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2. Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

Author

Gollmann-Tepeköylü, Can, Graber, Michael, Hirsch, Jakob, Mair, Sophia, Naschberger, Andreas, Pölzl, Leo, Nägele, Felix, Kirchmair, Elke, Degenhart, Gerald, Demetz, Egon, Hilbe, Richard, Chen, Hao-Yu, Engert, James, Böhm, Anna, Franz, Nadja, Lobenwein, Daniela, Lener, Daniela, Fuchs, Christiane, Weihs, Anna, Töchterle, Sonja, Vogel, Georg, Schweiger, Victor, Eder, Jonas, Pietschmann, Peter, Seifert, Markus, Kronenberg, Florian, Coassin, Stefan, Blumer, Michael, Hackl, Hubert, Meyer, Dirk, Feuchtner, Gudrun, Kirchmair, Rudolf, Troppmair, Jakob, Krane, Markus, Weiss, Günther, Thanassoulis, George, Grimm, Michael, Rupp, Bernhard, Huber, Lukas, Zhang, Shen-Ying, Casanova, Jean-Laurent, Tancevski, Ivan, Holfeld, Johannes, and Tsimikas, Sotirios

Subjects
Toll-like receptor 3, aortic valve disease, biglycan, extracellular matrix, osteogenesis, proteins, Adult, Animals, Humans, Mice, Aortic Valve, Aortic Valve Stenosis, Biglycan, Calcinosis, Cells, Cultured, Toll-Like Receptor 3, Zebrafish
Abstract

BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/β receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

Published
2023

3. Genetic determinants of complement activation in the general population

Author

Noce, Damia, Foco, Luisa, Orth-Höller, Dorothea, König, Eva, Barbieri, Giulia, Pietzner, Maik, Ghasemi-Semeskandeh, Dariush, Coassin, Stefan, Fuchsberger, Christian, Gögele, Martin, Del Greco M., Fabiola, De Grandi, Alessandro, Summerer, Monika, Wheeler, Eleanor, Langenberg, Claudia, Lass-Flörl, Cornelia, Pramstaller, Peter Paul, Kronenberg, Florian, Würzner, Reinhard, and Pattaro, Cristian

Published
2024
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4. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Gorski, Mathias, Jung, Bettina, Li, Yong, Matias-Garcia, Pamela R, Wuttke, Matthias, Coassin, Stefan, Thio, Chris HL, Kleber, Marcus E, Winkler, Thomas W, Wanner, Veronika, Chai, Jin-Fang, Chu, Audrey Y, Cocca, Massimiliano, Feitosa, Mary F, Ghasemi, Sahar, Hoppmann, Anselm, Horn, Katrin, Li, Man, Nutile, Teresa, Scholz, Markus, Sieber, Karsten B, Teumer, Alexander, Tin, Adrienne, Wang, Judy, Tayo, Bamidele O, Ahluwalia, Tarunveer S, Almgren, Peter, Bakker, Stephan JL, Banas, Bernhard, Bansal, Nisha, Biggs, Mary L, Boerwinkle, Eric, Bottinger, Erwin P, Brenner, Hermann, Carroll, Robert J, Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Coresh, Josef, de Borst, Martin H, Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Franke, Andre, Freitag-Wolf, Sandra, Gampawar, Piyush, Gansevoort, Ron T, Ghanbari, Mohsen, Gieger, Christian, Hamet, Pavel, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Foo, Valencia Hui Xian, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M Arfan, Josyula, Navya Shilpa, Kähönen, Mika, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K, Kühnel, Brigitte, Lange, Leslie A, Lehtimäki, Terho, Lieb, Wolfgang, Loos, Ruth JF, Lukas, Mary Ann, Lyytikäinen, Leo-Pekka, Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P, Mononen, Nina, Mychaleckyj, Josyf C, Nadkarni, Girish N, Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M, O’Donoghue, Michelle L, Orho-Melander, Marju, Pendergrass, Sarah A, Penninx, Brenda WJH, Preuss, Michael H, Psaty, Bruce M, Raffield, Laura M, Raitakari, Olli T, Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M, Rosenkranz, Alexander R, Rossing, Peter, Rotter, Jerome I, Sabanayagam, Charumathi, Schmidt, Helena, and Schmidt, Reinhold

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Human Genome, Kidney Disease, Rare Diseases, Genetics, Aetiology, 2.1 Biological and endogenous factors, Renal and urogenital, AMP-Activated Protein Kinases, Creatinine, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Protein Disulfide-Isomerases, United Kingdom, acute kidney injury, end-stage kidney disease, genome-wide association study, rapid eGFRcrea decline, Lifelines Cohort Study, Regeneron Genetics Center, Urology & Nephrology, Clinical sciences
Abstract

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Published
2021

10. Nanopore sequencing with unique molecular identifiers enables accurate mutation analysis and haplotyping in the complex Lipoprotein(a) KIV-2 VNTR

Author

Amstler, Stephan, primary, Streiter, Gertraud, additional, Pfurtscheller, Cathrin, additional, Forer, Lukas, additional, Di Maio, Silvia, additional, Weissensteiner, Hansi, additional, Paulweber, Bernhard, additional, Schoenherr, Sebastian, additional, Kronenberg, Florian, additional, and Coassin, Stefan, additional

Published
2024
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12. Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease

