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101. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Author

Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S.J., Jensen, R.A., Rawal, R., Roef, G.L., Plantinga, T.S., Vermeulen, S., Lahti, J., Simmonds, M.J., Husemoen, L.L., Freathy, R.M., Shields, B.M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T.I., Plia, M.G., Sala, C., Volker, U., Richards, J.B., Sweep, C.G.J., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y.E., Visser, W.E., Hattersley, A.T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., Bunt, M. van de, Liyanarachchi, S., Heier, M., Grabe, H.J., Masciullo, C., Galesloot, T.E., Lim, E.M., Reischl, E., Leedman, P.J., Lai, S., Delitala, A., Bremner, A.P., Philips, D.I., Beilby, J.P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E.E., Palotie, A., Feddema, P., Fletcher, S.J., Schramm, K., Rotter, J.I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G.L., He, H., Franklyn, J.A., Tiller, D., Vaidya, B., Meyer, T., Jorgensen, T., Eriksson, J.G., O'Leary, P.C., Wichmann, E., Hermus, A.R.M.M., Psaty, B.M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., Chapelle, A. dela, Netea-Maier, R.T., Gough, S.C., Meyer Zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Smit, J.W.A., Kiemeney, B., et al., Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S.J., Jensen, R.A., Rawal, R., Roef, G.L., Plantinga, T.S., Vermeulen, S., Lahti, J., Simmonds, M.J., Husemoen, L.L., Freathy, R.M., Shields, B.M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T.I., Plia, M.G., Sala, C., Volker, U., Richards, J.B., Sweep, C.G.J., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y.E., Visser, W.E., Hattersley, A.T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., Bunt, M. van de, Liyanarachchi, S., Heier, M., Grabe, H.J., Masciullo, C., Galesloot, T.E., Lim, E.M., Reischl, E., Leedman, P.J., Lai, S., Delitala, A., Bremner, A.P., Philips, D.I., Beilby, J.P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E.E., Palotie, A., Feddema, P., Fletcher, S.J., Schramm, K., Rotter, J.I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G.L., He, H., Franklyn, J.A., Tiller, D., Vaidya, B., Meyer, T., Jorgensen, T., Eriksson, J.G., O'Leary, P.C., Wichmann, E., Hermus, A.R.M.M., Psaty, B.M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., Chapelle, A. dela, Netea-Maier, R.T., Gough, S.C., Meyer Zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Smit, J.W.A., Kiemeney, B., and et al.

Abstract

Contains fulltext : 138209.pdf (publisher's version ) (Open Access), Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5x10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1x10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9x10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5x10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2x10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2x10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9x10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmu

Published
2014

102. Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Author

Medici, Marco, Porcu, E, Pistis, G, Teumer, A, Brown, SJ, Jensen, RA, Rawal, R, Roef, GL, Plantinga, TS, Vermeulen, SH, Lahti, J, Simmonds, MJ, Husemoen, LLN, Freathy, RM, Shields, BM, Pietzner, D, Nagy, R, Broer, Linda, Chaker, Layal, Korevaar, Tim, Plia, MG, Sala, C, Volker, U, Richards, JB, Sweep, FC, Gieger, C, Corre, T, Kajantie, E, Thuesen, B, Taes, YE, Visser, Edward, Hattersley, AT, Kratzsch, J, Hamilton, A, Li, W (Wenguang), Homuth, G, Lobina, M, Mariotti, S, Soranzo, N, Cocca, M, Nauck, M, Spielhagen, C, Ross, A, Arnold, A, van de Bunt, M, Liyanarachchi, S, Heier, M, Grabe, HJ, Masciullo, C, Galesloot, TE, Lim, EM, Reischl, E, Leedman, PJ, Lai, S, Delitala, A, Bremner, AP, Philips, DIW, Beilby, JP, Mulas, A, Vocale, M, Abecasis, G, Forsen, T, James, A, Widen, E, Hui, J, Prokisch, H, Rietzschel, EE, Palotie, A, Feddema, P, Fletcher, SJ, Schramm, K, Rotter, JI, Kluttig, A, Radke, D, Traglia, M, Surdulescu, GL, He, HL, Franklyn, JA, Tiller, D, Vaidya, B, Meyer, T, Jorgensen, T, Eriksson, JG, O'Leary, PC, Wichmann, E, Hermus, AR, Psaty, BM, Ittermann, T, Hofman, Bert, Bosi, E, Schlessinger, D, Wallaschofski, H, Pirastu, N, Aulchenko, YS, de la Chapelle, A, Netea-Maier, RT, Gough, SCL, Meyer zu Schwabedissen, H, Frayling, TM, Kaufman, JM, Linneberg, A, Raikkonen, K, Smit, JWA, Kiemeney, LA, Rivadeneira, Fernando, Uitterlinden, André, Walsh, JP, Meisinger, C, Heijer, Mariska, Visser, Theo, Spector, TD, Wilson, SG, Voelzke, H, Cappola, A, Toniolo, D, Sanna, S, Naitza, S, Peeters, Robin, Medici, Marco, Porcu, E, Pistis, G, Teumer, A, Brown, SJ, Jensen, RA, Rawal, R, Roef, GL, Plantinga, TS, Vermeulen, SH, Lahti, J, Simmonds, MJ, Husemoen, LLN, Freathy, RM, Shields, BM, Pietzner, D, Nagy, R, Broer, Linda, Chaker, Layal, Korevaar, Tim, Plia, MG, Sala, C, Volker, U, Richards, JB, Sweep, FC, Gieger, C, Corre, T, Kajantie, E, Thuesen, B, Taes, YE, Visser, Edward, Hattersley, AT, Kratzsch, J, Hamilton, A, Li, W (Wenguang), Homuth, G, Lobina, M, Mariotti, S, Soranzo, N, Cocca, M, Nauck, M, Spielhagen, C, Ross, A, Arnold, A, van de Bunt, M, Liyanarachchi, S, Heier, M, Grabe, HJ, Masciullo, C, Galesloot, TE, Lim, EM, Reischl, E, Leedman, PJ, Lai, S, Delitala, A, Bremner, AP, Philips, DIW, Beilby, JP, Mulas, A, Vocale, M, Abecasis, G, Forsen, T, James, A, Widen, E, Hui, J, Prokisch, H, Rietzschel, EE, Palotie, A, Feddema, P, Fletcher, SJ, Schramm, K, Rotter, JI, Kluttig, A, Radke, D, Traglia, M, Surdulescu, GL, He, HL, Franklyn, JA, Tiller, D, Vaidya, B, Meyer, T, Jorgensen, T, Eriksson, JG, O'Leary, PC, Wichmann, E, Hermus, AR, Psaty, BM, Ittermann, T, Hofman, Bert, Bosi, E, Schlessinger, D, Wallaschofski, H, Pirastu, N, Aulchenko, YS, de la Chapelle, A, Netea-Maier, RT, Gough, SCL, Meyer zu Schwabedissen, H, Frayling, TM, Kaufman, JM, Linneberg, A, Raikkonen, K, Smit, JWA, Kiemeney, LA, Rivadeneira, Fernando, Uitterlinden, André, Walsh, JP, Meisinger, C, Heijer, Mariska, Visser, Theo, Spector, TD, Wilson, SG, Voelzke, H, Cappola, A, Toniolo, D, Sanna, S, Naitza, S, and Peeters, Robin

Abstract

Author Summary Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction. Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,9

Published
2014

107. Gene Expansion Shapes Genome Architecture in the Human Pathogen Lichtheimia corymbifera: An Evolutionary Genomics Analysis in the Ancient Terrestrial Mucorales (Mucoromycotina)

Author

Schwartze, Volker U., primary, Winter, Sascha, additional, Shelest, Ekaterina, additional, Marcet-Houben, Marina, additional, Horn, Fabian, additional, Wehner, Stefanie, additional, Linde, Jörg, additional, Valiante, Vito, additional, Sammeth, Michael, additional, Riege, Konstantin, additional, Nowrousian, Minou, additional, Kaerger, Kerstin, additional, Jacobsen, Ilse D., additional, Marz, Manja, additional, Brakhage, Axel A., additional, Gabaldón, Toni, additional, Böcker, Sebastian, additional, and Voigt, Kerstin, additional

Published
2014
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108. Systematic identification of trans eQTLs as putative drivers of known disease associations

