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2. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Author

Sotoodehnia, Nona, Isaacs, Aaron, de Bakker, Paul IW, Dörr, Marcus, Newton-Cheh, Christopher, Nolte, Ilja M, van der Harst, Pim, Müller, Martina, Eijgelsheim, Mark, Alonso, Alvaro, Hicks, Andrew A, Padmanabhan, Sandosh, Hayward, Caroline, Smith, Albert Vernon, Polasek, Ozren, Giovannone, Steven, Fu, Jingyuan, Magnani, Jared W, Marciante, Kristin D, Pfeufer, Arne, Gharib, Sina A, Teumer, Alexander, Li, Man, Bis, Joshua C, Rivadeneira, Fernando, Aspelund, Thor, Köttgen, Anna, Johnson, Toby, Rice, Kenneth, Sie, Mark PS, Wang, Ying A, Klopp, Norman, Fuchsberger, Christian, Wild, Sarah H, Leach, Irene Mateo, Estrada, Karol, Völker, Uwe, Wright, Alan F, Asselbergs, Folkert W, Qu, Jiaxiang, Chakravarti, Aravinda, Sinner, Moritz F, Kors, Jan A, Petersmann, Astrid, Harris, Tamara B, Soliman, Elsayed Z, Munroe, Patricia B, Psaty, Bruce M, Oostra, Ben A, Cupples, L Adrienne, Perz, Siegfried, de Boer, Rudolf A, Uitterlinden, André G, Völzke, Henry, Spector, Timothy D, Liu, Fang-Yu, Boerwinkle, Eric, Dominiczak, Anna F, Rotter, Jerome I, van Herpen, Gé, Levy, Daniel, Wichmann, H-Erich, van Gilst, Wiek H, Witteman, Jacqueline CM, Kroemer, Heyo K, Kao, WH Linda, Heckbert, Susan R, Meitinger, Thomas, Hofman, Albert, Campbell, Harry, Folsom, Aaron R, van Veldhuisen, Dirk J, Schwienbacher, Christine, O'Donnell, Christopher J, Volpato, Claudia Beu, Caulfield, Mark J, Connell, John M, Launer, Lenore, Lu, Xiaowen, Franke, Lude, Fehrmann, Rudolf SN, te Meerman, Gerard, Groen, Harry JM, Weersma, Rinse K, van den Berg, Leonard H, Wijmenga, Cisca, Ophoff, Roel A, Navis, Gerjan, Rudan, Igor, Snieder, Harold, Wilson, James F, Pramstaller, Peter P, Siscovick, David S, Wang, Thomas J, Gudnason, Vilmundur, van Duijn, Cornelia M, Felix, Stephan B, Fishman, Glenn I, Jamshidi, Yalda, and Ch Stricker, Bruno H

Subjects
Biological Sciences, Genetics, Cardiovascular, Heart Disease, Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Published
2010

29. OATP1B3 is expressed in pancreatic β-islet cells and enhances the insulinotropic effect of the sulfonylurea derivative glibenclamide

Author

Schwabedissen, Henriette E. Meyer zu, Boettcher, Kerstin, Steiner, Tobias, Schwarz, Ute I., Keiser, Markus, Kroemer, Heyo K., and Siegmund, Werner

Subjects
Medical research, Medicine, Experimental, Gene expression -- Research, Polypeptides -- Physiological aspects, Diabetes -- Care and treatment -- Physiological aspects, Hypoglycemic agents -- Dosage and administration -- Physiological aspects, Health
Abstract

Organic anion transporting polypeptide OATP1B3 is a membrane-bound drug transporter that facilitates cellular entry of a variety of substrates. Most of the previous studies focused on its hepatic expression and function in hepatic drug elimination. In this study, we report expression of OATP1B3 in human pancreatic tissue, with the abundance of the transporter localized in the islets of Langerhans. Transport studies using OATP1B3-overexpressing MDCKII cells revealed significant inhibition of the cellular uptake of the known substrate cholecystokinin-8 in the presence of the insulinotropic antidiabetes compounds tolbutamide, glibenclamide, glimepiride, and nateglinide and identified glibenclamide as a novel substrate of OATP1B3. Sulfonylurea derivatives exert their insulinotropic effect by binding to the SUR1 subunit of the [K.sub.ATP] channels inducing insulin secretion in β-cells. Here, we show that transient overexpression of human OATP1B3 in a murine β-cell line (MIN6)-which exhibits glucose and glibenclamide-sensitive insulin secretion--significantly enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion. Taken together, our data provide evidence that the drug transporter OATP1B3 functions as a determinant of the insulinotropic effect of glibenclamide on the tissue level. Changes in transport activity based on drug-drug interactions or genetic variability may therefore influence glibenclamide efficacy. DOI: 10.2337/db13-1005, The organic anion transporting polypeptides (OATPs/ gene SLCO) belong to the solute carrier (SLC) superfamfly comprising membrane-bound transporters facilitating cellular entry and are characterized by a wide range of diverse [...]