Author

Eckardt, Kai-Uwe, Meiselbach, Heike, Schneider, Markus P., Schiffer, Mario, Prokosch, Hans-Ulrich, Bärthlein, Barbara, Beck, Andreas, Reis, André, Ekici, Arif B., Becker, Susanne, Becker-Grosspitsch, Dinah, Alberth-Schmidt, Ulrike, Hausknecht, Birgit, Weigel, Anke, Walz, Gerd, Köttgen, Anna, Schultheiß, Ulla T., Kotsis, Fruzsina, Meder, Simone, Mitsch, Erna, Reinhard, Ursula, Floege, Jürgen, Saritas, Turgay, Schaeffner, Elke, Baid-Agrawal, Seema, Theisen, Kerstin, Haller, Hermann, Menne, Jan, Zeier, Martin, Sommerer, Claudia, Theilinger, Johanna, Wolf, Gunter, Busch, Martin, Paul, Rainer, Sitter, Thomas, Wanner, Christoph, Krane, Vera, Börner-Klein, Antje, Bauer, Britta, Kronenberg, Florian, Raschenberger, Julia, Kollerits, Barbara, Forer, Lukas, Schönherr, Sebastian, Weissensteiner, Hansi, Oefner, Peter, Gronwald, Wolfram, Schmid, Matthias, Nadal, Jennifer, Schachtl-Riess, Johanna F., Kheirkhah, Azin, Grüneis, Rebecca, Di Maio, Silvia, Schoenherr, Sebastian, Streiter, Gertraud, Losso, Jamie Lee, Paulweber, Bernhard, Lamina, Claudia, and Coassin, Stefan

Published
2021
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13. Temporary adhesion of the proseriate flatworm Minona ileanae

Author

Pjeta, Robert, Wunderer, Julia, Bertemes, Philip, Hofer, Teresa, Salvenmoser, Willi, Lengerer, Birgit, Coassin, Stefan, Erhart, Gertraud, Beisel, Christian, Sobral, Daniel, Kremser, Leopold, Lindner, Herbert, Curini-Galletti, Marco, Stelzer, Claus-Peter, Hess, Michael W., and Ladurner, Peter

Published
2019

15. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author

Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, van der Harst, Pim, Navis, Gerjan, Rots, Marianne, Snieder, Harold, Swertz, Morris, Wolffenbuttel, Bruce H.R., Wijmenga, Cisca, Abecasis, Goncalo, Baras, Aris, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Lotta, Luca A., Overton, John D., Reid, Jeffrey G., Shuldiner, Alan, Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Schleicher, Thomas D., Padilla, Maria Sotiropoulos, Toledo, Karina, Widom, Louis, Wolf, Sarah E., Pradhan, Manasi, Manoochehri, Kia, Ulloa, Ricardo H., Bai, Xiaodong, Balasubramanian, Suganthi, Barnard, Leland, Blumenfeld, Andrew, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Maxwell, Evan K., Salerno, William, Staples, Jeffrey C., Jones, Marcus B., Mitnaul, Lyndon J., Gorski, Mathias, Jung, Bettina, Li, Yong, Matias-Garcia, Pamela R., Wuttke, Matthias, Coassin, Stefan, Thio, Chris H.L., Kleber, Marcus E., Winkler, Thomas W., Wanner, Veronika, Chai, Jin-Fang, Chu, Audrey Y., Cocca, Massimiliano, Feitosa, Mary F., Ghasemi, Sahar, Hoppmann, Anselm, Horn, Katrin, Li, Man, Nutile, Teresa, Scholz, Markus, Sieber, Karsten B., Teumer, Alexander, Tin, Adrienne, Wang, Judy, Tayo, Bamidele O., Ahluwalia, Tarunveer S., Almgren, Peter, Bakker, Stephan J.L., Banas, Bernhard, Bansal, Nisha, Biggs, Mary L., Boerwinkle, Eric, Bottinger, Erwin P., Brenner, Hermann, Carroll, Robert J., Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Coresh, Josef, de Borst, Martin H., Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Franke, Andre, Freitag-Wolf, Sandra, Gampawar, Piyush, Gansevoort, Ron T., Ghanbari, Mohsen, Gieger, Christian, Hamet, Pavel, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Xian Foo, Valencia Hui, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M. Arfan, Josyula, Navya Shilpa, Kähönen, Mika, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K., Kühnel, Brigitte, Lange, Leslie A., Lehtimäki, Terho, Lieb, Wolfgang, Loos, Ruth J.F., Lukas, Mary Ann, Lyytikäinen, Leo-Pekka, Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Mychaleckyj, Josyf C., Nadkarni, Girish N., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., O’Donoghue, Michelle L., Orho-Melander, Marju, Pendergrass, Sarah A., Penninx, Brenda W.J.H., Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rosenkranz, Alexander R., Rossing, Peter, Rotter, Jerome I., Sabanayagam, Charumathi, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Sedaghat, Sanaz, Shaffer, Christian M., Strauch, Konstantin, Szymczak, Silke, Taylor, Kent D., Tremblay, Johanne, Chaker, Layal, van der Most, Peter J., Verweij, Niek, Völker, Uwe, Waldenberger, Melanie, Wallentin, Lars, Waterworth, Dawn M., White, Harvey D., Wilson, James G., Wong, Tien-Yin, Woodward, Mark, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Yan, Wanner, Christoph, Böger, Carsten A., Köttgen, Anna, Kronenberg, Florian, Pattaro, Cristian, and Heid, Iris M.