Author

Westra, H.J. (Harm-Jan), Peters, M.J. (Marjolein), Esko, T. (Tõnu), Yaghootkar, H. (Hanieh), Schurmann, C. (Claudia), Kettunen, J. (Johannes), Christiansen, M.W. (Mark), Fairfax, B.P. (Benjamin), Schramm, K. (Katharina), Powell, J.E. (Joseph), Zhernakova, A. (Alexandra), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Karjalainen, J. (Juha), Withoff, S. (Sebo), Uitterlinden, A.G. (André), Hofman, B., Rivadeneira Ramirez, F. (Fernando), Hoen, P.A.C. (Peter) 't, Reinmaa, E. (Eva), Fischer, K. (Kathelijn), Nelis, M. (Mari), Milani, A.L. (Alfredo), Melzer, D. (David), Ferrucci, L. (Luigi), Singleton, A.B. (Andrew), Hernandez, D.G. (Dena), Nalls, M.A. (Michael), Homuth, G. (Georg), Nauck, M.A. (Matthias), Radke, D. (Dörte), Vol̈ker, U. (Uwe), Perola, M. (Markus), Salomaa, V. (Veikko), Brody, J.A. (Jennifer A.), Suchy-Dicey, A. (Astrid), Gharib, S.A. (Sina), Enquobahrie, D., Lumley, T. (Thomas), Montgomery, G.W., Makino, S. (Seiko), Prokisch, H. (Holger), Herder, C. (Christian), Roden, M. (Michael), Grallert, H. (Harald), Meitinger, T. (Thomas), Strauch, K. (Konstantin), Li, Y. (Yunmin), Jansen, J.R.C. (Jos), Visscher, P.M. (Peter M.), Knight, J.C. (Julian), Psaty, B.M. (Bruce), Ripatti, S. (Samuli), Teumer, A. (Alexander), Frayling, T.M. (Timothy), Metspalu, A. (Andres), Meurs, J.B.J. (Joyce) van, Franke, L. (Lude), Westra, H.J. (Harm-Jan), Peters, M.J. (Marjolein), Esko, T. (Tõnu), Yaghootkar, H. (Hanieh), Schurmann, C. (Claudia), Kettunen, J. (Johannes), Christiansen, M.W. (Mark), Fairfax, B.P. (Benjamin), Schramm, K. (Katharina), Powell, J.E. (Joseph), Zhernakova, A. (Alexandra), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Karjalainen, J. (Juha), Withoff, S. (Sebo), Uitterlinden, A.G. (André), Hofman, B., Rivadeneira Ramirez, F. (Fernando), Hoen, P.A.C. (Peter) 't, Reinmaa, E. (Eva), Fischer, K. (Kathelijn), Nelis, M. (Mari), Milani, A.L. (Alfredo), Melzer, D. (David), Ferrucci, L. (Luigi), Singleton, A.B. (Andrew), Hernandez, D.G. (Dena), Nalls, M.A. (Michael), Homuth, G. (Georg), Nauck, M.A. (Matthias), Radke, D. (Dörte), Vol̈ker, U. (Uwe), Perola, M. (Markus), Salomaa, V. (Veikko), Brody, J.A. (Jennifer A.), Suchy-Dicey, A. (Astrid), Gharib, S.A. (Sina), Enquobahrie, D., Lumley, T. (Thomas), Montgomery, G.W., Makino, S. (Seiko), Prokisch, H. (Holger), Herder, C. (Christian), Roden, M. (Michael), Grallert, H. (Harald), Meitinger, T. (Thomas), Strauch, K. (Konstantin), Li, Y. (Yunmin), Jansen, J.R.C. (Jos), Visscher, P.M. (Peter M.), Knight, J.C. (Julian), Psaty, B.M. (Bruce), Ripatti, S. (Samuli), Teumer, A. (Alexander), Frayling, T.M. (Timothy), Metspalu, A. (Andres), Meurs, J.B.J. (Joyce) van, and Franke, L. (Lude)

Abstract

Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3′ UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

Published
2013
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109. Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

Author

O'Seaghdha, C.M. (Conall), Wu, H. (Hongsheng), Yang, Q. (Qiong), Kapur, K. (Karen), Guessous, I. (Idris), Zuber, P. (Patrick), Köttgen, A. (Anna), Stoudmann, C. (Candice), Teumer, A. (Alexander), Kutalik, Z. (Zoltán), Mangino, M. (Massimo), Dehghan, A. (Abbas), Zhang, W. (Weihua), Eiriksdottir, G. (Gudny), Li, G. (Guo), Tanaka, T. (Toshiko), Portas, L. (Laura), Lopez, L.M. (Lorna), Hayward, C. (Caroline), Lohman, K. (Kurt), Matsuda, K. (Koichi), Padmanabhan, S. (Sandosh), Firsov, D. (Dmitri), Sorice, R., Ulivi, S. (Shelia), Brockhaus, A.C. (A. Catharina), Kleber, M.E. (Marcus), Mahajan, A. (Anubha), Ernst, F.D.J. (Florian), Gudnason, V. (Vilmundur), Launer, L.J. (Lenore), Mace, A. (Aurelien), Boerwinkle, E.A. (Eric), Arking, D.E. (Dan), Tanikawa, C. (Chizu), Nakamura, Y. (Yusuke), Brown, M.J. (Morris), Gaspoz, J.-M. (Jean-Michel), Theler, J.-M. (Jean-Marc), Siscovick, D.S. (David), Psaty, B.M. (Bruce), Bergmann, S.M. (Sven), Vollenweider, P. (Peter), Vitart, V. (Veronique), Wright, A.F. (Alan), Zemunik, T. (Tatijana), Boban, M. (Mladen), Kolcic, I. (Ivana), Navarro, P. (Pau), Brown, E.M. (Edward), Estrada Gil, K. (Karol), Ding, J. (Jingzhong), Harris, T.B. (Tamara), Bandinelli, S. (Stefania), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Girotto, S., Ruggiero, D., Adamo, P. (Pio) d', Robino, A. (Antonietta), Meitinger, T. (Thomas), Meisinger, C. (Christa), Davies, G. (Gail), Starr, J.M. (John), Chambers, J.C. (John), Boehm, B.O. (Bernhard), Winkelmann, B., Huang, J. (Jian), Murgia, D. (Daniela), Wild, S.H. (Sarah), Campbell, H. (Harry), Morris, A.D. (Andrew), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Vol̈ker, U. (Uwe), Hannemann, M. (Mario), Biffar, R. (Reiner), Hoffmann, W. (Wolfgang), Shin, S.-Y., Lescuyer, P. (Pierre), Henry, H. (Hughes), Schurmann, C. (Claudia), Munroe, P. (Patricia), Gasparini, P. (Paolo), Pirastu, N. (Nicola), Ciullo, M., Gieger, C. (Christian), März, W. (Winfried), Lind, L. (Lars), Spector, T.D. (Timothy), Smith, A.V. (Davey), Rudan, I. (Igor), Wilson, J.F. (James), Polasek, O. (Ozren), Deary, I.J. (Ian), Pirastu, M. (Mario), Ferrucci, L. (Luigi), Liu, Y. (YongMei), Kestenbaum, B. (Bryan), Kooner, J.S. (Jaspal), Witteman, J.C.M. (Jacqueline), Nauck, M. (Matthias), Kao, W.H.L. (Wen), Wallaschofski, H. (Henri), Bonny, O. (Olivier), Fox, C. (Craig), Bochud, M. (Murielle), O'Seaghdha, C.M. (Conall), Wu, H. (Hongsheng), Yang, Q. (Qiong), Kapur, K. (Karen), Guessous, I. (Idris), Zuber, P. (Patrick), Köttgen, A. (Anna), Stoudmann, C. (Candice), Teumer, A. (Alexander), Kutalik, Z. (Zoltán), Mangino, M. (Massimo), Dehghan, A. (Abbas), Zhang, W. (Weihua), Eiriksdottir, G. (Gudny), Li, G. (Guo), Tanaka, T. (Toshiko), Portas, L. (Laura), Lopez, L.M. (Lorna), Hayward, C. (Caroline), Lohman, K. (Kurt), Matsuda, K. (Koichi), Padmanabhan, S. (Sandosh), Firsov, D. (Dmitri), Sorice, R., Ulivi, S. (Shelia), Brockhaus, A.C. (A. Catharina), Kleber, M.E. (Marcus), Mahajan, A. (Anubha), Ernst, F.D.J. (Florian), Gudnason, V. (Vilmundur), Launer, L.J. (Lenore), Mace, A. (Aurelien), Boerwinkle, E.A. (Eric), Arking, D.E. (Dan), Tanikawa, C. (Chizu), Nakamura, Y. (Yusuke), Brown, M.J. (Morris), Gaspoz, J.-M. (Jean-Michel), Theler, J.-M. (Jean-Marc), Siscovick, D.S. (David), Psaty, B.M. (Bruce), Bergmann, S.M. (Sven), Vollenweider, P. (Peter), Vitart, V. (Veronique), Wright, A.F. (Alan), Zemunik, T. (Tatijana), Boban, M. (Mladen), Kolcic, I. (Ivana), Navarro, P. (Pau), Brown, E.M. (Edward), Estrada Gil, K. (Karol), Ding, J. (Jingzhong), Harris, T.B. (Tamara), Bandinelli, S. (Stefania), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Girotto, S., Ruggiero, D., Adamo, P. (Pio) d', Robino, A. (Antonietta), Meitinger, T. (Thomas), Meisinger, C. (Christa), Davies, G. (Gail), Starr, J.M. (John), Chambers, J.C. (John), Boehm, B.O. (Bernhard), Winkelmann, B., Huang, J. (Jian), Murgia, D. (Daniela), Wild, S.H. (Sarah), Campbell, H. (Harry), Morris, A.D. (Andrew), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Vol̈ker, U. (Uwe), Hannemann, M. (Mario), Biffar, R. (Reiner), Hoffmann, W. (Wolfgang), Shin, S.-Y., Lescuyer, P. (Pierre), Henry, H. (Hughes), Schurmann, C. (Claudia), Munroe, P. (Patricia), Gasparini, P. (Paolo), Pirastu, N. (Nicola), Ciullo, M., Gieger, C. (Christian), März, W. (Winfried), Lind, L. (Lars), Spector, T.D. (Timothy), Smith, A.V. (Davey), Rudan, I. (Igor), Wilson, J.F. (James), Polasek, O. (Ozren), Deary, I.J. (Ian), Pirastu, M. (Mario), Ferrucci, L. (Luigi), Liu, Y. (YongMei), Kestenbaum, B. (Bryan), Kooner, J.S. (Jaspal), Witteman, J.C.M. (Jacqueline), Nauck, M. (Matthias), Kao, W.H.L. (Wen), Wallaschofski, H. (Henri), Bonny, O. (Olivier), Fox, C. (Craig), and Bochud, M. (Murielle)

Abstract

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven l

Published
2013
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110. Common variants in mendelian kidney disease genes and their association with renal function