Published
2014
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30. Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms

Author

Meyer zu Schwabedissen, Henriette E., Verstuyft, Celine, Kroemer, Heyo K., Becquemont, Laurent, and Kim, Richard B.

Subjects
Biological transport -- Physiological aspects, Biological transport -- Genetic aspects, Biological transport -- Research, Membrane proteins -- Physiological aspects, Membrane proteins -- Genetic aspects, Membrane proteins -- Research, Single nucleotide polymorphisms -- Physiological aspects, Biological sciences
Abstract

Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB. Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol 298: F997-F1005, 2010. First published January 6, 2010; doi: 10.1152/ajprenal.00431.2009.--renal elimination of a number of cationic compounds is thought to be mediated by the organic cation transporter 2 (OCT2, SLC22A2), a drug uptake transporter expressed at the basolateral domain of renal tubular cells. Recently, the key efflux transporter for the secretion organic cations was identified as an electroneutral H+/organic cation exchanger termed the multidrug and toxin extrusion (MATE)-type transporter 1 (MATE1, SLC47A1). The key goals of this study were to assess the interplay between the renal cationic transporters OCT2 and MATEI and the functional assessment of genetic variation in human MATE1. First, the ability of various agents to interact with OCT2- or MATE1-mediated transport was determined using a recombinant vaccinia expression system. We were able to identify several drugs in clinical use with a divergent inhibitory capacity for these transporters. Subsequently, we further assessed the effect of those compounds on the cellular accumulation of shared substrates using OCT2 and MATE1 double-transfected cells. Consistent with data obtained using single transporter transfected cells, compounds that exhibited preferential inhibition of MATE1 such as rapamycin and mitoxantrone induced significant cellular accumulation of cationic substrates. We next assessed the functional relevance of MATE1 genetic polymorphisms. Significant loss of transport activity for metformin and tetraethylammonium was noted for two nonsynonymous single nucleotide polymorphisms (SNPs), c.404T>C (p.159T>M) and c.1012G>A (p.338V>A). The c.404T>C was only seen in Asian subjects with an allele frequency of 1%, and the c.1012G>A SNP was much more common, especially among those of African descent. In conclusion, we show that coordinate function of MATEI with OCT2 likely contributes to the vectorial renal elimination of organic cationic drugs and that altered activity of MATE 1, whether by drugs or polymorphisms, should be considered as an important determinant of renal cationic drug elimination. organic cation transporter; drug-drug interactions; polymorphisms; biological transport; metformin doi: 10.1152/ajprenal.00431.2009.

Published
2010

32. Genetic variants associated with cardiac structure and function

Author

Vasan, Ramachandran S., Glazer, Nicole L., Felix, Janine F., Lieb, Wolfgang, Wild, Philipp S., Felix, Stephan B, Watzinger, Norbert, Larson, Martin G., Smith, Nicholas L., Dehghan, Abbas, Gro-henning, Anika, Schillert, Arne, Teumer, Alexander, Schmidt, Reinhold, Kathiresan, Sekar, Lumley, Thomas, Aulchenko, Yurii S., Konig, Inke R., Zeller, Tanja, Homuth, Georg, Struchalin, Maksim, Aragam, Jayashri, Bis, Joshua C., Rivadeneira, Fernando, Erdmann, Jeanette, Schnabel, Renate B., Dorr, Marcus, Zweiker, Robert, Lind Lars, Rodeheffer, Richard J., Greiser, Karin Halina, Levy, Daniel, Haritunians, Talin, Deckers, Jaap W., Stritzke, Jan, Lackner, Karl J., Volker, Uwe, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johannes, OEDonnell, Christopher J., Heckbert, Susan R., Stricker, Bruno H., Ziegler, Andreas, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Rice, Kenneth, Arnett, Donna K., Hofman, Albert, Gottdiener, John S., Uitterlinden, Andre G., Meitinger, Thomas, Blettner, Maria, Friedrich, Nele, Wang, Thomas J., Psaty, Bruce M., van Duijn, Cornelia M., Wichmann, H.-Erich, Munzel, Thomas F., Kroemer, Heyo K., Benjamin, Emelia J., Rotter, Jerome I., Witteman, Jacqueline C., Schunkert, Heribert, Schmidt, Helena, Volzke, Henry, and Blankenberg, Stefan

Subjects
Cardiovascular diseases -- Genetic aspects, Echocardiography -- Usage, Heart -- Physiological aspects, Heart -- Genetic aspects, Meta-analysis -- Usage
Abstract

A study was conducted to investigate and identify genetic variants that are associated with cardiac structure and function through a meta-analysis. Results indicated that there were 5 genetic loci, associated with variance in cardiac dimensions and aortic root size; however, the proportion of variance is quite small.

