vollenweider, P, Volpato, C, Völzke, H, Waeber, G, Waite, L, Wallaschofski, H, Walters, G, Wang, Z, Wareham, N, Watanabe, R, Watkins, H, Weedon, M, Welch, R, Weyant, R, Wheeler, E, White, C, Wichmann, H, Widen, E, Wild, S, Willemsen, G, Willer, C, Wilsgaard, T, Wilson, J, van Wingerden, S, Winkelmann, B, Witte, D, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Yang, J, Yarnell, J, Zgaga, L, Zhao, J, Zillikens, M, Zitting, P, Zondervan, K, Abecasis GR, Absher D, Alavere H, Albrecht E, Allen HL, Almgren P, Amin N, Amouyel P, Anderson D, Arnold AM, Arveiler D, Aspelund T, Asselbergs FW, Assimes TL, Atalay M, Attwood AP, Atwood LD, Bakker SJ, Balkau B, Balmforth AJ, Barlassina C, Barroso I, Basart H, Bauer S, Beckmann JS, Beilby JP, Bennett AJ, Ben Shlomo Y, Bergman RN, Bergmann S, Berndt SI, Biffar R, Di Blasio AM, Boehm BO, Boehnke M, Boeing H, Boerwinkle E, Bolton JL, Bonnefond A, Bonnycastle LL, Boomsma DI, Borecki IB, Bornstein SR, Bouatia Naji N, Boucher G, Bragg Gresham JL, BRAMBILLA, PAOLO, Bruinenberg M, Buchanan TA, Buechler C, Cadby G, Campbell H, Caulfield MJ, Cavalcanti Proença C, CESANA, GIANCARLO, Chanock SJ, Chasman DI, Chen YD, Chines PS, Clegg DJ, Coin L, Collins FS, Connell JM, Cookson W, Cooper MN, Croteau Chonka DC, Cupples LA, Cusi D, Day FR, Day IN, Dedoussis GV, Dei M, Deloukas P, Dermitzakis ET, Dimas AS, Dimitriou M, Dixon AL, Dörr M, van Duijn CM, Ebrahim S, Edkins S, Eiriksdottir G, Eisinger K, Eklund N, Elliott P, Erbel R, Erdmann J, Erdos MR, Eriksson JG, Esko T, Estrada K, Evans DM, de Faire U, Fall T, Farrall M, Feitosa MF, Ferrario MM, Ferreira T, Ferrières J, Fischer K, Fisher E, Fowkes G, Fox CS, Franke L, Franks PW, Fraser RM, Frau F, Frayling T, Freimer NB, Froguel P, Fu M, Gaget S, Ganna A, Gejman PV, Gentilini D, Geus EJ, Gieger C, Gigante B, Gjesing AP, Glazer NL, Goddard ME, Goel A, Grallert H, Gräßler J, Grönberg H, Groop LC, Groves CJ, Gudnason V, Guiducci C, Gustafsson S, Gyllensten U, Hall AS, Hall P, Hallmans G, Hamsten A, Hansen T, Haritunians T, Harris TB, van der Harst P, Hartikainen AL, Hassanali N, Hattersley AT, Havulinna AS, Hayward C, Heard Costa NL, Heath AC, Hebebrand J, Heid IM, den Heijer M, Hengstenberg C, Herzig KH, Hicks AA, Hingorani A, Hinney A, Hirschhorn JN, Hofman A, Holmes CC, Homuth G, Hottenga JJ, Hovingh KG, Hu FB, Hu YJ, Huffman JE, Hui J, Huikuri H, Humphries SE, Hung J, Hunt SE, Hunter D, Hveem K, Hyppönen E, Igl W, Illig T, Ingelsson E, Iribarren C, Isomaa B, Jackson AU, Jacobs KB, James AL, Jansson JO, Jarick I, Jarvelin MR, Jöckel KH, Johansson Å, Johnson T, Jolley J, Jørgensen T, Jousilahti P, Jula A, Justice AE, Kaakinen M, Kähönen M, Kajantie E, Kanoni S, Kao WH, Kaplan LM, Kaplan RC, Kaprio J, Kapur K, Karpe F, Kathiresan S, Kee F, Keinanen Kiukaanniemi SM, Ketkar S, Kettunen J, Khaw KT, Kiemeney LA, Kilpeläinen TO, Kinnunen L, Kivimaki M, Kivmaki M, Van der Klauw MM, Kleber ME, Knowles JW, Koenig W, Kolcic I, Kolovou G, König IR, Koskinen S, Kovacs P, Kraft P, Kraja AT, Kristiansson K, KrjutÅjkov K, Kroemer HK, Krohn JP, Krzelj V, Kuh D, Kulzer JR, Kumari M, Kutalik Z, Kuulasmaa K, Kuusisto J, Kvaloy K, Laakso M, Laitinen JH, Lakka TA, Lamina C, Langenberg C, Lantieri O, Lathrop GM, Launer LJ, Lawlor DA, Lawrence RW, Leach IM, Lecoeur C, Lee SH, Lehtimäki T, Leitzmann MF, Lettre G, Levinson DF, Li G, Li S, Liang L, Lin DY, Lind L, Lindgren CM, Lindström J, Liu J, Liuzzi A, Locke AE, Lokki ML, Loley C, Loos RJ, Lorentzon M, Luan J, Luben RN, Ludwig B, Madden PA, Mägi R, Magnusson PK, Mangino M, Manunta P, Marek D, Marre M, Martin NG, März W, Maschio A, Mathieson I, McArdle WL, McCaroll SA, McCarthy A, McCarthy MI, McKnight B, Medina Gomez C, Medland SE, Meitinger T, Metspalu A, van Meurs JB, Meyre D, Midthjell K, Mihailov E, Milani L, Min JL, Moebus S, Moffatt MF, Mohlke KL, Molony C, Monda KL, Montgomery GW, Mooser V, Morken MA, Morris AD, Morris AP, Mühleisen TW, Müller Nurasyid M, Munroe PB, Musk AW, Narisu N, Navis G, Neale BM, Nelis M, Nemesh J, Neville MJ, Ngwa JS, Nicholson G, Nieminen MS, Njølstad I, Nohr EA, Nolte IM, North KE, Nöthen MM, Nyholt DR, O'Connell JR, Ohlsson C, Oldehinkel AJ, van Ommen GJ, Ong KK, Oostra BA, Ouwehand WH, Palmer CN, Palmer LJ, Palotie A, Paré G, Parker AN, Paternoster L, Pawitan Y, Pechlivanis S, Peden JF, Pedersen NL, Pedersen O, Pellikka N, Peltonen L, Penninx B, Perola M, Perry JR, Person T, Peters A, Peters MJ, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Power