Author

Parsa, A. (Afshin), Fuchsberger, C. (Christian), Köttgen, A. (Anna), O'Seaghdha, C.M. (Conall), Pattaro, C. (Cristian), Andrade, M. (Mariza) de, Chasman, D.I. (Daniel), Teumer, A. (Alexander), Endlich, K. (Karlhans), Olden, M. (Matthias), Chen, M-H. (Ming-Huei), Tin, A. (Adrienne), Kim, Y-J. (Yong-Jin), Taliun, D. (Daniel), Li, M. (Man), Feitosa, M.F. (Mary Furlan), Gorski, M. (Mathias), Yang, Q. (Qiong), Hundertmark, C. (Claudia), Foster, M.C. (Michael), Glazer, N. (Nicole), Isaacs, A.J. (Aaron), Rao, M. (Madhumathi), Smith, A.V. (Davey), O´Connell, J.R., Struchalin, M.V. (Maksim), Tanaka, T. (Toshiko), Li, G. (Guo), Hwang, S.J., Atkinson, E.J. (Elizabeth), Lohman, K. (Kurt), Cornelis, M. (Marilyn), Johansson, A. (Åsa), Tönjes, A. (Anke), Dehghan, A. (Abbas), Couraki, V. (Vincent), Holliday, E.G. (Elizabeth), Sorice, R., Kutalik, Z. (Zoltán), Lehtimäki, T. (Terho), Esko, T. (Tõnu), Deshmukh, H. (Harshal), Ulivi, S. (Shelia), Chu, A.Y. (Audrey), Murgia, D. (Daniela), Trompet, S. (Stella), Imboden, M. (Medea), Kollerits, B. (Barbara), Pistis, G. (Giorgio), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Aspelund, T. (Thor), Eiriksdottir, G. (Gudny), Mitchell, B.D. (Braxton), Boerwinkle, E.A. (Eric), Schmidt, H. (Helena), Hofer, E. (Edith), Hu, F.B. (Frank), Demirkan, A. (Ayşe), Oostra, B.A. (Ben), Turner, S.T. (Stephen), Ding, J. (Jingzhong), Andrews, J.S. (Jeanette), Freedman, B.I. (Barry), Giulianini, F. (Franco), Koenig, W. (Wolfgang), Illig, T. (Thomas), Döring, A. (Angela), Wichmann, H.E. (Heinz Erich), Zgaga, L. (Lina), Zemunik, T. (Tatijana), Boban, M. (Mladen), Minelli, C. (Cosetta), Wheeler, H.E. (Heather), Igl, W. (Wilmar), Zaboli, G. (Ghazal), Wild, S.H. (Sarah), Wright, A.F. (Alan), Campbell, H. (Harry), Ellinghaus, D. (David), Nöthlings, U. (Ute), Jacobs, G. (Gunnar), Biffar, R. (Reiner), Ernst, F.D.J. (Florian), Homuth, G. (Georg), Kroemer, H.K. (Heyo), Nauck, M. (Matthias), Stracke, S. (Sylvia), Vol̈ker, U. (Uwe), Völzke, H. (Henry), Kovacs, P. (Peter), Stumvoll, M. (Michael), Mägi, R. (Reedik), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Aulchenko, Y.S. (Yurii), Polasek, O. (Ozren), Hastie, N. (Nick), Vitart, V. (Veronique), Helmer, C. (Catherine), Wang, J.J. (Jie Jin), Stengel, B. (Bernd), Ruggiero, D., Bergmann, S.M. (Sven), Kähönen, M. (Mika), Viikari, J. (Jorma), Nikopensius, T. (Tiit), Province, M.A. (Mike), Colhoun, H.M. (H.), Doney, A.S.F. (Alex), Robino, A. (Antonietta), Krämer, B.K. (Bernhard), Portas, L. (Laura), Ford, I. (Ian), Buckley, B.M. (Brendan M.), Adam, M. (Martin), Thun, G.-A. (Gian-Andri), Paulweber, B. (Bernhard), Haun, M. (Margot), Sala, C. (Cinzia), Mitchell, P. (Paul), Ciullo, M., Vollenweider, P. (Peter), Raitakari, O. (Olli), Metspalu, A. (Andres), Palmer, C.N.A. (Colin), Gasparini, P. (Paolo), Pirastu, M. (Mario), Jukema, J.W. (Jan Wouter), Probst-Hensch, N.M. (Nicole M.), Kronenberg, F. (Florian), Toniolo, D. (Daniela), Gudnason, V. (Vilmundur), Shuldiner, A.R. (Alan), Coresh, J. (Josef), Schmidt, R. (Reinhold), Ferrucci, L. (Luigi), Duijn, C.M. (Cornelia) van, Borecki, I.B. (Ingrid), Kardia, S.L.R. (Sharon), Liu, Y. (YongMei), Curhan, G.C. (Gary), Rudan, I. (Igor), Gyllensten, U. (Ulf), Wilson, J.F. (James), Franke, A. (Andre), Pramstaller, P.P. (Peter Paul), Rettig, R. (Rainer), Prokopenko, I. (Inga), Witteman, J.C.M. (Jacqueline), Hayward, C. (Caroline), Ridker, P.M. (Paul), Bochud, M. (Murielle), Heid, I.M. (Iris), Siscovick, D.S. (David), Fox, C.S. (Caroline), Kao, W.H.L. (Wen), Böger, C.A. (Carsten), Parsa, A. (Afshin), Fuchsberger, C. (Christian), Köttgen, A. (Anna), O'Seaghdha, C.M. (Conall), Pattaro, C. (Cristian), Andrade, M. (Mariza) de, Chasman, D.I. (Daniel), Teumer, A. (Alexander), Endlich, K. (Karlhans), Olden, M. (Matthias), Chen, M-H. (Ming-Huei), Tin, A. (Adrienne), Kim, Y-J. (Yong-Jin), Taliun, D. (Daniel), Li, M. (Man), Feitosa, M.F. (Mary Furlan), Gorski, M. (Mathias), Yang, Q. (Qiong), Hundertmark, C. (Claudia), Foster, M.C. (Michael), Glazer, N. (Nicole), Isaacs, A.J. (Aaron), Rao, M. (Madhumathi), Smith, A.V. (Davey), O´Connell, J.R., Struchalin, M.V. (Maksim), Tanaka, T. (Toshiko), Li, G. (Guo), Hwang, S.J., Atkinson, E.J. (Elizabeth), Lohman, K. (Kurt), Cornelis, M. (Marilyn), Johansson, A. (Åsa), Tönjes, A. (Anke), Dehghan, A. (Abbas), Couraki, V. (Vincent), Holliday, E.G. (Elizabeth), Sorice, R., Kutalik, Z. (Zoltán), Lehtimäki, T. (Terho), Esko, T. (Tõnu), Deshmukh, H. (Harshal), Ulivi, S. (Shelia), Chu, A.Y. (Audrey), Murgia, D. (Daniela), Trompet, S. (Stella), Imboden, M. (Medea), Kollerits, B. (Barbara), Pistis, G. (Giorgio), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Aspelund, T. (Thor), Eiriksdottir, G. (Gudny), Mitchell, B.D. (Braxton), Boerwinkle, E.A. (Eric), Schmidt, H. (Helena), Hofer, E. (Edith), Hu, F.B. (Frank), Demirkan, A. (Ayşe), Oostra, B.A. (Ben), Turner, S.T. (Stephen), Ding, J. (Jingzhong), Andrews, J.S. (Jeanette), Freedman, B.I. (Barry), Giulianini, F. (Franco), Koenig, W. (Wolfgang), Illig, T. (Thomas), Döring, A. (Angela), Wichmann, H.E. (Heinz Erich), Zgaga, L. (Lina), Zemunik, T. (Tatijana), Boban, M. (Mladen), Minelli, C. (Cosetta), Wheeler, H.E. (Heather), Igl, W. (Wilmar), Zaboli, G. (Ghazal), Wild, S.H. (Sarah), Wright, A.F. (Alan), Campbell, H. (Harry), Ellinghaus, D. (David), Nöthlings, U. (Ute), Jacobs, G. (Gunnar), Biffar, R. (Reiner), Ernst, F.D.J. (Florian), Homuth, G. (Georg), Kroemer, H.K. (Heyo), Nauck, M. (Matthias), Stracke, S. (Sylvia), Vol̈ker, U. (Uwe), Völzke, H. (Henry), Kovacs, P. (Peter), Stumvoll, M. (Michael), Mägi, R. (Reedik), Hofman, A. (Albert), Uitterlinden, A.G. (André), Rivadeneira Ramirez, F. (Fernando), Aulchenko, Y.S. (Yurii), Polasek, O. (Ozren), Hastie, N. (Nick), Vitart, V. (Veronique), Helmer, C. (Catherine), Wang, J.J. (Jie Jin), Stengel, B. (Bernd), Ruggiero, D., Bergmann, S.M. (Sven), Kähönen, M. (Mika), Viikari, J. (Jorma), Nikopensius, T. (Tiit), Province, M.A. (Mike), Colhoun, H.M. (H.), Doney, A.S.F. (Alex), Robino, A. (Antonietta), Krämer, B.K. (Bernhard), Portas, L. (Laura), Ford, I. (Ian), Buckley, B.M. (Brendan M.), Adam, M. (Martin), Thun, G.-A. (Gian-Andri), Paulweber, B. (Bernhard), Haun, M. (Margot), Sala, C. (Cinzia), Mitchell, P. (Paul), Ciullo, M., Vollenweider, P. (Peter), Raitakari, O. (Olli), Metspalu, A. (Andres), Palmer, C.N.A. (Colin), Gasparini, P. (Paolo), Pirastu, M. (Mario), Jukema, J.W. (Jan Wouter), Probst-Hensch, N.M. (Nicole M.), Kronenberg, F. (Florian), Toniolo, D. (Daniela), Gudnason, V. (Vilmundur), Shuldiner, A.R. (Alan), Coresh, J. (Josef), Schmidt, R. (Reinhold), Ferrucci, L. (Luigi), Duijn, C.M. (Cornelia) van, Borecki, I.B. (Ingrid), Kardia, S.L.R. (Sharon), Liu, Y. (YongMei), Curhan, G.C. (Gary), Rudan, I. (Igor), Gyllensten, U. (Ulf), Wilson, J.F. (James), Franke, A. (Andre), Pramstaller, P.P. (Peter Paul), Rettig, R. (Rainer), Prokopenko, I. (Inga), Witteman, J.C.M. (Jacqueline), Hayward, C. (Caroline), Ridker, P.M. (Paul), Bochud, M. (Murielle), Heid, I.M. (Iris), Siscovick, D.S. (David), Fox, C.S. (Caroline), Kao, W.H.L. (Wen), and Böger, C.A. (Carsten)

Abstract

Many common genetic variants identified by genome-wide association studies for complex traitsmap to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research. Copyright

Published
2013
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111. Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy

Author

Ameling, S., Herda, L.R., Hammer, E., Steil, L., Teumer, A., Trimpert, C., Dorr, M., Kroemer, H.K., Klingel, K., Kandolf, R., Volker, U., Felix, S.B., Ameling, S., Herda, L.R., Hammer, E., Steil, L., Teumer, A., Trimpert, C., Dorr, M., Kroemer, H.K., Klingel, K., Kandolf, R., Volker, U., and Felix, S.B.