Published
2021
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16. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Author

Pattaro, Cristian, Teumer, Alexander, Gorski, Mathias, Chu, Audrey Y, Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthias, Foster, Meredith, Yang, Qiong, Chen, Ming-Huei, Pers, Tune H, Johnson, Andrew D, Ko, Yi-An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F, Isaacs, Aaron, Dehghan, Abbas, d'Adamo, Pio, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B, Nolte, Ilja M, van der Most, Peter J, Wright, Alan F, Shuldiner, Alan R, Morrison, Alanna C, Hofman, Albert, Smith, Albert V, Dreisbach, Albert W, Franke, Andre, Uitterlinden, Andre G, Metspalu, Andres, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I, Ponte, Belen, Oostra, Ben A, Paulweber, Bernhard, Krämer, Bernhard K, Mitchell, Braxton D, Buckley, Brendan M, Peralta, Carmen A, Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N, Shaffer, Christian M, Müller, Christian, Sala, Cinzia, van Duijn, Cornelia M, Saint-Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S, Ruderfer, Douglas, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J, Holliday, Elizabeth G, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P, Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B, Navis, Gerjan J, Curhan, Gary C, Ehret, George B, Homuth, Georg, Coassin, Stefan, Thun, Gian-Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W, Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H-Erich, Campbell, Harry, and Schmidt, Helena

Subjects
ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Humans, Genetic Predisposition to Disease, Gene Expression Regulation, Genotype, Renal Insufficiency, Chronic, Genome-Wide Association Study, Renal Insufficiency, Chronic
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Published
2016

17. When the genome bluffs: a tandem duplication event during generation of a novel Agmo knockout mouse model fools routine genotyping

Author

Sailer, Sabrina, Coassin, Stefan, Lackner, Katharina, Fischer, Caroline, McNeill, Eileen, Streiter, Gertraud, Kremser, Christian, Maglione, Manuel, Green, Catherine M., Moralli, Daniela, Moschen, Alexander R., Keller, Markus A., Golderer, Georg, Werner-Felmayer, Gabriele, Tegeder, Irmgard, Channon, Keith M., Davies, Benjamin, Werner, Ernst R., and Watschinger, Katrin

Published
2021
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18. 176 A genome-wide association screening of complement activation from a general population study

Author

Noce, Damia, primary, Foco, Luisa, additional, Orth-Höller, Dorothea, additional, König, Eva, additional, Barbieri, Giulia, additional, Pietzner, Maik, additional, Coassin, Stefan, additional, Fuchsberger, Christian, additional, Göggele, Martin, additional, Fabiola Del Greco, M, additional, De Grandi, Alessandro, additional, Summerer, Monika, additional, Wheeler, Eleanor, additional, Langenberg, Claudia, additional, Lass-Flörl, Cornelia, additional, Pramstaller, Peter, additional, Kronenberg, Florian, additional, Würzner, Reinhard, additional, and Pattaro, Cristian, additional

Published
2023
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20. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

Dastani, Zari, Hivert, Marie-France, Timpson, Nicholas, Perry, John RB, Yuan, Xin, Scott, Robert A, Henneman, Peter, Heid, Iris M, Kizer, Jorge R, Lyytikäinen, Leo-Pekka, Fuchsberger, Christian, Tanaka, Toshiko, Morris, Andrew P, Small, Kerrin, Isaacs, Aaron, Beekman, Marian, Coassin, Stefan, Lohman, Kurt, Qi, Lu, Kanoni, Stavroula, Pankow, James S, Uh, Hae-Won, Wu, Ying, Bidulescu, Aurelian, Rasmussen-Torvik, Laura J, Greenwood, Celia MT, Ladouceur, Martin, Grimsby, Jonna, Manning, Alisa K, Liu, Ching-Ti, Kooner, Jaspal, Mooser, Vincent E, Vollenweider, Peter, Kapur, Karen A, Chambers, John, Wareham, Nicholas J, Langenberg, Claudia, Frants, Rune, Willems-Vandijk, Ko, Oostra, Ben A, Willems, Sara M, Lamina, Claudia, Winkler, Thomas W, Psaty, Bruce M, Tracy, Russell P, Brody, Jennifer, Chen, Ida, Viikari, Jorma, Kähönen, Mika, Pramstaller, Peter P, Evans, David M, St Pourcain, Beate, Sattar, Naveed, Wood, Andrew R, Bandinelli, Stefania, Carlson, Olga D, Egan, Josephine M, Böhringer, Stefan, van Heemst, Diana, Kedenko, Lyudmyla, Kristiansson, Kati, Nuotio, Marja-Liisa, Loo, Britt-Marie, Harris, Tamara, Garcia, Melissa, Kanaya, Alka, Haun, Margot, Klopp, Norman, Wichmann, H-Erich, Deloukas, Panos, Katsareli, Efi, Couper, David J, Duncan, Bruce B, Kloppenburg, Margreet, Adair, Linda S, Borja, Judith B, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, Wilson, James G, Musani, Solomon, Guo, Xiuqing, Johnson, Toby, Semple, Robert, Teslovich, Tanya M, Allison, Matthew A, Redline, Susan, Buxbaum, Sarah G, Mohlke, Karen L, Meulenbelt, Ingrid, Ballantyne, Christie M, Dedoussis, George V, Hu, Frank B, Liu, Yongmei, Paulweber, Bernhard, Spector, Timothy D, Slagboom, P Eline, Ferrucci, Luigi, and Jula, Antti