C, Pramstaller PP, Preuss M, Price JF, Prokopenko I, Province MA, Psaty BM, Purcell S, Pütter C, Qi L, Quertermous T, Radhakrishnan A, Raitakari O, Randall JC, Rauramaa R, Rayner NW, Rehnberg E, Rendon A, Ridderstråle M, Ridker PM, Ripatti S, Rissanen A, Rivadeneira F, Rivolta C, Robertson NR, Rose LM, Rudan I, Saaristo TE, Sager H, Salomaa V, Samani NJ, Sambrook JG, Sanders AR, Sandholt C, Sanna S, Saramies J, Schadt EE, Scherag A, Schipf S, Schlessinger D, Schreiber S, Schunkert H, Schwarz PE, Scott LJ, Shi J, Shin SY, Shuldiner AR, Shungin D, Signorini S, Silander K, Sinisalo J, Skrobek B, Smit JH, Smith AV, Smith GD, Snieder H, Soranzo N, Sørensen TI, Sovio U, Spector TD, Speliotes EK, Stančáková A, Stark K, Stefansson K, Steinthorsdottir V, Stephens JC, Stirrups K, Stolk RP, Strachan DP, Strawbridge RJ, Stringham HM, Stumvoll M, Surakka I, Swift AJ, Syvanen AC, Tammesoo ML, Teder Laving M, Teslovich TM, Teumer A, Theodoraki EV, Thomson B, Thorand B, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tönjes A, Tregouet DA, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Tyrer J, Uda M, Uitterlinden AG, Usala G, Uusitupa M, Valle TT, Vandenput L, Vatin V, Vedantam S, de Vegt F, Vermeulen SH, Viikari J, Virtamo J, Visscher PM, Vitart V, Van Vliet Ostaptchouk JV, Voight BF, Vollenweider P, Volpato CB, Völzke H, Waeber G, Waite LL, Wallaschofski H, Walters GB, Wang Z, Wareham NJ, Watanabe RM, Watkins H, Weedon MN, Welch R, Weyant RJ, Wheeler E, White CC, Wichmann HE, Widen E, Wild SH, Willemsen G, Willer CJ, Wilsgaard T, Wilson JF, van Wingerden S, Winkelmann BR, Winkler TW, Witte DR, Witteman JC, Wolffenbuttel BH, Wong A, Wood AR, Workalemahu T, Wright AF, Yang J, Yarnell JW, Zgaga L, Zhao JH, Zillikens MC, Zitting P, Zondervan KT, Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis, G, Absher, D, Alavere, H, Albrecht, E, Allen, H, Almgren, P, Amin, N, Amouyel, P, Anderson, D, Arnold, A, Arveiler, D, Aspelund, T, Asselbergs, F, Assimes, T, Atalay, M, Attwood, A, Atwood, L, Bakker, S, Balkau, B, Balmforth, A, Barlassina, C, Barroso, I, Basart, H, Bauer, S, Beckmann, J, Beilby, J, Bennett, A, Ben Shlomo, Y, Bergman, R, Bergmann, S, Berndt, S, Biffar, R, Di Blasio, A, Boehm, B, Boehnke, M, Boeing, H, Boerwinkle, E, Bolton, J, Bonnefond, A, Bonnycastle, L, Boomsma, D, Borecki, I, Bornstein, S, Bouatia Naji, N, Boucher, G, Bragg Gresham, J, Brambilla, P, Bruinenberg, M, Buchanan, T, Buechler, C, Cadby, G, Campbell, H, Caulfield, M, Cavalcanti Proença, C, Cesana, G, Chanock, S, Chasman, D, Chen, Y, Chines, P, Clegg, D, Coin, L, Collins, F, Connell, J, Cookson, W, Cooper, M, Cupples, L, Cusi, D, Day, I, Dedoussis, G, Dei, M, Deloukas, P, Dermitzakis, E, Dimas, A, Dimitriou, M, Dixon, A, Dörr, M, van Duijn, C, Ebrahim, S, Edkins, S, Eiriksdottir, G, Eisinger, K, Eklund, N, Elliott, P, Erbel, R, Erdmann, J, Erdos, M, Eriksson, J, Estrada, K, Evans, D, de Faire, U, Farrall, M, Feitosa, M, Ferrario, M, Ferrières, J, Fischer, K, Fisher, E, Fowkes, G, Fox, C, Franke, L, Franks, P, Fraser, R, Frau, F, Frayling, T, Freimer, N, Froguel, P, Fu, M, Gaget, S, Ganna, A, Gejman, P, Gentilini, D, Geus, E, Gieger, C, Gigante, B, Gjesing, A, Glazer, N, Goddard, M, Goel, A, Grallert, H, Gräßler, J, Grönberg, H, Groop, L, Groves, C, Gudnason, V, Guiducci, C, Gyllensten, U, Hall, A, Hall, P, Hallmans, G, Hamsten, A, Hansen, T, Haritunians, T, Harris, T, van der Harst, P, Hartikainen, A, Hassanali, N, Hattersley, A, Havulinna, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, den Heijer, M, Hengstenberg, C, Herzig, K, Hicks, A, Hingorani, A, Hinney, A, Hirschhorn, J, Hofman, A, Holmes, C, Homuth, G, Hottenga, J, Hovingh, K, Hu, F, Hu, Y, Huffman, J, Hui, J, Huikuri, H, Humphries, S, Hung, J, Hunt, S, Hunter, D, Hveem, K, Hyppönen, E, Igl, W, Illig, T, Ingelsson, E, Iribarren, C, Isomaa, B, Jackson, A, Jacobs, K, James, A, Jansson, J, Jarick, I, Jarvelin, M, Jöckel, K, Johansson, Å, Johnson, T, Jolley, J, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kähönen, M, Kajantie, E, Kanoni, S, Kao, W, Kaplan, L, Kaplan, R, Kaprio, J, Kapur, K, Karpe, F, Kathiresan, S, Kee, F, Keinanen Kiukaanniemi, S, Ketkar, S, Kettunen, J, Khaw, K, Kiemeney, L, Kinnunen, L, Kivimaki, M, Kivmaki, M, Van der