Abstract

Item does not contain fulltext, AIMS: Immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG. METHODS AND RESULTS: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (>/=20 relative and >/=5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin-proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only. CONCLUSION: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeut

Published
2013

112. Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

Author

O'Seaghdha, CM, Wu, HS, Yang, Q, Kapur, K, Guessous, I, Zuber, AM, Kottgen, A, Stoudmann, C, Teumer, A, Kutalik, Z, Mangino, M, Dehghan, Abbas, Zhang, WH, Eiriksdottir, G, Li, G (Guo), Tanaka, T, Portas, L, Lopez, LM, Hayward, C, Lohman, K, Matsuda, K, Padmanabhan, S, Firsov, D, Sorice, R, Ulivi, S, Brockhaus, AC, Kleber, ME, Mahajan, A, Ernst, FD, Gudnason, V, Launer, LJ (Lenore), Mace, A, Boerwinckle, E, Arking, DE, Tanikawa, C, Nakamura, Y, Brown, MJ, Gaspoz, JM, Theler, JM, Siscovick, DS, Psaty, BM, Bergmann, S, Vollenweider, P, Vitart, V, Wright, AF, Zemunik, T, Boban, M, Kolcic, I, Navarro, P, Brown, EM, Estrada Gil, Karol, Ding, JZ (Jing Zhong), Harris, TB, Bandinelli, S, Hernandez, D, Singleton, AB, Girotto, G, Ruggiero, D, d'Adamo, AP, Robino, A, Meitinger, T, Meisinger, C, Davies, G, Starr, JM, Chambers, JC, Boehm, BO, Winkelmann, BR, Huang, J, Murgia, F, Wild, SH, Campbell, H, Morris, AP, Franco Duran, OH, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Volker, U, Hannemann, A, Biffar, R, Hoffmann, W, Shin, SY, Lescuyer, P, Henry, H, Schurmann, C, Munroe, PB, Gasparini, P, Pirastu, N, Ciullo, M, Gieger, C, Marz, W, Lind, L, Spector, TD, Smith, AV, Rudan, I, Wilson, JF, Polasek, O, Deary, IJ, Pirastu, M, Ferrucci, L, Liu, YM, Kestenbaum, B, Kooner, JS, Witteman, JCM, Nauck, M, Kao, WHL, Wallaschofski, H, Bonny, O, Fox, CS, Bochud, M, O'Seaghdha, CM, Wu, HS, Yang, Q, Kapur, K, Guessous, I, Zuber, AM, Kottgen, A, Stoudmann, C, Teumer, A, Kutalik, Z, Mangino, M, Dehghan, Abbas, Zhang, WH, Eiriksdottir, G, Li, G (Guo), Tanaka, T, Portas, L, Lopez, LM, Hayward, C, Lohman, K, Matsuda, K, Padmanabhan, S, Firsov, D, Sorice, R, Ulivi, S, Brockhaus, AC, Kleber, ME, Mahajan, A, Ernst, FD, Gudnason, V, Launer, LJ (Lenore), Mace, A, Boerwinckle, E, Arking, DE, Tanikawa, C, Nakamura, Y, Brown, MJ, Gaspoz, JM, Theler, JM, Siscovick, DS, Psaty, BM, Bergmann, S, Vollenweider, P, Vitart, V, Wright, AF, Zemunik, T, Boban, M, Kolcic, I, Navarro, P, Brown, EM, Estrada Gil, Karol, Ding, JZ (Jing Zhong), Harris, TB, Bandinelli, S, Hernandez, D, Singleton, AB, Girotto, G, Ruggiero, D, d'Adamo, AP, Robino, A, Meitinger, T, Meisinger, C, Davies, G, Starr, JM, Chambers, JC, Boehm, BO, Winkelmann, BR, Huang, J, Murgia, F, Wild, SH, Campbell, H, Morris, AP, Franco Duran, OH, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Volker, U, Hannemann, A, Biffar, R, Hoffmann, W, Shin, SY, Lescuyer, P, Henry, H, Schurmann, C, Munroe, PB, Gasparini, P, Pirastu, N, Ciullo, M, Gieger, C, Marz, W, Lind, L, Spector, TD, Smith, AV, Rudan, I, Wilson, JF, Polasek, O, Deary, IJ, Pirastu, M, Ferrucci, L, Liu, YM, Kestenbaum, B, Kooner, JS, Witteman, JCM, Nauck, M, Kao, WHL, Wallaschofski, H, Bonny, O, Fox, CS, and Bochud, M

Abstract

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

Published
2013

113. Defining the structure of the general stress regulon of Bacillus subtilis using targeted microarray analysis and random forest classification.

Author

Nannapaneni, P., Hertwig, F., Depke, M., Hecker, M., Mader, U., Volker, U., Steil, L., Hijum, S.A.F.T. van, Nannapaneni, P., Hertwig, F., Depke, M., Hecker, M., Mader, U., Volker, U., Steil, L., and Hijum, S.A.F.T. van

Abstract

1 maart 2012, Item does not contain fulltext, The structure of the SigB-dependent general stress regulon of Bacillus subtilis has previously been characterized by proteomics approaches as well as DNA array-based expression studies. However, comparing the SigB targets published in three previous major transcriptional profiling studies it is obvious that although each of them identified well above 100 target genes, only 67 were identified in all three studies. These substantial differences can likely be attributed to the different strains, growth conditions, microarray platforms and experimental setups used in the studies. In order to gain a better understanding of the structure of this important regulon, a targeted DNA microarray analysis covering most of the known SigB-inducing conditions was performed, and the changes in expression kinetics of 252 potential members of the SigB regulon and appropriate control genes were recorded. Transcriptional data for the B. subtilis wild-type strain 168 and its isogenic sigB mutant BSM29 were analysed using random forest, a machine learning algorithm, by incorporating the knowledge from previous studies. This analysis revealed a strictly SigB-dependent expression pattern for 166 genes following ethanol, butanol, osmotic and oxidative stress, low-temperature growth and heat shock, as well as limitation of oxygen or glucose. Kinetic analysis of the data for the wild-type strain identified 30 additional members of the SigB regulon, which were also subject to control by additional transcriptional regulators, thus displaying atypical SigB-independent induction patterns in the mutant strain under some of the conditions tested. For 19 of these 30 SigB regulon members, published reports support control by secondary regulators along with SigB. Thus, this microarray-based study assigns a total of 196 genes to the SigB-dependent general stress regulon of B. subtilis.

Published
2012

114. Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.