Subjects
DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Genetic Predisposition to Disease, Glucose Tolerance Test, Waist-Hip Ratio, Gene Expression, Polymorphism, Single Nucleotide, African Americans, Asian Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Adiponectin, Cholesterol, HDL, Metabolic Networks and Pathways, Genome-Wide Association Study, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Cholesterol, HDL, Genetics, Developmental Biology
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

Published
2012

22. Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

Author

Böger, Carsten A, Gorski, Mathias, Li, Man, Hoffmann, Michael M, Huang, Chunmei, Yang, Qiong, Teumer, Alexander, Krane, Vera, O'Seaghdha, Conall M, Kutalik, Zoltán, Wichmann, H-Erich, Haak, Thomas, Boes, Eva, Coassin, Stefan, Coresh, Josef, Kollerits, Barbara, Haun, Margot, Paulweber, Bernhard, Köttgen, Anna, Li, Guo, Shlipak, Michael G, Powe, Neil, Hwang, Shih-Jen, Dehghan, Abbas, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Albert, Beckmann, Jacques S, Krämer, Bernhard K, Witteman, Jacqueline, Bochud, Murielle, Siscovick, David, Rettig, Rainer, Kronenberg, Florian, Wanner, Christoph, Thadhani, Ravi I, Heid, Iris M, Fox, Caroline S, Kao, WH, and CKDGen Consortium

Subjects
CKDGen Consortium, Humans, Kidney Diseases, Kidney Failure, Chronic, Chronic Disease, Creatinine, Adaptor Proteins, Signal Transducing, Follow-Up Studies, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genetic Association Studies, Uromodulin, ErbB Receptors, Kidney Disease, Genetics, Clinical Research, Renal and urogenital, Developmental Biology
Abstract

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR

Published
2011

23. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Author

Schmidt, Amand F, Swerdlow, Daniel I, Holmes, Michael V, Patel, Riyaz S, Fairhurst-Hunter, Zammy, Lyall, Donald M, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hyppönen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik, Hovingh, G Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Liu, Tian, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F, Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G, Onland-Moret, N Charlotte, van der Schouw, Yvonne T, Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J, Langenberg, Claudia, Scott, Robert, Luan, Jian'an, Bobak, Martin, Malyutina, Sofia, Pająk, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Husemoen, Lise Lotte Nystrup, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Simonsen, Kenneth Starup, Cooper, Jackie, Humphries, Steve E, Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S, McCarty, Catherine A, Kirchner, H Lester, Larson, Eric B, Crosslin, David R, de Andrade, Mariza, Roden, Dan M, Denny, Joshua C, Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, van der Harst, Pim, Said, M Abdullah, Eppinga, Ruben N, Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, Dennis O, Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M, Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P, Smith, Daniel J, Meade, Tom, Maitland-van der Zee, Anke H, Baranova, Ekaterina V, Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L, Grobbee, Diederick E, Froguel, Philippe, Thuillier, Dorothée, Balkau, Beverley, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Ridker, Paul M, Chasman, Daniel I, Reiner, Alex P, Lange, Leslie A, Ritchie, Marylyn D, Asselbergs, Folkert W, Casas, Juan-Pablo, Keating, Brendan J, Preiss, David, Hingorani, Aroon D, and Sattar, Naveed

Published
2017
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24. Development of an LC-MRM-MS-Based Candidate Reference Measurement Procedure for Standardization of Serum Apolipoprotein (a) Tests

Author

Ruhaak, L Renee, primary, Romijn, Fred P H T M, additional, Begcevic Brkovic, Ilijana, additional, Kuklenyik, Zsusanna, additional, Dittrich, Julia, additional, Ceglarek, Uta, additional, Hoofnagle, Andrew N, additional, Althaus, Harald, additional, Angles-Cano, Eduardo, additional, Coassin, Stefan, additional, Delatour, Vincent, additional, Deprez, Liesbet, additional, Dikaios, Ioannis, additional, Kostner, Gerhard M, additional, Kronenberg, Florian, additional, Lyle, Alicia, additional, Prinzing, Urban, additional, Vesper, Hubert W, additional, and Cobbaert, Christa M, additional

Published
2023
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25. Commutability Assessment of Candidate Reference Materials for Lipoprotein(a) by Comparison of a MS-based Candidate Reference Measurement Procedure with Immunoassays

Author

Dikaios, Ioannis, primary, Althaus, Harald, additional, Angles-Cano, Eduardo, additional, Ceglarek, Uta, additional, Coassin, Stefan, additional, Cobbaert, Christa M, additional, Delatour, Vincent, additional, Dieplinger, Benjamin, additional, Grimmler, Matthias, additional, Hoofnagle, Andrew N, additional, Kostner, Gerhard M, additional, Kronenberg, Florian, additional, Kuklenyik, Zsusanna, additional, Lyle, Alicia N, additional, Prinzing, Urban, additional, Ruhaak, L Renee, additional, Scharnagl, Hubert, additional, Vesper, Hubert W, additional, and Deprez, Liesbet, additional