Klauw, M, Kleber, M, Knowles, J, Koenig, W, Kolcic, I, Kolovou, G, König, I, Koskinen, S, Kovacs, P, Kraft, P, Kraja, A, Kristiansson, K, Krjutåjkov, K, Kroemer, H, Krohn, J, Krzelj, V, Kuh, D, Kulzer, J, Kumari, M, Kuulasmaa, K, Kuusisto, J, Kvaloy, K, Laakso, M, Laitinen, J, Lakka, T, Lamina, C, Langenberg, C, Lantieri, O, Lathrop, G, Launer, L, Lawlor, D, Lawrence, R, Leach, I, Lecoeur, C, Lee, S, Lehtimäki, T, Leitzmann, M, Lettre, G, Levinson, D, Li, G, Li, S, Liang, L, Lin, D, Lind, L, Lindgren, C, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Loley, C, Lorentzon, M, Luben, R, Ludwig, B, Madden, P, Magnusson, P, Mangino, M, Manunta, P, Marek, D, Marre, M, Martin, N, März, W, Maschio, A, Mathieson, I, Mcardle, W, Mccaroll, S, Mccarthy, A, Mccarthy, M, Mcknight, B, Medina Gomez, C, Medland, S, Meitinger, T, Metspalu, A, van Meurs, J, Meyre, D, Midthjell, K, Mihailov, E, Milani, L, Min, J, Moebus, S, Moffatt, M, Mohlke, K, Molony, C, Monda, K, Montgomery, G, Mooser, V, Morken, M, Morris, A, Mühleisen, T, Müller Nurasyid, M, Munroe, P, Musk, A, Narisu, N, Navis, G, Neale, B, Nelis, M, Nemesh, J, Neville, M, Ngwa, J, Nicholson, G, Nieminen, M, Njølstad, I, Nohr, E, Nolte, I, North, K, Nöthen, M, Nyholt, D, O'Connell, J, Ohlsson, C, Oldehinkel, A, van Ommen, G, Ong, K, Oostra, B, Ouwehand, W, Palmer, C, Palmer, L, Palotie, A, Paré, G, Parker, A, Paternoster, L, Pawitan, Y, Pechlivanis, S, Peden, J, Pedersen, N, Pedersen, O, Pellikka, N, Peltonen, L, Penninx, B, Perola, M, Perry, J, Person, T, Peters, A, Peters, M, Pichler, I, Pietiläinen, K, Platou, C, Polasek, O, Pouta, A, Power, C, Pramstaller, P, Preuss, M, Price, J, Prokopenko, I, Province, M, Psaty, B, Purcell, S, Pütter, C, Qi, L, Quertermous, T, Radhakrishnan, A, Raitakari, O, Rauramaa, R, Rayner, N, Rehnberg, E, Rendon, A, Ridderstråle, M, Ridker, P, Ripatti, S, Rissanen, A, Rivadeneira, F, Rivolta, C, Robertson, N, Rose, L, Rudan, I, Saaristo, T, Sager, H, Salomaa, V, Samani, N, Sambrook, J, Sanders, A, Sandholt, C, Sanna, S, Saramies, J, Schadt, E, Schipf, S, Schlessinger, D, Schreiber, S, Schunkert, H, Schwarz, P, Scott, L, Shi, J, Shin, S, Shuldiner, A, Shungin, D, Signorini, S, Silander, K, Sinisalo, J, Skrobek, B, Smit, J, Smith, A, Smith, G, Snieder, H, Soranzo, N, Sørensen, T, Sovio, U, Spector, T, Speliotes, E, Stančáková, A, Stark, K, Stefansson, K, Steinthorsdottir, V, Stephens, J, Stirrups, K, Stolk, R, Strachan, D, Strawbridge, R, Stringham, H, Stumvoll, M, Surakka, I, Swift, A, Syvanen, A, Tammesoo, M, Teder Laving, M, Teslovich, T, Teumer, A, Theodoraki, E, Thomson, B, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Timpson, N, Tönjes, A, Tregouet, D, Tremoli, E, Trip, M, Tuomi, T, Tuomilehto, J, Tyrer, J, Uda, M, Uitterlinden, A, Usala, G, Uusitupa, M, Valle, T, Vandenput, L, Vatin, V, de Vegt, F, Vermeulen, S, Viikari, J, Virtamo, J, Visscher, P, Vitart, V, Van Vliet Ostaptchouk, J, Voight, B, Vollenweider, P, Volpato, C, Völzke, H, Waeber, G, Waite, L, Wallaschofski, H, Walters, G, Wang, Z, Wareham, N, Watanabe, R, Watkins, H, Weedon, M, Welch, R, Weyant, R, Wheeler, E, White, C, Wichmann, H, Widen, E, Wild, S, Willemsen, G, Willer, C, Wilsgaard, T, Wilson, J, van Wingerden, S, Winkelmann, B, Witte, D, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Yang, J, Yarnell, J, Zgaga, L, Zhao, J, Zillikens, M, Zitting, P, Zondervan, K, Abecasis GR, Absher D, Alavere H, Albrecht E, Allen HL, Almgren P, Amin N, Amouyel P, Anderson D, Arnold AM, Arveiler D, Aspelund T, Asselbergs FW, Assimes TL, Atalay M, Attwood AP, Atwood LD, Bakker SJ, Balkau B, Balmforth AJ, Barlassina C, Barroso I, Basart H, Bauer S, Beckmann JS, Beilby JP, Bennett AJ, Ben Shlomo Y, Bergman RN, Bergmann S, Berndt SI, Biffar R, Di Blasio AM, Boehm BO, Boehnke M, Boeing H, Boerwinkle E, Bolton JL, Bonnefond A, Bonnycastle LL, Boomsma DI, Borecki IB, Bornstein SR, Bouatia Naji N, Boucher G, Bragg Gresham JL, BRAMBILLA, PAOLO, Bruinenberg M, Buchanan TA, Buechler C, Cadby G, Campbell H, Caulfield MJ, Cavalcanti Proença C, CESANA, GIANCARLO, Chanock SJ, Chasman DI, Chen YD, Chines PS, Clegg DJ, Coin L, Collins FS, Connell JM, Cookson W, Cooper MN, Croteau Chonka DC, Cupples LA, Cusi D, Day FR, Day IN, Dedoussis GV, Dei M, Deloukas P, Dermitzakis ET, Dimas AS, Dimitriou M, Dixon AL, Dörr M, van Duijn CM, Ebrahim S, Edkins S, Eiriksdottir G, Eisinger K, Eklund N, Elliott P, Erbel R, Erdmann J, Erdos MR, Eriksson JG, Esko T, Estrada K, Evans DM, de Faire U, Fall T, Farrall M, Feitosa MF, Ferrario MM, Ferreira T, Ferrières J, Fischer K, Fisher E, Fowkes G, Fox CS, Franke L, Franks PW, Fraser RM, Frau F, Frayling T, Freimer NB, Froguel P, Fu M, Gaget S, Ganna A, Gejman