Author

Murabito, J.M., White, C.C., Kavousi, M., Sun, Y.V., Feitosa, M.F., Nambi, V., Lamina, C., Schillert, A., Coassin, S., Bis, J.C., Broer, L., Crawford, D.C., Franceschini, N., Frikke-Schmidt, R., Haun, M., Holewijn, S., Huffman, J.E., Hwang, S.J., Kiechl, S., Kollerits, B., Montasser, M.E., Nolte, I.M., Rudock, M.E., Senft, A., Teumer, A., Harst, P. van der, Vitart, V., Waite, L.L., Wood, A.R., Wassel, C.L., Absher, D.M., Allison, M.A., Amin, N., Arnold, A., Asselbergs, F.W., Aulchenko, Y., Bandinelli, S., Barbalic, M., Boban, M., Brown-Gentry, K., Couper, D.J., Criqui, M.H., Dehghan, A., Heijer, M. den, Dieplinger, B., Ding, J., Dorr, M., Espinola-Klein, C., Felix, S.B., Ferrucci, L., Folsom, A.R., Fraedrich, G., Gibson, Q., Goodloe, R., Gunjaca, G., Haltmayer, M., Heiss, G., Hofman, A., Kieback, A., Kiemeney, L.A.L.M., Kolcic, I., Kullo, I.J., Kritchevsky, S.B., Lackner, K.J., Li, X., Lieb, W., Lohman, K., Meisinger, C., Melzer, D., Mohler 3rd, E.R., Mudnic, I., Mueller, T., Navis, G., Oberhollenzer, F., Olin, J.W., O'Connell, J., O'Donnell, C.J., Palmas, W., Penninx, B.W.J.H., Petersmann, A., Polasek, O., Psaty, B.M., Rantner, B., Rice, K., Rivadeneira, F., Rotter, J.I., Seldenrijk, A., Stadler, M., Summerer, M., Tanaka, T., Tybjaerg-Hansen, A., Uitterlinden, A.G., Gilst, W.H. van, Vermeulen, S., Wild, S.H., Wild, P.S., Willeit, J., Zeller, T., Zemunik, T., Zgaga, L., Assimes, T.L., Blankenberg, S., Boerwinkle, E., Campbell, H., Cooke, J.P., Graaf, J. de, Herrington, D., Kardia, S.L., Mitchell, B.D., Murray, A., Munzel, T., Newman, A.B., Oostra, B.A., Rudan, I., Shuldiner, A.R., Snieder, H., Duijn, C.M. van, Volker, U., Wright, A.F., Wichmann, H.E., Wilson, J.F., Witteman, J.C., Liu, Y., Hayward, C., Borecki, I.B., Ziegler, A., North, K.E., Cupples, L.A., Kronenberg, F., Murabito, J.M., White, C.C., Kavousi, M., Sun, Y.V., Feitosa, M.F., Nambi, V., Lamina, C., Schillert, A., Coassin, S., Bis, J.C., Broer, L., Crawford, D.C., Franceschini, N., Frikke-Schmidt, R., Haun, M., Holewijn, S., Huffman, J.E., Hwang, S.J., Kiechl, S., Kollerits, B., Montasser, M.E., Nolte, I.M., Rudock, M.E., Senft, A., Teumer, A., Harst, P. van der, Vitart, V., Waite, L.L., Wood, A.R., Wassel, C.L., Absher, D.M., Allison, M.A., Amin, N., Arnold, A., Asselbergs, F.W., Aulchenko, Y., Bandinelli, S., Barbalic, M., Boban, M., Brown-Gentry, K., Couper, D.J., Criqui, M.H., Dehghan, A., Heijer, M. den, Dieplinger, B., Ding, J., Dorr, M., Espinola-Klein, C., Felix, S.B., Ferrucci, L., Folsom, A.R., Fraedrich, G., Gibson, Q., Goodloe, R., Gunjaca, G., Haltmayer, M., Heiss, G., Hofman, A., Kieback, A., Kiemeney, L.A.L.M., Kolcic, I., Kullo, I.J., Kritchevsky, S.B., Lackner, K.J., Li, X., Lieb, W., Lohman, K., Meisinger, C., Melzer, D., Mohler 3rd, E.R., Mudnic, I., Mueller, T., Navis, G., Oberhollenzer, F., Olin, J.W., O'Connell, J., O'Donnell, C.J., Palmas, W., Penninx, B.W.J.H., Petersmann, A., Polasek, O., Psaty, B.M., Rantner, B., Rice, K., Rivadeneira, F., Rotter, J.I., Seldenrijk, A., Stadler, M., Summerer, M., Tanaka, T., Tybjaerg-Hansen, A., Uitterlinden, A.G., Gilst, W.H. van, Vermeulen, S., Wild, S.H., Wild, P.S., Willeit, J., Zeller, T., Zemunik, T., Zgaga, L., Assimes, T.L., Blankenberg, S., Boerwinkle, E., Campbell, H., Cooke, J.P., Graaf, J. de, Herrington, D., Kardia, S.L., Mitchell, B.D., Murray, A., Munzel, T., Newman, A.B., Oostra, B.A., Rudan, I., Shuldiner, A.R., Snieder, H., Duijn, C.M. van, Volker, U., Wright, A.F., Wichmann, H.E., Wilson, J.F., Witteman, J.C., Liu, Y., Hayward, C., Borecki, I.B., Ziegler, A., North, K.E., Cupples, L.A., and Kronenberg, F.

Abstract

Item does not contain fulltext, BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. METHODS AND RESULTS: Continuous ABI and PAD (ABI

Published
2012

115. Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

Author

Pattaro, C, Kottgen, A, Teumer, A, Garnaas, M, Boger, CA, Fuchsberger, C, Olden, M, Chen, MH, Tin, A, Taliun, D, Li, M, Gao, XY, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, Aaron, Liu, CT, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G (Guo), Johnson, AD, Gierman, HJ, Feitosa, M, Hwang, SJ, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Tonjes, A, Dehghan, Abbas, Chouraki, V, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, TB, Launer, LJ (Lenore), Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, Heléna, Cavalieri, M, Rao, M, Hu, FB, Demirkan, Ayse, Oostra, Ben, de Andrade, M, Turner, ST, Ding, JZ (Jing Zhong), Andrews, JS, Freedman, BI, Koenig, W, Illig, T, Doring, A, Wichmann, HE, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nothlings, U, Jacobs, Gunar, Biffar, R, Endlich, K, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Volker, U, Volzke, H, Kovacs, P, Stumvoll, M, Magi, R, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Ruggiero, D, Bergmann, S, Kahonen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Giulianini, F, Kramer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, GA, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, Duijn, Cornelia, Borecki, I, Kardia, SLR, Liu, YM, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, JCM, Hayward, C, Ridker, P, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Chasman, DI, Kao, WHL, Fox, CS, Pattaro, C, Kottgen, A, Teumer, A, Garnaas, M, Boger, CA, Fuchsberger, C, Olden, M, Chen, MH, Tin, A, Taliun, D, Li, M, Gao, XY, Gorski, M, Yang, Q, Hundertmark, C, Foster, MC, O'Seaghdha, CM, Glazer, N, Isaacs, Aaron, Liu, CT, Smith, AV, O'Connell, JR, Struchalin, M, Tanaka, T, Li, G (Guo), Johnson, AD, Gierman, HJ, Feitosa, M, Hwang, SJ, Atkinson, EJ, Lohman, K, Cornelis, MC, Johansson, A, Tonjes, A, Dehghan, Abbas, Chouraki, V, Holliday, EG, Sorice, R, Kutalik, Z, Lehtimaki, T, Esko, T, Deshmukh, H, Ulivi, S, Chu, AY, Murgia, F, Trompet, S, Imboden, M, Kollerits, B, Pistis, G, Harris, TB, Launer, LJ (Lenore), Aspelund, T, Eiriksdottir, G, Mitchell, BD, Boerwinkle, E, Schmidt, Heléna, Cavalieri, M, Rao, M, Hu, FB, Demirkan, Ayse, Oostra, Ben, de Andrade, M, Turner, ST, Ding, JZ (Jing Zhong), Andrews, JS, Freedman, BI, Koenig, W, Illig, T, Doring, A, Wichmann, HE, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, HE, Igl, W, Zaboli, G, Wild, SH, Wright, AF, Campbell, H, Ellinghaus, D, Nothlings, U, Jacobs, Gunar, Biffar, R, Endlich, K, Ernst, F, Homuth, G, Kroemer, HK, Nauck, M, Stracke, S, Volker, U, Volzke, H, Kovacs, P, Stumvoll, M, Magi, R, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Aulchenko, YS, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, JJ, Ruggiero, D, Bergmann, S, Kahonen, M, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Doney, A, Robino, A, Giulianini, F, Kramer, BK, Portas, L, Ford, I, Buckley, BM, Adam, M, Thun, GA, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, SK, Vollenweider, P, Raitakari, O, Metspalu, A, Palmer, C, Gasparini, P, Pirastu, M, Jukema, JW, Probst-Hensch, NM, Kronenberg, F, Toniolo, D, Gudnason, V, Shuldiner, AR, Coresh, J, Schmidt, R, Ferrucci, L, Siscovick, DS, Duijn, Cornelia, Borecki, I, Kardia, SLR, Liu, YM, Curhan, GC, Rudan, I, Gyllensten, U, Wilson, JF, Franke, A, Pramstaller, PP, Rettig, R, Prokopenko, I, Witteman, JCM, Hayward, C, Ridker, P, Parsa, A, Bochud, M, Heid, IM, Goessling, W, Chasman, DI, Kao, WHL, and Fox, CS

Abstract

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

Published
2012

116. Characterization of the human myocardial proteome in inflammatory dilated cardiomyopathy by label-free quantitative shotgun proteomics of heart biopsies

Author

Hammer, E., Goritzka, M., Ameling, S., Darm, K., Steil, L., Klingel, K., Trimpert, C., Herda, L.R., Dorr, M., Kroemer, H.K., Kandolf, R., Staudt, A., Felix, S.B., Volker, U., Hammer, E., Goritzka, M., Ameling, S., Darm, K., Steil, L., Klingel, K., Trimpert, C., Herda, L.R., Dorr, M., Kroemer, H.K., Kandolf, R., Staudt, A., Felix, S.B., and Volker, U.

Abstract

Item does not contain fulltext, Dilated cardiomyopathy (DCM) is characterized by contractile dysfunction leading to heart failure. The molecular changes in the human heart associated with this disease have so far mostly been addressed at the gene expression level and only a few studies have analyzed global changes in the myocardial proteome. Therefore, our objective was to investigate the changes in the proteome in patients suffering from inflammatory DCM (iDCM) and chronic viral infection by a comprehensive quantitative approach. Comparative proteomic profiling of endomyocardial biopsies (EMB) from 10 patients with iDCM (left ventricular ejection fraction <40%, symptoms of heart failure) as well as 7 controls with normal left ventricular function and histology was performed by label-free proteome analysis (LC-MS/MS). Mass spectrometric data were analyzed with the Rosetta Elucidator software package. The analysis covered a total of 485 proteins. Among the 174 proteins displaying at least a 1.3-fold change in intensity (p < 0.05), major changes were observed for mitochondrial and cytoskeletal proteins, but also metabolic pathways were affected in iDCM compared to controls. In iDCM patients, we observed decreased levels of mitochondrial proteins involved in oxidative phosphorylation and tricarboxylic acid cycle. Furthermore, deregulation of proteins of carbohydrate metabolism, the actin cytoskeleton, and extracellular matrix remodeling was observed. Proteomic observations were confirmed by gene expression data and immunohistochemistry (e.g. collagen I and VI). This study demonstrates that label-free, mass spectrometry-centered approaches can identify disease dependent alterations in the proteome from small tissue samples such as endomyocardial biopsies. Thus, this technique might allow better disease characterization and may be a valuable tool in potential clinical proteomic studies.