Published
2023
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26. Update of the effect estimates for common variants associated with carotid intima media thickness within four independent samples: The Bonn IMT Family Study, the Heinz Nixdorf Recall Study, the SAPHIR Study and the Bruneck Study

Author

Geisel, Marie H., Coassin, Stefan, Heßler, Nicole, Bauer, Marcus, Eisele, Lewin, Erbel, Raimund, Haun, Margot, Hennig, Frauke, Moskau-Hartmann, Susanna, Hoffmann, Barbara, Jöckel, Karl-Heinz, Kedenko, Lyudmyla, Kiechl, Stefan, Kollerits, Barbara, Mahabadi, Amir-Abbas, Moebus, Susanne, Nürnberg, Gudrun, Nürnberg, Peter, Paulweber, Bernhard, Vens, Maren, Willeit, Johann, Willeit, Karin, Klockgether, Thomas, Ziegler, Andreas, Scherag, André, and Kronenberg, Florian

Published
2016
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27. Commutability Assessment of Candidate Reference Materials for Lipoprotein(a) by Comparison of a MS-based Candidate Reference Measurement Procedure with Immunoassays

Author

Dikaios, Ioannis, Althaus, Harald, Angles-Cano, Eduardo, Ceglarek. Uta, Coassin, Stefan, Cobbaert, Christa M., Delatour, Vincent, Dieplinger, Benjamin, Grimmler, Matthias, Hoofnagle, Andrew N., Kostner, Gerhard M., Kronenberg, Florian, Kuklenyik, Zsusanna, Prinzing, Urban, Ruhaak, Renee, Scharnagl, Hubert, Vesper, Hubert W., and Deprez, Liesbet

Subjects
Horizon 2020, candidate reference material, 18HLT10, Commutability, Lipoprotein (a), EMPIR, CardioMet, mass spectrometry
Abstract

Elevated concentrations of lipoprotein( a) [Lp(a)] are directly related to an increased risk of cardiovascular diseases, making it a relevant biomarker for clinical risk assessment. However, the lack of global standardization of current Lp(a) measurement procedures (MPs) leads to inconsistent patient care. The International Federation for Clinical Chemistry and Laboratory Medicine working group on quantitating apolipoproteins by mass spectrometry (MS) aims to develop a next-generation SI (International system of units)-traceable reference measurement system consisting of a MS-based, peptide-calibrated reference measurement procedure (RMP) and secondary serum-based reference materials (RMs) certified for their apolipoprotein( a) [apo(a)] content. To reach measurement standardization through this new measurement system, 2 essential requirements need to be fulfilled: a sufficient correlation among the MPs and appropriate commutability of future serum-based RMs. METHODS: The correlation among the candidate RMP (cRMP) and immunoassay-based MPs was assessed by measuring a panel of 39 clinical samples (CS). In addition, the commutability of 14 different candidate RMs was investigated. RESULTS: Results of the immunoassay-based MPs and the cRMPs demonstrated good linear correlations for the CS but some significant sample-specific differences were also observed. The results of the commutability study show that RMs based on unspiked human serum pools can be commutable with CS, whereas human pools spiked with recombinant apo(a) show different behavior compared to CS. CONCLUSIONS: The results of this study show that unspiked human serum pools are the preferred candidate secondary RMs in the future SI-traceable Lp(a) Reference Measurement System.

Published
2023

29. The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat

Author

Grüneis, Rebecca, primary, Weissensteiner, Hansi, additional, Lamina, Claudia, additional, Schönherr, Sebastian, additional, Forer, Lukas, additional, Di Maio, Silvia, additional, Streiter, Gertraud, additional, Peters, Annette, additional, Gieger, Christian, additional, Kronenberg, Florian, additional, and Coassin, Stefan, additional

Published
2022
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31. Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk

Author

Coassin, Stefan, primary, Chemello, Kevin, additional, Khantalin, Ilya, additional, Forer, Lukas, additional, Döttelmayer, Patricia, additional, Schönherr, Sebastian, additional, Grüneis, Rebecca, additional, Chong-Hong-Fong, Clément, additional, Nativel, Brice, additional, Ramin-Mangata, Stéphane, additional, Gallo, Antonio, additional, Roche, Mathias, additional, Mühlegger, Beatrix, additional, Gieger, Christian, additional, Peters, Annette, additional, Zschocke, Johannes, additional, Marimoutou, Catherine, additional, Meilhac, Olivier, additional, Lamina, Claudia, additional, Kronenberg, Florian, additional, Blanchard, Valentin, additional, and Lambert, Gilles, additional

Published
2022
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35. Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease

