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6. Novel Genetic Markers Associate With Atrial Fibrillation Risk in Europeans and Japanese

Author

Lubitz, Steven A, Lunetta, Kathryn L, Lin, Honghuang, Arking, Dan E, Trompet, Stella, Li, Guo, Krijthe, Bouwe P, Chasman, Daniel I, Barnard, John, Kleber, Marcus E, Dörr, Marcus, Ozaki, Kouichi, Smith, Albert V, Müller-Nurasyid, Martina, Walter, Stefan, Agarwal, Sunil K, Bis, Joshua C, Brody, Jennifer A, Chen, Lin Y, Everett, Brendan M, Ford, Ian, Franco, Oscar H, Harris, Tamara B, Hofman, Albert, Kääb, Stefan, Mahida, Saagar, Kathiresan, Sekar, Kubo, Michiaki, Launer, Lenore J, Macfarlane, Peter W, Magnani, Jared W, McKnight, Barbara, McManus, David D, Peters, Annette, Psaty, Bruce M, Rose, Lynda M, Rotter, Jerome I, Silbernagel, Guenther, Smith, Jonathan D, Sotoodehnia, Nona, Stott, David J, Taylor, Kent D, Tomaschitz, Andreas, Tsunoda, Tatsuhiko, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Murabito, Joanne M, Sinner, Moritz F, Gudnason, Vilmundur, Felix, Stephan B, März, Winfried, Chung, Mina, Albert, Christine M, Stricker, Bruno H, Tanaka, Toshihiro, Heckbert, Susan R, Jukema, J Wouter, Alonso, Alvaro, Benjamin, Emelia J, and Ellinor, Patrick T

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Human Genome, Genetics, Prevention, Cardiovascular, Heart Disease, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Asian People, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors, White People, Homeobox Protein PITX2, atrial fibrillation, atrial flutter, genetic, prognosis, risk, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

ObjectivesThis study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.BackgroundAF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.MethodsWe performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).ResultsWe observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.ConclusionsThe chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

Published
2014

17. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease

Author

Gylling, Helena, Plat, Jogchum, Turley, Stephen, Ginsberg, Henry N., Ellegård, Lars, Jessup, Wendy, Jones, Peter J., Lütjohann, Dieter, Maerz, Winfried, Masana, Luis, Silbernagel, Günther, Staels, Bart, Borén, Jan, Catapano, Alberico L., De Backer, Guy, Deanfield, John, Descamps, Olivier S., Kovanen, Petri T., Riccardi, Gabriele, Tokgözoglu, Lale, and Chapman, M. John

Published
2014
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20. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author

Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David, Shin, So-Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Johnson, Andrew D., Smith, Nicholas L., Williams, Scott M., Ikram, Mohammad A., Kleber, Marcus E., Becker, Diane M., Truong, Vinh, Mychaleckyj, Josyf C., Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H., Williams, Frances M.K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M.C., Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H., Silveira, Angela, Navis, Gerjan J., Lohman, Kurt, Chen, Ming-Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C., Chambers, John C., Saleheen, Danish, Lundmark, Per, Psaty, Bruce M., Strawbridge, Rona J., Boehm, Bernhard O., Carter, Angela M., Meisinger, Christa, Peden, John F., Bis, Joshua C., McKnight, Barbara, Öhrvik, John, Taylor, Kent, Franzosi, Maria Grazia, Seedorf, Udo, Collins, Rory, Franco-Cereceda, Anders, Syvänen, Ann-Christine, Goodall, Alison H., Yanek, Lisa R., Cushman, Mary, Müller-Nurasyid, Martina, Folsom, Aaron R., Basu, Saonli, Matijevic, Nena, van Gilst, Wiek H., Kooner, Jaspal S., Hofman, Albert, Danesh, John, Clarke, Robert, Meigs, James B., Kathiresan, Sekar, Reilly, Muredach P., Klopp, Norman, Harris, Tamara B., Winkelmann, Bernhard R., Grant, Peter J., Hillege, Hans L., Watkins, Hugh, Spector, Timothy D., Becker, Lewis C., Tracy, Russell P., März, Winfried, Uitterlinden, Andre G., Eriksson, Per, Cambien, Francois, Morange, Pierre-Emmanuel, Koenig, Wolfgang, Soranzo, Nicole, van der Harst, Pim, Liu, Yongmei, O'Donnell, Christopher J., and Hamsten, Anders

Published
2012
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23. Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