Published
2011

117. Genetic determinants of serum testosterone concentrations in men

Author

Ohlsson, C., Wallaschofski, H., Lunetta, K.L., Stolk, L., Perry, J.R.B., Koster, A., Petersen, A.K., Eriksson, J., Lehtimaki, T., Huhtaniemi, I.T., Hammond, G.L., Maggio, M., Coviello, A.D., Ferrucci, L., Heier, M., Hofman, A., Holliday, K.L., Jansson, J.O., Kahonen, M., Karasik, D., Karlsson, M.K., Kiel, D.P., Liu, Y.M., Ljunggren, O., Lorentzon, M., Lyytikainen, L.P., Meitinger, T., Mellstrom, D., Melzer, D., Miljkovic, I., Nauck, M., Nilsson, M., Penninx, B.W.J.H., Pye, S.R., Vasan, R.S., Reincke, M., Rivadeneira, F., Tajar, A., Teumer, A., Uitterlinden, A. G., Ulloor, J., Viikari, J., Volker, U., Volzke, H., Wichmann, H. E., Wu, T.S., Zhuang, W.V., Ziv, E., Wu, F.C.W., Raitakari, O., Eriksson, A., Bidlingmaier, M., Harris, T.B., Murray, A., de Jong, F.H., Murabito, J.M., Bhasin, S., Vandenput, L., Haring, R., Ohlsson, C., Wallaschofski, H., Lunetta, K.L., Stolk, L., Perry, J.R.B., Koster, A., Petersen, A.K., Eriksson, J., Lehtimaki, T., Huhtaniemi, I.T., Hammond, G.L., Maggio, M., Coviello, A.D., Ferrucci, L., Heier, M., Hofman, A., Holliday, K.L., Jansson, J.O., Kahonen, M., Karasik, D., Karlsson, M.K., Kiel, D.P., Liu, Y.M., Ljunggren, O., Lorentzon, M., Lyytikainen, L.P., Meitinger, T., Mellstrom, D., Melzer, D., Miljkovic, I., Nauck, M., Nilsson, M., Penninx, B.W.J.H., Pye, S.R., Vasan, R.S., Reincke, M., Rivadeneira, F., Tajar, A., Teumer, A., Uitterlinden, A. G., Ulloor, J., Viikari, J., Volker, U., Volzke, H., Wichmann, H. E., Wu, T.S., Zhuang, W.V., Ziv, E., Wu, F.C.W., Raitakari, O., Eriksson, A., Bidlingmaier, M., Harris, T.B., Murray, A., de Jong, F.H., Murabito, J.M., Bhasin, S., Vandenput, L., and Haring, R.

Published
2011
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118. Genetic Determinants of Serum Testosterone Concentrations in Men

Author

Ohlsson, C, Wallaschofski, H, Lunetta, KL, Stolk, Lisette, Perry, JRB, Koster, A, Petersen, AK, Eriksson, J, Lehtimaki, T, Huhtaniemi, IT, Hammond, GL, Maggio, M, Coviello, AD, Ferrucci, L, Heier, M, Hofman, Bert, Holliday, KL, Jansson, JO, Kahonen, M, Karasik, D, Karlsson, MK, Kiel, DP, Liu, YM, Ljunggren, O, Lorentzon, M, Lyytikainen, LP, Meitinger, T, Mellstrom, D, Melzer, D, Miljkovic, I, Nauck, M, Nilsson, M, Penninx, B, Pye, SR, Vasan, RS, Reincke, M, Rivadeneira, Fernando, Tajar, A, Teumer, A, Uitterlinden, André, Ulloor, J, Viikari, J, Volker, U, Volzke, H, Wichmann, HE, Wu, TS, Zhuang, WV, Ziv, E, Wu, FCW, Raitakari, O, Eriksson, A, Bidlingmaier, M, Harris, TB, Murray, A, Jong, Frank, Murabito, JM, Bhasin, S, Vandenput, L, Haring, R, Ohlsson, C, Wallaschofski, H, Lunetta, KL, Stolk, Lisette, Perry, JRB, Koster, A, Petersen, AK, Eriksson, J, Lehtimaki, T, Huhtaniemi, IT, Hammond, GL, Maggio, M, Coviello, AD, Ferrucci, L, Heier, M, Hofman, Bert, Holliday, KL, Jansson, JO, Kahonen, M, Karasik, D, Karlsson, MK, Kiel, DP, Liu, YM, Ljunggren, O, Lorentzon, M, Lyytikainen, LP, Meitinger, T, Mellstrom, D, Melzer, D, Miljkovic, I, Nauck, M, Nilsson, M, Penninx, B, Pye, SR, Vasan, RS, Reincke, M, Rivadeneira, Fernando, Tajar, A, Teumer, A, Uitterlinden, André, Ulloor, J, Viikari, J, Volker, U, Volzke, H, Wichmann, HE, Wu, TS, Zhuang, WV, Ziv, E, Wu, FCW, Raitakari, O, Eriksson, A, Bidlingmaier, M, Harris, TB, Murray, A, Jong, Frank, Murabito, JM, Bhasin, S, Vandenput, L, and Haring, R

Abstract

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as,300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2x10(-41) and rs6258, p = 2.3x10(-22)). Subjects with >= 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6610216). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

Published
2011

119. Antibody responses in furunculosis patients vaccinated with autologous formalin-killed Staphylococcus aureus

Author

Holtfreter, S, Jursa-Kulesza, J, Masiuk, H, Verkaik, Nelianne, de Vogel, Corne, Kolata, J, Nowosiad, M, Steil, L, van Wamel, Willem, Belkum, Alex, Volker, U, Giedrys-Kalemba, S, Broker, BM, Holtfreter, S, Jursa-Kulesza, J, Masiuk, H, Verkaik, Nelianne, de Vogel, Corne, Kolata, J, Nowosiad, M, Steil, L, van Wamel, Willem, Belkum, Alex, Volker, U, Giedrys-Kalemba, S, and Broker, BM

Abstract

Autologous vaccines (short: autovaccines) have been used since the beginning of the 20th century to treat chronic staphylococcal infections, but their mechanisms of action are still obscure. This prospective pilot study involved four patients with furunculosis who were vaccinated with autologous formalin-killed Staphylococcus aureus cells. Vaccines were individually prepared from the infecting S. aureus strain and repeatedly injected subcutaneously in increasing doses over several months. We characterized the virulence gene repertoire and spa genotype of the infecting and colonising S. aureus strains. Serum antibody responses to secreted and surface-bound bacterial antigens were determined by two-dimensional immunoblotting and flow-cytometry based assays (LuminexA (R)). All patients reported clinical improvement. Molecular characterization showed that all strains isolated from one patient over time belonged to the same S. aureus clone. Already before treatment, there was robust antibody binding to a broad range of staphylococcal antigens. Autovaccination moderately boosted the IgG response to extracellular antigens in two patients, while the antibody response of the other two patients was not affected. Similarly, vaccination moderately enhanced the antibody response against some staphylococcal surface proteins, e.g. ClfA, ClfB, SdrD and SdrE. In summary, autovaccination only slightly boosted the pre-existing serum antibody response, predominantly to bacterial surface antigens.

Published
2011

121. Trophoblast-Endometrial Interaction in a 3D Culture System

Author

Volker U. Buck, Oliver Krings, Rudolf E. Leube, Irmgard Classen-Linke, Birgit Gellersen, and Fabia Flensberg

Subjects
medicine.anatomical_structure, Reproductive Medicine, medicine, Obstetrics and Gynecology, Trophoblast, Biology, Developmental Biology, Cell biology
Published
2013
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124. Direct Analysis and Identification of Pathogenic Lichtheimia Species by Matrix-Assisted Laser Desorption Ionization–Time of Flight Analyzer-Mediated Mass Spectrometry

Author

Schrödl, Wieland, primary, Heydel, Tilo, additional, Schwartze, Volker U., additional, Hoffmann, Kerstin, additional, Große-Herrenthey, Anke, additional, Walther, Grit, additional, Alastruey-Izquierdo, Ana, additional, Rodriguez-Tudela, Juan Luis, additional, Olias, Philipp, additional, Jacobsen, Ilse D., additional, de Hoog, G. Sybren, additional, and Voigt, Kerstin, additional

Published
2012
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125. Ketoacidosis alone does not predispose to mucormycosis by Lichtheimiain a murine pulmonary infection model

Author

Schulze, Bianca, Rambach, Günter, Schwartze, Volker U., Voigt, Kerstin, Schubert, Katja, Speth, Cornelia, and Jacobsen, Ilse D.

Abstract

ABSTRACTMucormycosis is a rare fungal infection; however, the number of cases increased during the last decades. The main risk factors are immunosuppression and uncontrolled diabetes mellitus. Although Lichtheimiaspecies represent a common cause of mucormycosis in Europe, virulence and pathogenesis of this genus has not been investigated in detail yet. Using murine pulmonary infection models, we found that immunosuppression is essential for establishment of infection. The disease was characterized by necrosis, angioinvasion, thrombosis, and the lethal course of infection was associated with systemic activation of platelets. Furthermore, dissemination to internal organs was frequently observed. While the virulence potential of individual L. corymbiferaand L. ramosaisolates differed, pathogenicity of both species was comparable. Although ketoacidosis promoted Rhizopusinfection in mice, it did not predispose mice to infection with Lichtheimiain the absence of additional immunosuppression. This might partially explain the dominance of Rhizopusas cause of mucormycosis in countries with high prevalence of ketoacidotic patients.