PV, Gentilini D, Geus EJ, Gieger C, Gigante B, Gjesing AP, Glazer NL, Goddard ME, Goel A, Grallert H, Gräßler J, Grönberg H, Groop LC, Groves CJ, Gudnason V, Guiducci C, Gustafsson S, Gyllensten U, Hall AS, Hall P, Hallmans G, Hamsten A, Hansen T, Haritunians T, Harris TB, van der Harst P, Hartikainen AL, Hassanali N, Hattersley AT, Havulinna AS, Hayward C, Heard Costa NL, Heath AC, Hebebrand J, Heid IM, den Heijer M, Hengstenberg C, Herzig KH, Hicks AA, Hingorani A, Hinney A, Hirschhorn JN, Hofman A, Holmes CC, Homuth G, Hottenga JJ, Hovingh KG, Hu FB, Hu YJ, Huffman JE, Hui J, Huikuri H, Humphries SE, Hung J, Hunt SE, Hunter D, Hveem K, Hyppönen E, Igl W, Illig T, Ingelsson E, Iribarren C, Isomaa B, Jackson AU, Jacobs KB, James AL, Jansson JO, Jarick I, Jarvelin MR, Jöckel KH, Johansson Å, Johnson T, Jolley J, Jørgensen T, Jousilahti P, Jula A, Justice AE, Kaakinen M, Kähönen M, Kajantie E, Kanoni S, Kao WH, Kaplan LM, Kaplan RC, Kaprio J, Kapur K, Karpe F, Kathiresan S, Kee F, Keinanen Kiukaanniemi SM, Ketkar S, Kettunen J, Khaw KT, Kiemeney LA, Kilpeläinen TO, Kinnunen L, Kivimaki M, Kivmaki M, Van der Klauw MM, Kleber ME, Knowles JW, Koenig W, Kolcic I, Kolovou G, König IR, Koskinen S, Kovacs P, Kraft P, Kraja AT, Kristiansson K, KrjutÅjkov K, Kroemer HK, Krohn JP, Krzelj V, Kuh D, Kulzer JR, Kumari M, Kutalik Z, Kuulasmaa K, Kuusisto J, Kvaloy K, Laakso M, Laitinen JH, Lakka TA, Lamina C, Langenberg C, Lantieri O, Lathrop GM, Launer LJ, Lawlor DA, Lawrence RW, Leach IM, Lecoeur C, Lee SH, Lehtimäki T, Leitzmann MF, Lettre G, Levinson DF, Li G, Li S, Liang L, Lin DY, Lind L, Lindgren CM, Lindström J, Liu J, Liuzzi A, Locke AE, Lokki ML, Loley C, Loos RJ, Lorentzon M, Luan J, Luben RN, Ludwig B, Madden PA, Mägi R, Magnusson PK, Mangino M, Manunta P, Marek D, Marre M, Martin NG, März W, Maschio A, Mathieson I, McArdle WL, McCaroll SA, McCarthy A, McCarthy MI, McKnight B, Medina Gomez C, Medland SE, Meitinger T, Metspalu A, van Meurs JB, Meyre D, Midthjell K, Mihailov E, Milani L, Min JL, Moebus S, Moffatt MF, Mohlke KL, Molony C, Monda KL, Montgomery GW, Mooser V, Morken MA, Morris AD, Morris AP, Mühleisen TW, Müller Nurasyid M, Munroe PB, Musk AW, Narisu N, Navis G, Neale BM, Nelis M, Nemesh J, Neville MJ, Ngwa JS, Nicholson G, Nieminen MS, Njølstad I, Nohr EA, Nolte IM, North KE, Nöthen MM, Nyholt DR, O'Connell JR, Ohlsson C, Oldehinkel AJ, van Ommen GJ, Ong KK, Oostra BA, Ouwehand WH, Palmer CN, Palmer LJ, Palotie A, Paré G, Parker AN, Paternoster L, Pawitan Y, Pechlivanis S, Peden JF, Pedersen NL, Pedersen O, Pellikka N, Peltonen L, Penninx B, Perola M, Perry JR, Person T, Peters A, Peters MJ, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Power C, Pramstaller PP, Preuss M, Price JF, Prokopenko I, Province MA, Psaty BM, Purcell S, Pütter C, Qi L, Quertermous T, Radhakrishnan A, Raitakari O, Randall JC, Rauramaa R, Rayner NW, Rehnberg E, Rendon A, Ridderstråle M, Ridker PM, Ripatti S, Rissanen A, Rivadeneira F, Rivolta C, Robertson NR, Rose LM, Rudan I, Saaristo TE, Sager H, Salomaa V, Samani NJ, Sambrook JG, Sanders AR, Sandholt C, Sanna S, Saramies J, Schadt EE, Scherag A, Schipf S, Schlessinger D, Schreiber S, Schunkert H, Schwarz PE, Scott LJ, Shi J, Shin SY, Shuldiner AR, Shungin D, Signorini S, Silander K, Sinisalo J, Skrobek B, Smit JH, Smith AV, Smith GD, Snieder H, Soranzo N, Sørensen TI, Sovio U, Spector TD, Speliotes EK, Stančáková A, Stark K, Stefansson K, Steinthorsdottir V, Stephens JC, Stirrups K, Stolk RP, Strachan DP, Strawbridge RJ, Stringham HM, Stumvoll M, Surakka I, Swift AJ, Syvanen AC, Tammesoo ML, Teder Laving M, Teslovich TM, Teumer A, Theodoraki EV, Thomson B, Thorand B, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tönjes A, Tregouet DA, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Tyrer J, Uda M, Uitterlinden AG, Usala G, Uusitupa M, Valle TT, Vandenput L, Vatin V, Vedantam S, de Vegt F, Vermeulen SH, Viikari J, Virtamo J, Visscher PM, Vitart V, Van Vliet Ostaptchouk JV, Voight BF, Vollenweider P, Volpato CB, Völzke H, Waeber G, Waite LL, Wallaschofski H, Walters GB, Wang Z, Wareham NJ, Watanabe RM, Watkins H, Weedon MN, Welch R, Weyant RJ, Wheeler E, White CC, Wichmann HE, Widen E, Wild SH, Willemsen G, Willer CJ, Wilsgaard T, Wilson JF, van Wingerden S, Winkelmann BR, Winkler TW, Witte DR, Witteman JC, Wolffenbuttel BH, Wong A, Wood AR, Workalemahu T, Wright AF, Yang J, Yarnell JW, Zgaga L, Zhao JH, Zillikens MC, Zitting P, and Zondervan KT