Author

Schachtl-Riess, Johanna F., Kheirkhah, Azin, Grüneis, Rebecca, Di Maio, Silvia, Schoenherr, Sebastian, Streiter, Gertraud, Losso, Jamie Lee, Paulweber, Bernhard, Eckardt, Kai-Uwe, Köttgen, Anna, Lamina, Claudia, Kronenberg, Florian, Coassin, Stefan, For The GCKD Investigators, Meiselbach, Heike, Schneider, Markus P., Schiffer, Mario, Prokosch, Hans-Ulrich, Bärthlein, Barbara, Beck, Andreas, Reis, André, Ekici, Arif B., Becker, Susanne, Becker-Grosspitsch, Dinah, Alberth-Schmidt, Ulrike, Hausknecht, Birgit, Weigel, Anke, Walz, Gerd, Schultheiß, Ulla T., Kotsis, Fruzsina, Meder, Simone, Mitsch, Erna, Reinhard, Ursula, Floege, Jürgen, Saritas, Turgay, Schaeffner, Elke, Baid-Agrawal, Seema, Theisen, Kerstin, Haller, Hermann, Menne, Jan, Zeier, Martin, Sommerer, Claudia, Theilinger, Johanna, Wolf, Gunter, Busch, Martin, Paul, Rainer, Sitter, Thomas, Wanner, Christoph, Krane, Vera, Börner-Klein, Antje, Bauer, Britta, Raschenberger, Julia, Kollerits, Barbara, Forer, Lukas, Schönherr, Sebastian, Weissensteiner, Hansi, Oefner, Peter J., Gronwald, Wolfram, Schmid, Matthias, and Nadal, Jennifer

Subjects
medicine.medical_specialty, 610 Medizin, Coronary Artery Disease, Mendelian randomization, cardiovascular disease, cohort study, copy number variation, genetic variability, lipoprotein(a), Coronary artery disease, Kringles, Internal medicine, Medicine, Humans, Copy-number variation, Genetic variability, Prospective Studies, Risk factor, ddc:610, biology, business.industry, Genetic Variation, Lipoprotein(a), medicine.disease, biology.protein, Cardiology, lipids (amino acids, peptides, and proteins), biological phenomena, cell phenomena, and immunity, Cardiology and Cardiovascular Medicine, business, Lipoprotein, Cohort study
Abstract

Background: Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants. Objectives: This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD. Methods: We genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project. Results: The 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably. Conclusions: Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction.

Published
2021

36. The size of apolipoprotein (a) is an independent determinant of the reduction in lipoprotein (a) induced by PCSK9 inhibitors

Author

Blanchard, Valentin, primary, Chemello, Kévin, additional, Hollstein, Tim, additional, Hong-Fong, Clément Chong, additional, Schumann, Friederike, additional, Grenkowitz, Thomas, additional, Nativel, Brice, additional, Coassin, Stefan, additional, Croyal, Mikaël, additional, Kassner, Ursula, additional, Lamina, Claudia, additional, Steinhagen-Thiessen, Elisabeth, additional, and Lambert, Gilles, additional

Published
2021
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38. Additional file 1 of When the genome bluffs: a tandem duplication event during generation of a novel Agmo knockout mouse model fools routine genotyping

Author

Sailer, Sabrina, Coassin, Stefan, Lackner, Katharina, Fischer, Caroline, McNeill, Eileen, Streiter, Gertraud, Kremser, Christian, Maglione, Manuel, Green, Catherine M., Moralli, Daniela, Moschen, Alexander R., Keller, Markus A., Golderer, Georg, Werner-Felmayer, Gabriele, Tegeder, Irmgard, Channon, Keith M., Davies, Benjamin, Werner, Ernst R., and Watschinger, Katrin

Subjects
Data_FILES
Abstract

Additional file 1. Additional figures and tables.

Published
2021
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39. Cis-epistasis at the LPA locus and risk of cardiovascular diseases

Author

Zeng, Lingyao, primary, Moser, Sylvain, additional, Mirza-Schreiber, Nazanin, additional, Lamina, Claudia, additional, Coassin, Stefan, additional, Nelson, Christopher P, additional, Annilo, Tarmo, additional, Franzén, Oscar, additional, Kleber, Marcus E, additional, Mack, Salome, additional, Andlauer, Till F M, additional, Jiang, Beibei, additional, Stiller, Barbara, additional, Li, Ling, additional, Willenborg, Christina, additional, Munz, Matthias, additional, Kessler, Thorsten, additional, Kastrati, Adnan, additional, Laugwitz, Karl-Ludwig, additional, Erdmann, Jeanette, additional, Moebus, Susanne, additional, Nöthen, Markus M, additional, Peters, Annette, additional, Strauch, Konstantin, additional, Müller-Nurasyid, Martina, additional, Gieger, Christian, additional, Meitinger, Thomas, additional, Steinhagen-Thiessen, Elisabeth, additional, März, Winfried, additional, Metspalu, Andres, additional, Björkegren, Johan L M, additional, Samani, Nilesh J, additional, Kronenberg, Florian, additional, Müller-Myhsok, Bertram, additional, and Schunkert, Heribert, additional

Published
2021
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40. Somatic mutations throughout the entire mitochondrial genome are associated with elevated PSA levels in prostate cancer patients

Author

Kloss-Brandstatter, Anita, Schafer, Georg, Erhart, Gertraud, Huttenhofer, Alexander, Coassin, Stefan, Seifarth, Christof, Summerer, Monika, Bektic, Jasmin, Klocker, Helmut, and Kronenberg, Florian

Subjects
Prostate cancer -- Genetic aspects, Prostate cancer -- Care and treatment, Gene therapy -- Analysis, Gene mutations -- Analysis, Biological sciences
Abstract

A rigorous high-quality sequencing strategy was used to sequence the entire mitochondrial genome in macrodissected prostate cancer tissue and distant benign cells and analyze frequency and nature of somatic mtDNA mutations and their suitability for monitoring malignant transformation, tumor progression and metastasis. The somatic mutations in transfer RNAs (tRNAs) was found to be associated with elevated prostate specific antigen (PSA) levels, and the degree of heteroplasmy increased with increasing tumor activity and hence somatic mutations in the mitochondrial genome are frequent events in prostate cancer.