Author

Saxena, Richa, Elbers, Clara C., Guo, Yiran, Peter, Inga, Gaunt, Tom R., Mega, Jessica L., Lanktree, Matthew B., Tare, Archana, Castillo, Berta Almoguera, Li, Yun R., Johnson, Toby, Bruinenberg, Marcel, Gilbert-Diamond, Diane, Rajagopalan, Ramakrishnan, Voight, Benjamin F., Balasubramanyam, Ashok, Barnard, John, Bauer, Florianne, Baumert, Jens, Bhangale, Tushar, Böhm, Bernhard O., Braund, Peter S., Burton, Paul R., Chandrupatla, Hareesh R., Clarke, Robert, Cooper-DeHoff, Rhonda M., Crook, Errol D., Davey-Smith, George, Day, Ian N., de Boer, Anthonius, de Groot, Mark C.H., Drenos, Fotios, Ferguson, Jane, Fox, Caroline S., Furlong, Clement E., Gibson, Quince, Gieger, Christian, Gilhuijs-Pederson, Lisa A., Glessner, Joseph T., Goel, Anuj, Gong, Yan, Grant, Struan F.A., Grobbee, Diederick E., Hastie, Claire, Humphries, Steve E., Kim, Cecilia E., Kivimaki, Mika, Kleber, Marcus, Meisinger, Christa, Kumari, Meena, Langaee, Taimour Y., Lawlor, Debbie A., Li, Mingyao, Lobmeyer, Maximilian T., Maitland-van der Zee, Anke-Hilse, Meijs, Matthijs F.L., Molony, Cliona M., Morrow, David A., Murugesan, Gurunathan, Musani, Solomon K., Nelson, Christopher P., Newhouse, Stephen J., O'Connell, Jeffery R., Padmanabhan, Sandosh, Palmen, Jutta, Patel, Sanjey R., Pepine, Carl J., Pettinger, Mary, Price, Thomas S., Rafelt, Suzanne, Ranchalis, Jane, Rasheed, Asif, Rosenthal, Elisabeth, Ruczinski, Ingo, Shah, Sonia, Shen, Haiqing, Silbernagel, Günther, Smith, Erin N., Spijkerman, Annemieke W.M., Stanton, Alice, Steffes, Michael W., Thorand, Barbara, Trip, Mieke, van der Harst, Pim, van der A, Daphne L., van Iperen, Erik P.A., van Setten, Jessica, van Vliet-Ostaptchouk, Jana V., Verweij, Niek, Wolffenbuttel, Bruce H.R., Young, Taylor, Zafarmand, M. Hadi, Zmuda, Joseph M., Boehnke, Michael, Altshuler, David, McCarthy, Mark, Kao, W.H. Linda, Pankow, James S., Cappola, Thomas P., Sever, Peter, Poulter, Neil, Caulfield, Mark, Dominiczak, Anna, Shields, Denis C., Bhatt, Deepak L., Zhang, Li, Curtis, Sean P., Danesh, John, Casas, Juan P., van der Schouw, Yvonne T., Onland-Moret, N. Charlotte, Doevendans, Pieter A., Dorn, Gerald W., II, Farrall, Martin, FitzGerald, Garret A., Hamsten, Anders, Hegele, Robert, Hingorani, Aroon D., Hofker, Marten H., Huggins, Gordon S., Illig, Thomas, Jarvik, Gail P., Johnson, Julie A., Klungel, Olaf H., Knowler, William C., Koenig, Wolfgang, März, Winfried, Meigs, James B., Melander, Olle, Munroe, Patricia B., Mitchell, Braxton D., Bielinski, Susan J., Rader, Daniel J., Reilly, Muredach P., Rich, Stephen S., Rotter, Jerome I., Saleheen, Danish, Samani, Nilesh J., Schadt, Eric E., Shuldiner, Alan R., Silverstein, Roy, Kottke-Marchant, Kandice, Talmud, Philippa J., Watkins, Hugh, Asselbergs, Folkert W., de Bakker, Paul I.W., McCaffery, Jeanne, Wijmenga, Cisca, Sabatine, Marc S., Wilson, James G., Reiner, Alex, Bowden, Donald W., Hakonarson, Hakon, Siscovick, David S., and Keating, Brendan J.

Published
2012
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27. Cholesterol Efflux Capacity and Cardiovascular Disease: The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study

Author

Ritsch, Andreas, Duerr, Angela, Kahler, Patrick, Hunjadi, Monika, Stojakovic, Tatjana, Silbernagel, Guenther, Scharnagl, Hubert, Kleber, Marcus E., and März, Winfried

Subjects
cardiovascular risk, lcsh:Biology (General), nutritional and metabolic diseases, lipids (amino acids, peptides, and proteins), high-density lipoprotein, dysfunctional HDL, mortality, lcsh:QH301-705.5, Article, cholesterol efflux capacity
Abstract