Abstract

Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

Published
2014

162. Small noncoding differentially methylated copy-number variants, including IncRNA genes, cause a lethal lung developmental disorder

Author

Szafranski, P. (Przemyslaw), Dharmadhikari, A.V. (Avinash), Brosens, E. (Erwin), Gurha, P. (Priyatansh), Kołodziejska, K.E. (Katarzyna), Zhishuo, O. (Ou), Dittwald, P. (Piotr), Majewski, J. (Jacek), Mohan, K.N. (K. Naga), Chen, B.P.C. (Benjamin), Person, A.D. (Anthony), Tibboel, D. (Dick), Klein, J.E.M.M. (Annelies) de, Pinner, J. (Jason), Chopra PhD, M. (Mickey), Malcolm, G. (Girvan), Peters, G., Arbuckle, S. (Susan), Guiang III, S.F. (Sixto), Hustead, V.A. (Virginia), Jessurun, J. (Jose), Hirsch, R. (Russel), Witte, D. (David), Maystadt, I. (Isabelle), Sebire, N. (Neil), Fisher, R. (Rachel), Langston, C. (Claire), Sen, P. (Partha), Stankiewicz, P. (Paweł), Szafranski, P. (Przemyslaw), Dharmadhikari, A.V. (Avinash), Brosens, E. (Erwin), Gurha, P. (Priyatansh), Kołodziejska, K.E. (Katarzyna), Zhishuo, O. (Ou), Dittwald, P. (Piotr), Majewski, J. (Jacek), Mohan, K.N. (K. Naga), Chen, B.P.C. (Benjamin), Person, A.D. (Anthony), Tibboel, D. (Dick), Klein, J.E.M.M. (Annelies) de, Pinner, J. (Jason), Chopra PhD, M. (Mickey), Malcolm, G. (Girvan), Peters, G., Arbuckle, S. (Susan), Guiang III, S.F. (Sixto), Hustead, V.A. (Virginia), Jessurun, J. (Jose), Hirsch, R. (Russel), Witte, D. (David), Maystadt, I. (Isabelle), Sebire, N. (Neil), Fisher, R. (Rachel), Langston, C. (Claire), Sen, P. (Partha), and Stankiewicz, P. (Paweł)

Abstract

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (IncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including IncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific IncRNAgenes. These deletions define a distant cis-regulatory region that harbors, besides lncRNAgenes, also a differentially methylated CpGisland, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. Wesuggest that lung-transcribed 16q24.1 IncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of IncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Published
2013
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163. The Extended Enterprise Coherence-Governance Assessment

Author

Aier, S., Ekstedt, M., Matthes, F., Proper, E., Sanz, J., Wagter, R., Proper, H.A., Witte, D., Aier, S., Ekstedt, M., Matthes, F., Proper, E., Sanz, J., Wagter, R., Proper, H.A., and Witte, D.