Published
2017
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126. Wasserstoff — Energie mit Zukunft

Author

Volker U. Hoffmann

Subjects
Physics, Index (economics), Analytical chemistry
Abstract

Note: Bibliogr. : p. 168-169. Index Reference Record created on 2004-09-07, modified on 2016-08-08

Published
1994
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127. Wasserstoff als Energieträger

Author

Volker U. Hoffmann

Abstract

Die energetische Nutzung von Wasserstoff ist keineswegs eine nur auf die fernere Zukunft orientierte Angelegenheit, wie dies auf den ersten Blick vielleicht erscheinen mag. Immerhin hat die Menschheit bei ihrem bisherigen Umgang mit Energietragem der unterschiedlichsten Herkunft, auch schon uber lange Zeit hinweg den Wasserstoff indirekt und gewissermasen unbewust in grosen Mengen fur energetische Zwecke eingesetzt.

Published
1994
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129. Wasserstofftransport und -speicherung

Author

Volker U. Hoffmann

Abstract

Um Wasserstoff fur die vorgesehene technische oder energetische Nutzung zu jeder beliebigen Zeit und an jedem beliebigen Ort in ausreichenden Mengen verfugbar zu haben, bedarf es neben den entsprechenden Erzeugungskapazitaten auch effektiver Transport- und Speichertechnologien. Bedingt durch den bereits recht umfangreichen Wasserstoffeinsatz, vor allem in der chemischen Industrie, sind einige dieser Technologien schon vorhanden und weisen einen hohen technischen Stand auf. An ihrer Vervollkommnung wird aber ebenso intensiv gearbeitet wie an der Entwicklung neuer Technologien.

Published
1994
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131. Ergebnisse der Standardauswertung des 1000-Dächer-Programms

Author

Volker U. Hoffmann

Abstract

Die Begrenztheit der Energieressourcen sowie die Gefahr von Umweltschadigungen und Klimaveranderungen durch das Verbrennen fossiler Energietrager fordern rasch wirksame Masnahmen zum effizienten Umgang mit Energie, zur betrachtlichen Energieeinsparung und zur Erschliesung CO2-freier Energiequellen. Als eine der vielen Moglichkeiten dazu kann die Photovoltaik, die Technik der direkten Umwandlung von Sonnenlicht in elektrischen Strom angesehen werden /1/.

Published
1994
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132. Am Anfang war der Wasserstoff

Author

Volker U. Hoffmann

Abstract

So lautet nicht nur der Titel eines lesenswerten popularwissenschaftlichen Buches, sondern das war die Realitat vor mehr als 20 Mrd. Jahren. Nahezu alle Naturwissenschaftler sind sich heute daruber einig, das in jener sehr fernen Vergangenheit tatsachlich nichts anderes vorhanden war als der Wasserstoff. Und sie sehen daher in ihm mit Fug und Recht das Urelement aller Entwicklung.

Published
1994
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133. Cohort Profile: The Study of Health in Pomerania

Author

Volzke, H., primary, Alte, D., additional, Schmidt, C. O., additional, Radke, D., additional, Lorbeer, R., additional, Friedrich, N., additional, Aumann, N., additional, Lau, K., additional, Piontek, M., additional, Born, G., additional, Havemann, C., additional, Ittermann, T., additional, Schipf, S., additional, Haring, R., additional, Baumeister, S. E., additional, Wallaschofski, H., additional, Nauck, M., additional, Frick, S., additional, Arnold, A., additional, Junger, M., additional, Mayerle, J., additional, Kraft, M., additional, Lerch, M. M., additional, Dorr, M., additional, Reffelmann, T., additional, Empen, K., additional, Felix, S. B., additional, Obst, A., additional, Koch, B., additional, Glaser, S., additional, Ewert, R., additional, Fietze, I., additional, Penzel, T., additional, Doren, M., additional, Rathmann, W., additional, Haerting, J., additional, Hannemann, M., additional, Ropcke, J., additional, Schminke, U., additional, Jurgens, C., additional, Tost, F., additional, Rettig, R., additional, Kors, J. A., additional, Ungerer, S., additional, Hegenscheid, K., additional, Kuhn, J.-P., additional, Kuhn, J., additional, Hosten, N., additional, Puls, R., additional, Henke, J., additional, Gloger, O., additional, Teumer, A., additional, Homuth, G., additional, Volker, U., additional, Schwahn, C., additional, Holtfreter, B., additional, Polzer, I., additional, Kohlmann, T., additional, Grabe, H. J., additional, Rosskopf, D., additional, Kroemer, H. K., additional, Kocher, T., additional, Biffar, R., additional, John, U., additional, and Hoffmann, W., additional

Published
2010
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134. Adaptation to thermotolerance in Rhizopus coincides with virulence as revealed by avian and invertebrate infection models, phylogeny, physiological and metabolic flexibility.

Author

Kaerger, Kerstin, Schwartze, Volker U, Dolatabadi, Somayeh, Nyilasi, Ildikó, Kovács, Stella A, Binder, Ulrike, Papp, Tamás, Hoog, Sybren de, Jacobsen, Ilse D, and Voigt, Kerstin

Subjects
*MUCORMYCOSIS, *EFFECT of heat on fungi, *IMMUNOSUPPRESSION, *MYCOSES, *RHIZOPUS, *MICROBIAL virulence
Abstract

Mucormycoses are fungal infections caused by the ancient Mucorales. They are rare, but increasingly reported. Predisposing conditions supporting and favoring mucormycoses in humans and animals include diabetic ketoacidosis, immunosuppression and haematological malignancies. However, comprehensive surveys to elucidate fungal virulence in ancient fungi are limited and so far focused on Lichtheimia and Mucor. The presented study focused on one of the most important causative agent of mucormycoses, the genus Rhizopus (Rhizopodaceae). All known clinically-relevant species are thermotolerant and are monophyletic. They are more virulent compared to non-clinically, mesophilic species. Although adaptation to elevated temperatures correlated with the virulence of the species, mesophilic strains showed also lower virulence in Galleria mellonella incubated at permissive temperatures indicating the existence of additional factors involved in the pathogenesis of clinical Rhizopus species. However, neither specific adaptation to nutritional requirements nor stress resistance correlated with virulence, supporting the idea that Mucorales are predominantly saprotrophs without a specific adaptation to warm blooded hosts. [ABSTRACT FROM AUTHOR]

Published
2015
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135. Gene Expansion Shapes Genome Architecture in the Human Pathogen Lichtheimia corymbifera: An Evolutionary Genomics Analysis in the Ancient Terrestrial Mucorales (Mucoromycotina).

Author

Schwartze, Volker U., Winter, Sascha, Shelest, Ekaterina, Marcet-Houben, Marina, Horn, Fabian, Wehner, Stefanie, Linde, Jörg, Valiante, Vito, Sammeth, Michael, Riege, Konstantin, Nowrousian, Minou, Kaerger, Kerstin, Jacobsen, Ilse D., Marz, Manja, Brakhage, Axel A., Gabaldón, Toni, Böcker, Sebastian, and Voigt, Kerstin

Subjects
*GENOMICS, *MUCORALES, *MUCORMYCOSIS, *NUCLEOTIDE sequence, *RHIZOPUS oryzae
Abstract

Lichtheimia species are the second most important cause of mucormycosis in Europe. To provide broader insights into the molecular basis of the pathogenicity-associated traits of the basal Mucorales, we report the full genome sequence of L. corymbifera and compared it to the genome of Rhizopus oryzae, the most common cause of mucormycosis worldwide. The genome assembly encompasses 33.6 MB and 12,379 protein-coding genes. This study reveals four major differences of the L. corymbifera genome to R. oryzae: (i) the presence of an highly elevated number of gene duplications which are unlike R. oryzae not due to whole genome duplication (WGD), (ii) despite the relatively high incidence of introns, alternative splicing (AS) is not frequently observed for the generation of paralogs and in response to stress, (iii) the content of repetitive elements is strikingly low (<5%), (iv) L. corymbifera is typically haploid. Novel virulence factors were identified which may be involved in the regulation of the adaptation to iron-limitation, e.g. LCor01340.1 encoding a putative siderophore transporter and LCor00410.1 involved in the siderophore metabolism. Genes encoding the transcription factors LCor08192.1 and LCor01236.1, which are similar to GATA type regulators and to calcineurin regulated CRZ1, respectively, indicating an involvement of the calcineurin pathway in the adaption to iron limitation. Genes encoding MADS-box transcription factors are elevated up to 11 copies compared to the 1–4 copies usually found in other fungi. More findings are: (i) lower content of tRNAs, but unique codons in L. corymbifera, (ii) Over 25% of the proteins are apparently specific for L. corymbifera. (iii) L. corymbifera contains only 2/3 of the proteases (known to be essential virulence factors) in comparision to R. oryzae. On the other hand, the number of secreted proteases, however, is roughly twice as high as in R. oryzae. [ABSTRACT FROM AUTHOR]

Published
2014
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136. Adaptation to thermotolerance in Rhizopuscoincides with virulence as revealed by avian and invertebrate infection models, phylogeny, physiological and metabolic flexibility

Author

Kaerger, Kerstin, Schwartze, Volker U, Dolatabadi, Somayeh, Nyilasi, Ildikó, Kovács, Stella A, Binder, Ulrike, Papp, Tamás, Hoog, Sybren de, Jacobsen, Ilse D, and Voigt, Kerstin

Abstract

Mucormycoses are fungal infections caused by the ancient Mucorales. They are rare, but increasingly reported. Predisposing conditions supporting and favoring mucormycoses in humans and animals include diabetic ketoacidosis, immunosuppression and haematological malignancies. However, comprehensive surveys to elucidate fungal virulence in ancient fungi are limited and so far focused on Lichtheimiaand Mucor. The presented study focused on one of the most important causative agent of mucormycoses, the genus Rhizopus(Rhizopodaceae). All known clinically-relevant species are thermotolerant and are monophyletic. They are more virulent compared to non-clinically, mesophilic species. Although adaptation to elevated temperatures correlated with the virulence of the species, mesophilic strains showed also lower virulence in Galleria mellonellaincubated at permissive temperatures indicating the existence of additional factors involved in the pathogenesis of clinical Rhizopusspecies. However, neither specific adaptation to nutritional requirements nor stress resistance correlated with virulence, supporting the idea that Mucorales are predominantly saprotrophs without a specific adaptation to warm blooded hosts.