Published
2009

40. Identification of Genetic Loci Associated With Helicobacter pylori Serologic Status

Author

Mayerle, Julia, den Hoed, Caroline M., Schurmann, Claudia, Stolk, Lisette, Homuth, Georg, Peters, Marjolein J., Capelle, Lisette G., Zimmermann, Kathrin, Rivadeneira, Fernando, Gruska, Sybille, Völzke, Henry, de Vries, Annemarie C., Völker, Uwe, Teumer, Alexander, van Meurs, Joyce B., Steinmetz, Ivo, Nauck, Matthias, Ernst, Florian, Weiss, Frank-Ulrich, Hofman, Albert, Zenker, Martin, Kroemer, Heyo K., Prokisch, Holger, Uitterlinden, Andre G., Lerch, Markus M., and Kuipers, Ernst

Published
2013
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43. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Author

Chasman, Daniel I., Fuchsberger, Christian, Pattaro, Cristian, Teumer, Alexander, Böger, Carsten A., Endlich, Karlhans, Olden, Matthias, Chen, Ming-Huei, Tin, Adrienne, Taliun, Daniel, Li, Man, Gao, Xiaoyi, Gorski, Mathias, Yang, Qiong, Hundertmark, Claudia, Foster, Meredith C., OʼSeaghdha, Conall M., Glazer, Nicole, Isaacs, Aaron, Liu, Ching-Ti, Smith, Albert V., OʼConnell, Jeffrey R., Struchalin, Maksim, Tanaka, Toshiko, Li, Guo, Johnson, Andrew D., Gierman, Hinco J., Feitosa, Mary F., Hwang, Shih-Jen, Atkinson, Elizabeth J., Lohman, Kurt, Cornelis, Marilyn C., Johansson, Åsa, Tönjes, Anke, Dehghan, Abbas, Lambert, Jean-Charles, Holliday, Elizabeth G., Sorice, Rossella, Kutalik, Zoltan, Lehtimäki, Terho, Esko, Tõnu, Deshmukh, Harshal, Ulivi, Sheila, Chu, Audrey Y., Murgia, Federico, Trompet, Stella, Imboden, Medea, Coassin, Stefan, Pistis, Giorgio, Harris, Tamara B., Launer, Lenore J., Aspelund, Thor, Eiriksdottir, Gudny, Mitchell, Braxton D., Boerwinkle, Eric, Schmidt, Helena, Cavalieri, Margherita, Rao, Madhumathi, Hu, Frank, Demirkan, Ayse, Oostra, Ben A., de Andrade, Mariza, Turner, Stephen T., Ding, Jingzhong, Andrews, Jeanette S., Freedman, Barry I., Giulianini, Franco, Koenig, Wolfgang, Illig, Thomas, Meisinger, Christa, Gieger, Christian, Zgaga, Lina, Zemunik, Tatijana, Boban, Mladen, Minelli, Cosetta, Wheeler, Heather E., Igl, Wilmar, Zaboli, Ghazal, Wild, Sarah H., Wright, Alan F., Campbell, Harry, Ellinghaus, David, Nöthlings, Ute, Jacobs, Gunnar, Biffar, Reiner, Ernst, Florian, Homuth, Georg, Kroemer, Heyo K., Nauck, Matthias, Stracke, Sylvia, Völker, Uwe, Völzke, Henry, Kovacs, Peter, Stumvoll, Michael, Mägi, Reedik, Hofman, Albert, Uitterlinden, Andre G., Rivadeneira, Fernando, Aulchenko, Yurii S., Polasek, Ozren, Hastie, Nick, Vitart, Veronique, Helmer, Catherine, Wang, Jie Jin, Stengel, Bénédicte, Ruggiero, Daniela, Bergmann, Sven, Kähönen, Mika, Viikari, Jorma, Nikopensius, Tiit, Province, Michael, Ketkar, Shamika, Colhoun, Helen, Doney, Alex, Robino, Antonietta, Krämer, Bernhard K., Portas, Laura, Ford, Ian, Buckley, Brendan M., Adam, Martin, Thun, Gian-Andri, Paulweber, Bernhard, Haun, Margot, Sala, Cinzia, Mitchell, Paul, Ciullo, Marina, Kim, Stuart K., Vollenweider, Peter, Raitakari, Olli, Metspalu, Andres, Palmer, Colin, Gasparini, Paolo, Pirastu, Mario, Jukema, J. Wouter, Probst-Hensch, Nicole M., Kronenberg, Florian, Toniolo, Daniela, Gudnason, Vilmundur, Shuldiner, Alan R., Coresh, Josef, Schmidt, Reinhold, Ferrucci, Luigi, Siscovick, David S., van Duijn, Cornelia M., Borecki, Ingrid B., Kardia, Sharon L.R., Liu, Yongmei, Curhan, Gary C., Rudan, Igor, Gyllensten, Ulf, Wilson, James F., Franke, Andre, Pramstaller, Peter P., Rettig, Rainer, Prokopenko, Inga, Witteman, Jacqueline, Hayward, Caroline, Ridker, Paul M, Parsa, Afshin, Bochud, Murielle, Heid, Iris M., Kao, W.H. Linda, Fox, Caroline S., and Köttgen, Anna

Published
2012
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