Abstract

Item does not contain fulltext

Published
2012

164. A Practice-Based Framework for Enterprise Coherence

Author

Proper, E., Wagter, R., Proper, H.A., Witte, D., Proper, E., Wagter, R., Proper, H.A., and Witte, D.

Abstract

Contains fulltext : 103233.pdf (publisher's version ) (Closed access)

Published
2012

167. The role of anthropometric and other predictors for diabetes among urban Tanzanians with tuberculosis

Author

Faurholt-Jepsen, Daniel, Range, N, PrayGod, G, Jeremiah, K, Faurholt-Jepsen, Maria, Aabye, M G, Changalucha, J, Christensen, Dirk Lund, Witte, D R, Andersen, A B, Friis, Henrik, Faurholt-Jepsen, Daniel, Range, N, PrayGod, G, Jeremiah, K, Faurholt-Jepsen, Maria, Aabye, M G, Changalucha, J, Christensen, Dirk Lund, Witte, D R, Andersen, A B, and Friis, Henrik

Abstract

As diabetes impairs tuberculosis (TB) treatment outcomes, it is essential to identify diabetes among TB patients. While little is known about predictors of diabetes among healthy individuals in Africa, predictors among TB patients are almost non-existent.

Published
2012

168. The frequent UCP2 -866G>A polymorphism protects against insulin resistance and is associated with obesity:a study of obesity and related metabolic traits among 17¿636 Danes

Author

Andersen, G, Dalgaard, L T, Justesen, J M, Anthonsen, S, Nielsen, T, Thørner, L W, Witte, D, Jørgensen, T, Clausen, J O, Lauritzen, Torsten, Holmkvist, J, Hansen, T, Pedersen, O, Andersen, G, Dalgaard, L T, Justesen, J M, Anthonsen, S, Nielsen, T, Thørner, L W, Witte, D, Jørgensen, T, Clausen, J O, Lauritzen, Torsten, Holmkvist, J, Hansen, T, and Pedersen, O

Abstract

CONTEXT:Uncoupling protein 2 (UCP2) is involved in regulating ATP synthesis, generation of reactive oxygen species and glucose-stimulated insulin secretion in ß-cells. Polymorphisms in UCP2 may be associated with obesity and type 2 diabetes mellitus.OBJECTIVE:To determine the influence of a functional UCP2 promoter polymorphism (-866G>A, rs659366) on obesity, type 2 diabetes and intermediary metabolic traits. Furthermore, to include these and previously published data in a meta-analysis of this variant with respect to its impact on obesity and type 2 diabetes.DESIGN:We genotyped UCP2 rs659366 in a total of 17¿636 Danish individuals and established case-control studies of obese and non-obese subjects and of type 2 diabetic and glucose-tolerant subjects. Meta-analyses were made in own data set and in publicly available data sets. Quantitative traits relevant for obesity and type 2 diabetes were analysed within separate study populations.RESULTS:We found no consistent associations between the UCP2 -866G-allele and obesity or type 2 diabetes. Yet, a meta-analysis of data from 12¿984 subjects showed an association with obesity (GA vs GG odds ratio (OR) (95% confidence interval (CI)): 0.894(0.826-0.968) P=0.00562, and AA vs GG OR(95% CI): 0.892(0.800-0.996), P=0.0415. Moreover, a meta-analysis for type 2 diabetes of 15¿107 individuals showed no association. The -866G-allele was associated with elevated fasting serum insulin levels (P=0.002) and HOMA insulin resistance index (P=0.0007). Insulin sensitivity measured during intravenous glucose tolerance test in young Caucasian subjects (n=377) was decreased in carriers of the GG genotype (P=0.05).CONCLUSIONS:The UCP2 -866G-allele is associated with decreased insulin sensitivity in Danish subjects and is associated with obesity in a combined meta-analysis.International Journal of Obesity advance online publication, 21 February 2012; doi:10.1038/ijo.2012.22.

Published
2012

169. Enterprise Coherence Assessment

Author

Harmsen, F., Grahlmann, K., Proper, E., Wagter, R., Proper, H.A., Witte, D., Harmsen, F., Grahlmann, K., Proper, E., Wagter, R., Proper, H.A., and Witte, D.

Abstract

Contains fulltext : 91772.pdf (publisher's version ) (Closed access)

Published
2011

170. Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals

Author

Burgdorf, K S, Gjesing, A P, Grarup, N, Justesen, J M, Sandholt, C H, Witte, D R, Jørgensen, T, Madsbad, S, Hansen, T, Pedersen, O, Burgdorf, K S, Gjesing, A P, Grarup, N, Justesen, J M, Sandholt, C H, Witte, D R, Jørgensen, T, Madsbad, S, Hansen, T, and Pedersen, O

Abstract

AIMS/HYPOTHESIS: Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting. METHODS: By applying an additive genetic model, 14 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n¿=¿6,039). RESULTS: Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p¿=¿4.0¿×¿10(-7)) and increased disposition index of 5.6% (p¿=¿6.4¿×¿10(-5)). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p¿=¿0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p¿=¿0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p¿=¿0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p¿=¿0.00036) and 4.0% decrease in Matsuda index (p¿=¿2¿×¿10(-4)). CONCLUSIONS: Our correlative findings from analysing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.