Published
2015
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139. Direct Analysis and Identification of Pathogenic LichtheimiaSpecies by Matrix-Assisted Laser Desorption Ionization–Time of Flight Analyzer-Mediated Mass Spectrometry

Author

Schrödl, Wieland, Heydel, Tilo, Schwartze, Volker U., Hoffmann, Kerstin, Große-Herrenthey, Anke, Walther, Grit, Alastruey-Izquierdo, Ana, Rodriguez-Tudela, Juan Luis, Olias, Philipp, Jacobsen, Ilse D., de Hoog, G. Sybren, and Voigt, Kerstin

Abstract

ABSTRACTZygomycetes of the order Mucorales can cause life-threatening infections in humans. These mucormycoses are emerging and associated with a rapid tissue destruction and high mortality. The resistance of Mucorales to antimycotic substances varies between and within clinically important genera such as Mucor, Rhizopus, and Lichtheimia. Thus, an accurate diagnosis before onset of antimycotic therapy is recommended. Matrix-assisted laser desorption ionization (MALDI)–time of flight (TOF) mass spectrometry (MS) is a potentially powerful tool to rapidly identify infectious agents on the species level. We investigated the potential of MALDI-TOF MS to differentiate Lichtheimiaspecies, one of the most important agents of mucormycoses. Using the Bruker Daltonics FlexAnalysis (version 3.0) software package, a spectral database library with m/zratios of 2,000 to 20,000 Da was created for 19 type and reference strains of clinically relevant Zygomycetes of the order Mucorales (12 species in 7 genera). The database was tested for accuracy by use of 34 clinical and environmental isolates of Lichtheimiacomprising a total of five species. Our data demonstrate that MALDI-TOF MS can be used to clearly discriminate Lichtheimiaspecies from other pathogenic species of the Mucorales. Furthermore, the method is suitable to discriminate species within the genus. The reliability and robustness of the MALDI-TOF-based identification are evidenced by high score values (above 2.3) for the designation to a certain species and by moderate score values (below 2.0) for the discrimination between clinically relevant (Lichtheimia corymbifera, L. ramosa, and L. ornata) and irrelevant (L. hyalosporaand L. sphaerocystis) species. In total, all 34 strains were unequivocally identified by MALDI-TOF MS with score values of >1.8 down to the generic level, 32 out of 34 of the Lichtheimiaisolates (except CNM-CM 5399 and FSU 10566) were identified accurately with score values of >2 (probable species identification), and 25 of 34 isolates were identified to the species level with score values of >2.3 (highly probable species identification). The MALDI-TOF MS-based method reported here was found to be reproducible and accurate, with low consumable costs and minimal preparation time.

Published
2012
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141. Genome-wide association and functional follow-up reveals new loci for kidney function

Author

Pattaro, C., Kottgen, A., Teumer, A., Garnaas, M., Boger, C. A., Fuchsberger, C., Olden, M., Chen, M. H., Tin, A., Taliun, D., Li, M., Gao, X., Gorski, M., Yang, Q., Hundertmark, C., Foster, M. C., O'Seaghdha, C. M., Glazer, N., Isaacs, A., Liu, C. T., Smith, A. V., O'Connell, J. R., Struchalin, M., Tanaka, T., Li, G., Johnson, A. D., Gierman, H. J., Feitosa, M., Hwang, S. J., Atkinson, E. J., Lohman, K., Cornelis, M. C., Johansson, A., Tonjes, A., Dehghan, A., Chouraki, V., Holliday, E. G., Sorice, R., Kutalik, Z., Lehtimaki, T., Esko, T., Deshmukh, H., Ulivi, S., Chu, A. Y., Murgia, F., Trompet, S., Imboden, M., Kollerits, B., Pistis, G., Harris, T. B., Launer, L. J., Aspelund, T., Eiriksdottir, G., Mitchell, B. D., Boerwinkle, E., Schmidt, H., Cavalieri, M., Rao, M., Hu, F. B., Demirkan, A., Oostra, B. A., de, A. M., Turner, S. T., Ding, J., Andrews, J. S., Freedman, B. I., Koenig, W., Illig, T., Doring, A., Wichmann, H. E., Kolcic, I., Zemunik, T., Boban, M., Minelli, C., Wheeler, H. E., Igl, W., Zaboli, G., Wild, S. H., Wright, A. F., Campbell, H., Ellinghaus, D., Nothlings, U., Jacobs, G., Biffar, R., Endlich, K., Ernst, F., Homuth, G., Kroemer, H. K., Nauck, M., Stracke, S., Volker, U., Volzke, H., Kovacs, P., Stumvoll, M., Magi, R., Hofman, A., Uitterlinden, A. G., Rivadeneira, F., Aulchenko, Y. S., Polasek, O., Hastie, N., Vitart, V., Helmer, C., Wang, J. J., Ruggiero, D., Bergmann, S., Kahonen, M., Viikari, J., Nikopensius, T., Province, M., Ketkar, S., Colhoun, H., Doney, A., Robino, A., Giulianini, F., Kramer, B. K., Portas, L., Ford, I., Buckley, B. M., Adam, M., Thun, G. A., Paulweber, B., Haun, M., Sala, C., Metzger, M., Mitchell, P., Ciullo, M., Kim, S. K., Vollenweider, P., Raitakari, O., Metspalu, A., Palmer, C., Gasparini, P., Pirastu, M., Jukema, J. W., Probst-Hensch, N. M., Kronenberg, F., Toniolo, D., Gudnason, V., Shuldiner, A. R., Coresh, J., Schmidt, R., Ferrucci, L., Siscovick, D. S., van, Duijn, Borecki, I., Kardia, S. L., Liu, Y., Curhan, G. C., Rudan, I., Gyllensten, U., Wilson, J. F., Franke, A., Pramstaller, P. P., Rettig, R., Prokopenko, I., Witteman, J. C., Hayward, C., Ridker, P., Parsa, A., Bochud, M., Heid, I. M., Goessling, W., Chasman, D. I., Kao, W. H., and Fox, C. S.

Subjects
3. Good health

142. Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease

Author

Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S. J., Jensen, R. A., Rawal, R., Roef, G. L., Plantinga, T. S., Vermeulen, S. H., Lahti, J., Simmonds, M. J., Husemoen, L. N. N., Freathy, R. M., Shields, B. M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T. I. M., Plia, M. G., Sala, C., Volker, U., Richards, J. B., Sweep, F. C., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y. E., Visser, W. E., Hattersley, A. T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., van de Bunt, M., Liyanarachchi, S., Heier, M., Grabe, H. J., Masciullo, C., Galesloot, T. E., Lim, E. M., Reischl, E., Leedman, P. J., Lai, S., Delitala, A., Bremner, A. P., Philips, D. I. W., Beilby, J. P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E. E., Palotie, A., Feddema, P., Fletcher, S. J., Schramm, K., Rotter, J. I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G. L., He, H., Franklyn, J. A., Tiller, D., Vaidya, B., de Meyer, T., Jørgensen, T., Eriksson, J. G., O’Leary, P. C., Wichmann, E., Hermus, A. R., Psaty, B. M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., de la Chapelle, A., Netea-Maier, R.T., Gough, S.C.L., Meyer zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Linneberg, A., Raikkonen, K., Smit, J.W.A., Kiemeney, L.A., Rivadeneira, F., Uitterlinden, A.G., Walsh, J.P., Meisinger, C., den Heijer, M., Visser, T.J., Spector, T.D., Wilson, S.G., Volzke, H., Cappola, A., Toniolo, D., Sanna, S., Naitza, S., Peeters, R.P., Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S. J., Jensen, R. A., Rawal, R., Roef, G. L., Plantinga, T. S., Vermeulen, S. H., Lahti, J., Simmonds, M. J., Husemoen, L. N. N., Freathy, R. M., Shields, B. M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T. I. M., Plia, M. G., Sala, C., Volker, U., Richards, J. B., Sweep, F. C., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y. E., Visser, W. E., Hattersley, A. T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., van de Bunt, M., Liyanarachchi, S., Heier, M., Grabe, H. J., Masciullo, C., Galesloot, T. E., Lim, E. M., Reischl, E., Leedman, P. J., Lai, S., Delitala, A., Bremner, A. P., Philips, D. I. W., Beilby, J. P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E. E., Palotie, A., Feddema, P., Fletcher, S. J., Schramm, K., Rotter, J. I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G. L., He, H., Franklyn, J. A., Tiller, D., Vaidya, B., de Meyer, T., Jørgensen, T., Eriksson, J. G., O’Leary, P. C., Wichmann, E., Hermus, A. R., Psaty, B. M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., de la Chapelle, A., Netea-Maier, R.T., Gough, S.C.L., Meyer zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Linneberg, A., Raikkonen, K., Smit, J.W.A., Kiemeney, L.A., Rivadeneira, F., Uitterlinden, A.G., Walsh, J.P., Meisinger, C., den Heijer, M., Visser, T.J., Spector, T.D., Wilson, S.G., Volzke, H., Cappola, A., Toniolo, D., Sanna, S., Naitza, S., and Peeters, R.P.

Abstract

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10−8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10−8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10−6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10−4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10−7 and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10−5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10−3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do

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