Published
2010

41. size of apolipoprotein (a) is an independent determinant of the reduction in lipoprotein (a) induced by PCSK9 inhibitors.

Author

Blanchard, Valentin, Chemello, Kévin, Hollstein, Tim, Hong-Fong, Clément Chong, Schumann, Friederike, Grenkowitz, Thomas, Nativel, Brice, Coassin, Stefan, Croyal, Mikaël, Kassner, Ursula, Lamina, Claudia, Steinhagen-Thiessen, Elisabeth, and Lambert, Gilles

Subjects
LIPOPROTEIN A, LIQUID chromatography-mass spectrometry, PROTEIN domains
Abstract

Aims Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein. Methods and results The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charité Hospital (Berlin) between 2015 and 2020. They were hypercholesterolaemic at very high cardiovascular disease risk with low-density lipoprotein (LDL)-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150 mg) or Evolocumab (140 mg) every 2 weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by western blot. PCSK9i sharply reduced LDL-cholesterol (−57%), apoB100 (−47%), and Lp(a) (−36%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r  = 0.363, P  = 0.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r  = 0.350, P  = 0.0001) and larger (r  = 0.324, P  = 0.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (P  < 0.0001). Conclusions The size of apo(a) is an independent determinant of the response to PCSK9i. Each additional kringle domain is associated with a 3% additional reduction in Lp(a). This explains in part the variable efficacy of PCSK9i and allows to identify patients who will benefit most from these therapies in terms of Lp(a) lowering. [ABSTRACT FROM AUTHOR]

Published
2022
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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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44. Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Author

Zeng, Lingyao, Moser, Sylvain, Mirza-Schreiber, Nazanin, Lamina, Claudia, Coassin, Stefan, Nelson, Christopher P, Annilo, Tarmo, Franzén, Oscar, Kleber, Marcus E, Mack, Salome, Andlauer, Till F M, Jiang, Beibei, Stiller, Barbara, Li, Ling, Willenborg, Christina, Munz, Matthias, Kessler, Thorsten, Kastrati, Adnan, Laugwitz, Karl-Ludwig, and Erdmann, Jeanette

Subjects
PERIPHERAL vascular diseases, CARDIOVASCULAR diseases risk factors, GENOME-wide association studies, CORONARY artery disease, LOCUS (Genetics)
Abstract

Aims Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD. Methods and results We tested for epistatic interactions in 10 CAD case–control studies and UK Biobank with focus on 8068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD [odds ratio (OR) = 1.37, P  = 1.07 × 10−11], peripheral arterial disease (OR = 1.22, P  = 2.32 × 10−4), aortic stenosis (OR = 1.47, P  = 6.95 × 10−7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, P  = 1.41 × 10−8), and Lp(a) serum levels (beta = 0.58, P  = 8.7 × 10−32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, P  = 9.97 × 10−32) and individuals homozygous for the minor allele (relative OR = 1.77, P  = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele. Conclusions These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Published
2022
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45. Lipoprotein(a) and SARS‐CoV‐2 infections: Susceptibility to infections, ischemic heart disease and thromboembolic events.

Author

Di Maio, Silvia, Lamina, Claudia, Coassin, Stefan, Forer, Lukas, Würzner, Reinhard, Schönherr, Sebastian, and Kronenberg, Florian

Subjects
MYOCARDIAL ischemia, CORONARY disease, SARS-CoV-2, THROMBOEMBOLISM, COVID-19 pandemic
Abstract

Background: Comorbidities including ischemic heart disease (IHD) worsen outcomes after SARS‐CoV‐2 infections. High lipoprotein(a) [Lp(a)] concentrations are a strong risk factor for IHD and possibly for thromboembolic events. We therefore evaluated whether SARS‐CoV‐2 infections modify the risk of high Lp(a) concentrations for IHD or thromboembolic events during the first 8.5 months follow‐up of the pandemic. Method: Cohort study using data from the UK Biobank during the SARS‐CoV‐2 pandemic. Baseline Lp(a) was compared between SARS‐CoV‐2 positive patients and the population controls. Results: SARS‐CoV‐2 positive patients had Lp(a) concentrations similar to the population controls. The risk for IHD increased with higher Lp(a) concentrations in both, the population controls (n = 435,104) and SARS‐CoV‐2 positive patients (n = 6937). The causality of the findings was supported by a genetic risk score for Lp(a). A SARS‐CoV‐2 infection modified the association with a steeper increase in risk for infected patients (interaction p‐value = 0.03). Although SARS‐CoV‐2 positive patients had a five‐times higher frequency of thromboembolic events compared to the population controls (1.53% vs. 0.31%), the risk was not influenced by Lp(a). Conclusions: SARS‐CoV‐2 infections enforce the association between high Lp(a) and IHD but the risk for thromboembolic events is not influenced by Lp(a). [ABSTRACT FROM AUTHOR]

Published
2022
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47. CUBN Is a Gene Locus for Albuminuria