Published
2011

171. Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

Author

Torekov, S S, Ma, L, Grarup, N, Hartmann, B, Hainerová, I A, Kielgast, U, Kissow, H, Rosenkilde, M, Lebl, J, Witte, D R, Jørgensen, T, Sandbaek, A, Lauritzen, T, Madsen, O D, Wang, J, Linneberg, A, Madsbad, S, Holst, J J, Hansen, T, Pedersen, O, Torekov, S S, Ma, L, Grarup, N, Hartmann, B, Hainerová, I A, Kielgast, U, Kissow, H, Rosenkilde, M, Lebl, J, Witte, D R, Jørgensen, T, Sandbaek, A, Lauritzen, T, Madsen, O D, Wang, J, Linneberg, A, Madsbad, S, Holst, J J, Hansen, T, and Pedersen, O

Abstract

The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.

Published
2011

172. The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals

Author

Grarup, N, Overvad, M, Sparsø, T, Witte, D R, Pisinger, C, Jørgensen, Torben, Yamauchi, T, Hara, K, Maeda, S, Kadowaki, T, Hansen, T, Pedersen, Oluf, Grarup, N, Overvad, M, Sparsø, T, Witte, D R, Pisinger, C, Jørgensen, Torben, Yamauchi, T, Hara, K, Maeda, S, Kadowaki, T, Hansen, T, and Pedersen, Oluf

Abstract

A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits.

Published
2011

173. Comparing risk profiles of individuals diagnosed with diabetes by OGTT and HbA1c The Danish Inter99 study

Author

Borg, R, Vistisen, D, Witte, D R, Borch-Johnsen, K, Borg, R, Vistisen, D, Witte, D R, and Borch-Johnsen, K

Abstract

AIMS: Glycated haemoglobin (HbA(1c)) has been proposed as an alternative to the oral glucose tolerance test for diagnosing diabetes. We compared the cardiovascular risk profile of individuals identified by these two alternative methods.METHODS: We assessed the prevalence of cardiovascular risk factors in individuals with undiagnosed diabetes according to the World Health Organization classification or by the newly proposed HbA(1c) level >or= 6.5% among 6258 participants of the Danish Inter99 study. Receiver operating curve analysis assessed the ability of fasting: 2-h plasma glucose and HbA(1c) to distinguish between individuals at high and low risk of ischemic heart disease, predicted by the PRECARD program.RESULTS: Prevalence of undiagnosed diabetes was 4.1% [95% confidence interval (CI) 3.7-4.7%] by the current oral glucose tolerance test definition, whereas 6.6% (95% CI 6.0-7.2%) had diabetes by HbA(1c) levels. HbA(1c)-defined individuals were relatively older with higher proportions of men, smokers, lipid abnormalities and macro-albuminuria, but they were leaner and had lower blood pressure. HbA(1c) was better than fasting- and 2-h plasma glucose at distinguishing between individuals of high and low predicted risk of ischaemic heart disease; however, the difference between HbA(1c) and fasting- and 2-h plasma glucose was not statistically significant.CONCLUSIONS: Compared with the current oral glucose tolerance test definition, more individuals were classified as having diabetes based on the HbA(1c) criteria. This group had as unfavourable a risk profile as those identified by the oral glucose tolerance test.

Published
2010

174. Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

Author

Andersson, E A, Pilgaard, K, Pisinger, C, Harder, M N, Grarup, N, Faerch, K, Poulsen, P, Witte, D R, Jørgensen, Torben, Vaag, A, Hansen, T, Pedersen, Oluf, Andersson, E A, Pilgaard, K, Pisinger, C, Harder, M N, Grarup, N, Faerch, K, Poulsen, P, Witte, D R, Jørgensen, Torben, Vaag, A, Hansen, T, and Pedersen, Oluf

Abstract

The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.

Published
2010

175. Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes

Author

Pilgaard, K, Færch, K, Carstensen, B, Poulsen, P, Pisinger, C, Pedersen, Oluf, Witte, D R, Hansen, T, Jørgensen, Torben, Vaag, A, Pilgaard, K, Færch, K, Carstensen, B, Poulsen, P, Pisinger, C, Pedersen, Oluf, Witte, D R, Hansen, T, Jørgensen, Torben, and Vaag, A

Abstract

We studied the associations of size at birth and prematurity with type 2 diabetes, insulin sensitivity and beta cell function in the Danish population-based Inter99 study (ClinicalTrials.gov NCT00289237).

Published
2010

176. Sex differences in glucose levels: a consequence of physiology or methodological convenience? The Inter99 study

Author

Faerch, K, Borch-Johnsen, Knut, Vaag, A, Jørgensen, Torben, Witte, D R, Faerch, K, Borch-Johnsen, Knut, Vaag, A, Jørgensen, Torben, and Witte, D R

Abstract

We aimed to examine whether sex differences in fasting plasma glucose (FPG), 2 h post-OGTT plasma glucose (2hPG) and HbA(1c) could be explained by differences in body size and/or body composition between men and women in a general non-diabetic Danish population. Moreover, we aimed to study to what degree the newly suggested high-risk HbA(1c) criteria overlapped with the current OGTT-based criteria of glucose intolerance.

Published
2010

177. Differential relationship between physical activity and progression to diabetes by glucose tolerance status: the Inter99 Study

Author

Engberg, S, Glümer, C, Witte, D R, Jørgensen, Torben, Borch-Johnsen, Knut, Engberg, S, Glümer, C, Witte, D R, Jørgensen, Torben, and Borch-Johnsen, Knut

Abstract

The aim of the study was to analyse how strongly commuting and leisure-time physical activity affect progression to diabetes and to study whether this relationship is different in individuals with isolated impaired fasting glucose (i-IFG) and isolated impaired glucose tolerance (i-IGT).

Published
2010

178. Predictors of future fasting and 2-h post-OGTT plasma glucose levels in middle-aged men and women-the Inter99 study

Author

Faerch, K, Vaag, A, Witte, D R, Jørgensen, Torben, Pedersen, Oluf, Borch-Johnsen, K, Faerch, K, Vaag, A, Witte, D R, Jørgensen, Torben, Pedersen, Oluf, and Borch-Johnsen, K

Abstract

Udgivelsesdato: 2009-Apr, AIMS: Screening and prevention strategies for Type 2 diabetes require insight into the aetiological and potentially different risk factors leading to early impairments of fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels. We studied whether risk factors predicting subtle elevations of FPG levels were different from those predicting elevations of 2hPG levels in men and women. METHODS: We used baseline and 5-year follow-up data from middle-aged men and women with normal glucose tolerance (NGT) at baseline in the Danish population-based Inter99 study (n = 3164). Anthropometric and non-anthropometric baseline predictors of the 5-year FPG and 2hPG levels were estimated in linear regression models stratified by gender. RESULTS: In men, but not in women, smoking and family history of diabetes predicted increased FPG levels, whereas high physical activity predicted a decline in 2hPG levels. Among the anthropometric variables, large waist circumference was the strongest predictor of increased FPG levels in men, whereas high body mass index (BMI) was the strongest predictor of increased FPG levels in women. In both men and women, BMI and waist circumference were equally strong in predicting 2hPG levels. Furthermore, short height predicted increased 2hPG levels in men, and short height and low hip circumference predicted increased 2hPG levels in women. CONCLUSIONS: Risk factors that predict future FPG levels are different from those predicting future 2hPG levels. Furthermore, different risk factors predict glycaemic levels in men compared with women. These findings indicate that different aetiological pathways may lead to Type 2 diabetes in men and women.

Published
2009

179. Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

Author

Wu, J. (Jianqiang), Williams, J.P. (Jon), Rizvi, T.A. (Tilat), Kordich, J.J. (Jennifer), Witte, D. (David), Meijer, D.N. (Dies), Stemmer-Rachamimov, A.O. (Anat), Cancelas, J.A. (Jose), Ratner, N. (Nancy), Wu, J. (Jianqiang), Williams, J.P. (Jon), Rizvi, T.A. (Tilat), Kordich, J.J. (Jennifer), Witte, D. (David), Meijer, D.N. (Dies), Stemmer-Rachamimov, A.O. (Anat), Cancelas, J.A. (Jose), and Ratner, N. (Nancy)

Abstract

Neurofibromatosis type 1 (Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5 + 1, but not earlier (neural crest) or later (mature Schwann cell), results in colony-forming cells capable of multilineage differentiation. In vivo, inactivation of Nf1 using a DhhCre driver beginning at E12.5 elicits plexiform neurofibromas, dermal neurofibromas, and pigmentation. Tumor Schwann cells uniquely show biallelic Nf1 inactivation. Peripheral nerve and tumors contain transiently proliferating Schwann cells that lose axonal contact, providing insight into early neurofibroma formation. We suggest that timing of Nf1 mutation is critical for neurofibroma formation.

Published
2008
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182. Expression of the putative proto-oncogene His-1 in normal and neoplastic tissues

Author

Li, J., Witte, D. P., Van Dyke, T., and Askew, D. S.

Subjects
Choroid Plexus Neoplasms, RNA, Untranslated, Carcinoma, Blotting, Northern, Proto-Oncogene Mas, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Alternative Splicing, Mice, Leukemia, Myeloid, Proto-Oncogenes, Tumor Cells, Cultured, Animals, Humans, RNA, Long Noncoding, RNA, Neoplasm, In Situ Hybridization, Research Article
Abstract

The His-1 gene is expressed as a 3-kb spliced and polyadenylated RNA that is believed to function in the absence of an encoded protein. The precise function of the His-1 gene is unknown, but its transcriptional activation in a series of mouse leukemias has implicated the His-1 RNA in leukemogenesis when it is abnormally expressed. To study the oncogenic potential of this gene in more detail, we have examined the normal tissue distribution of His-1 RNA during mouse embryogenesis and in various adult tissues. His-1 expression was detected at low levels in the epithelia of the adult mouse stomach, prostate, seminal vesicle, and the developing choroid plexus by in situ hybridization. All other tissues examined lacked detectable levels of hybridizing RNA, suggesting that normal His-1 gene expression is highly restricted to these epithelial sites. These transcripts were not detectable by Northern blot analysis of normal tissues but were readily identified in five mouse leukemias and in five carcinomas of the choroid plexus. These data indicate that the His-1 gene expression is highly restricted and suggest that inappropriate activation of this gene may contribute to carcinogenesis.

Published
1997

183. Winner of the Theodore E. Woodward Award: c-Myb and the coordinate regulation of thymic genes

Author

Hutton, J. J., Ess, K. C., Witte, D. P., and Aronow, B. J.

Subjects
Base Sequence, Adenosine Deaminase, Molecular Sequence Data, Awards and Prizes, Gene Expression Regulation, Developmental, DNA, Oncogenes, Thymus Gland, United States, Hematopoiesis, Embryonic and Fetal Development, Proto-Oncogene Proteins c-myb, Proto-Oncogene Proteins, Trans-Activators, Animals, Humans, RNA, Messenger, Societies, Medical, Research Article
Published
1996

191. The frequent UCP2 −866G>A polymorphism protects against insulin resistance and is associated with obesity: a study of obesity and related metabolic traits among 17 636 Danes

Author

Andersen, G, primary, Dalgaard, L T, additional, Justesen, J M, additional, Anthonsen, S, additional, Nielsen, T, additional, Thørner, L W, additional, Witte, D, additional, Jørgensen, T, additional, Clausen, J O, additional, Lauritzen, T, additional, Holmkvist, J, additional, Hansen, T, additional, and Pedersen, O, additional

Published
2012
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193. Kalzifikation oder Ossifikation?

Author

Bartl, C, Lichtenberg, S, Magosch, P, Witte, D, Habermeyer, P, Bartl, R, Bartl, C, Lichtenberg, S, Magosch, P, Witte, D, Habermeyer, P, and Bartl, R

Published
2004

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