Author

Böger, Carsten A., Chen, Ming-Huei, Tin, Adrienne, Olden, Matthias, Köttgen, Anna, de Boer, Ian H., Fuchsberger, Christian, OʼSeaghdha, Conall M., Pattaro, Cristian, Teumer, Alexander, Liu, Ching-Ti, Glazer, Nicole L., Li, Man, OʼConnell, Jeffrey R., Tanaka, Toshiko, Peralta, Carmen A., Kutalik, Zoltán, Luan, Jianʼan, Zhao, Jing Hua, Hwang, Shih-Jen, Akylbekova, Ermeg, Kramer, Holly, van der Harst, Pim, Smith, Albert V., Lohman, Kurt, de Andrade, Mariza, Hayward, Caroline, Kollerits, Barbara, Tönjes, Anke, Aspelund, Thor, Ingelsson, Erik, Eiriksdottir, Gudny, Launer, Lenore J., Harris, Tamara B., Shuldiner, Alan R., Mitchell, Braxton D., Arking, Dan E., Franceschini, Nora, Boerwinkle, Eric, Egan, Josephine, Hernandez, Dena, Reilly, Muredach, Townsend, Raymond R., Lumley, Thomas, Siscovick, David S., Psaty, Bruce M., Kestenbaum, Bryan, Haritunians, Talin, Bergmann, Sven, Vollenweider, Peter, Waeber, Gerard, Mooser, Vincent, Waterworth, Dawn, Johnson, Andrew D., Florez, Jose C., Meigs, James B., Lu, Xiaoning, Turner, Stephen T., Atkinson, Elizabeth J., Leak, Tennille S., Aasarød, Knut, Skorpen, Frank, Syvänen, Ann-Christine, Illig, Thomas, Baumert, Jens, Koenig, Wolfgang, Krämer, Bernhard K., Devuyst, Olivier, Mychaleckyj, Josyf C., Minelli, Cosetta, Bakker, Stephan J.L., Kedenko, Lyudmyla, Paulweber, Bernhard, Coassin, Stefan, Endlich, Karlhans, Kroemer, Heyo K., Biffar, Reiner, Stracke, Sylvia, Völzke, Henry, Stumvoll, Michael, Mägi, Reedik, Campbell, Harry, Vitart, Veronique, Hastie, Nicholas D., Gudnason, Vilmundur, Kardia, Sharon L.R., Liu, Yongmei, Polasek, Ozren, Curhan, Gary, Kronenberg, Florian, Prokopenko, Inga, Rudan, Igor, Ärnlöv, Johan, Hallan, Stein, Navis, Gerjan, Parsa, Afshin, Ferrucci, Luigi, Coresh, Josef, Shlipak, Michael G., Bull, Shelley B., Paterson, Andrew D., Wichmann, H.-Erich, Wareham, Nicholas J., Loos, Ruth J.F., Rotter, Jerome I., Pramstaller, Peter P., Cupples, L. Adrienne, Beckmann, Jacques S., Yang, Qiong, Heid, Iris M., Rettig, Rainer, Dreisbach, Albert W., Bochud, Murielle, Fox, Caroline S., and Kao, W.H.L.

Published
2011
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49. A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter

Author

Coassin, Stefan, primary, Hermann-Kleiter, Natascha, additional, Haun, Margot, additional, Wahl, Simone, additional, Wilson, Rory, additional, Paulweber, Bernhard, additional, Kunze, Sonja, additional, Meitinger, Thomas, additional, Strauch, Konstantin, additional, Peters, Annette, additional, Waldenberger, Melanie, additional, Kronenberg, Florian, additional, and Lamina, Claudia, additional

Published
2020
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50. The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development

Author

Demetz, Egon, primary, Tymoszuk, Piotr, additional, Hilbe, Richard, additional, Volani, Chiara, additional, Haschka, David, additional, Heim, Christiane, additional, Auer, Kristina, additional, Lener, Daniela, additional, Zeiger, Lucas B, additional, Pfeifhofer-Obermair, Christa, additional, Boehm, Anna, additional, Obermair, Gerald J, additional, Ablinger, Cornelia, additional, Coassin, Stefan, additional, Lamina, Claudia, additional, Kager, Juliane, additional, Petzer, Verena, additional, Asshoff, Malte, additional, Schroll, Andrea, additional, Nairz, Manfred, additional, Dichtl, Stefanie, additional, Seifert, Markus, additional, von Raffay, Laura, additional, Fischer, Christine, additional, Barros-Pinkelnig, Marina, additional, Brigo, Natascha, additional, Valente de Souza, Lara, additional, Sopper, Sieghart, additional, Hirsch, Jakob, additional, Graber, Michael, additional, Gollmann-Tepeköylü, Can, additional, Holfeld, Johannes, additional, Halper, Julia, additional, Macheiner, Sophie, additional, Gostner, Johanna, additional, Vogel, Georg F, additional, Pechlaner, Raimund, additional, Moser, Patrizia, additional, Imboden, Medea, additional, Marques-Vidal, Pedro, additional, Probst-Hensch, Nicole M, additional, Meiselbach, Heike, additional, Strauch, Konstantin, additional, Peters, Annette, additional, Paulweber, Bernhard, additional, Willeit, Johann, additional, Kiechl, Stefan, additional, Kronenberg, Florian, additional, Theurl, Igor, additional, Tancevski, Ivan, additional, and Weiss, Guenter, additional

Published
2020
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