(1) Background and Aims: Efforts to reduce coronary artery disease (CAD) by raising high-density lipoprotein (HDL) cholesterol (HDL-C) have not been uniformly successful. A more important factor than HDL-C may be cellular cholesterol efflux mediated by HDL, which has been shown to be associated with CAD. In this report, we analyzed the influence of cardiovascular biomarkers and risk factors on cholesterol efflux in a prospective observational study of patients referred to coronary angiography. (2) Methods: HDL-mediated efflux capacity was determined for 2468 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 9.9 years. Primary and secondary endpoints were cardiovascular and all-cause mortality, respectively. (3) Results: Cholesterol efflux strongly correlated with HDL-related markers including HDL cholesterol, HDL phospholipids, and apolipoproteins AI and AII, as well as HDL particle concentration, which was not seen for low density lipoprotein (LDL) markers including LDL cholesterol and apoB. Cholesterol efflux was associated negatively with C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), and serum amyloid A. Cardiovascular mortality was higher in patients in the lowest cholesterol efflux quartile. This association was weakened, but not fully abolished, after adjustment for HDL cholesterol. (4) Conclusions: We demonstrate that cholesterol efflux was associated with HDL-composition as well as inflammatory burden in patients referred for coronary angiography, and that this inversely predicts cardiovascular mortality independently of HDL cholesterol.

Published
2020

28. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Lagou, Vasiliki, Maegi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gadin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amelie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O'Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tonu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Guenther, Meyer, Julia, Mueller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian'an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf de, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, de Geus, Eco J. C. N., Blueher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindstroem, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Toenjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., Maerz, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Koerner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Maennistoe, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim van der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josee, Barroso, Ines, Morris, Andrew P., Prokopenko, Inga, Lagou, Vasiliki, Maegi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gadin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amelie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O'Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tonu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Guenther, Meyer, Julia, Mueller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian'an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf de, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, de Geus, Eco J. C. N., Blueher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindstroem, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Toenjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., Maerz, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Koerner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Maennistoe, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim van der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josee, Barroso, Ines, Morris, Andrew P., and Prokopenko, Inga

Abstract

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

Published
2021
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29. The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease

Author

Silbernagel, Guenther, Fauler, Guenter, Renner, Wilfried, Landl, Eva M., Hoffmann, Michael Marcus, Winkelmann, Bernhard R., Böhm, Bernhard O., März, Winfried, Silbernagel, Guenther, Fauler, Guenter, Renner, Wilfried, Landl, Eva M., Hoffmann, Michael Marcus, Winkelmann, Bernhard R., Böhm, Bernhard O., and März, Winfried

Abstract

Changes in the balance of cholesterol absorption and synthesis and moderately elevated plasma plant sterols have been suggested to be atherogenic. Measuring cholestanol, lathosterol, campesterol, and sitosterol, we investigated the relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease (CAD) in 2,440 participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. The coronary status was determined by angiography, and the severity of CAD was assessed by the Friesinger Score (FS). An increase in the ratio of cholestanol to cholesterol was associated with high FS (P = 0.006). In contrast, a high ratio of lathosterol to cholesterol went in parallel with low FS (P < 0.001). Whereas the campesterol to cholesterol ratio significantly correlated with the FS (P = 0.026), the relationship of the sitosterol to cholesterol ratio with the FS did not reach statistical significance in the whole group. Increased campesterol, sitosterol, and cholestanol to lathosterol ratios were associated high FS (P < 0.001). To conclude, there is a modest association of high cholesterol absorption and low cholesterol synthesis with an increased severity of CAD. An atherogenic role of plasma plant sterols themselves, however, seems unlikely in subjects without sitosterolaemia.

Published
2021

30. The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality

Author

Silbernagel, Guenther, Fauler, Guenter, Hoffmann, Michael Marcus, Lütjohann, Dieter, Winkelmann, Bernhard R., Böhm, Bernhard O., März, Winfried, Silbernagel, Guenther, Fauler, Guenter, Hoffmann, Michael Marcus, Lütjohann, Dieter, Winkelmann, Bernhard R., Böhm, Bernhard O., and März, Winfried

Abstract

Moderately elevated levels of plasma plant sterols have been suspected to be causally involved in atherosclerosis. The aim of this study was to investigate whether plant sterols and other markers of sterol metabolism predicted all-cause and cardiovascular mortality in participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. A total of 1,257 individuals who did not use statins and at baseline had a mean (± SD) age of 62.8 (± 11.0) years were included in the present analysis. Lathosterol, cholestanol, campesterol, and sitosterol were measured to estimate cholesterol synthesis and absorption. The mean (± SD) time of the follow-up for all-cause and cardiovascular mortality was 7.32 (± 2.3) years. All-cause (P = 0.001) and cardiovascular (P = 0.006) mortality were decreased in the highest versus the lowest lathosterol to cholesterol tertile. In contrast, subjects in the third cholestanol to cholesterol tertile had increased all-cause (P < 0.001) and cardiovascular mortality (P = 0.010) compared with individuals in the first tertile. The third campesterol to cholesterol tertile was associated with increased all-cause mortality (P = 0.025). Sitosterol to cholesterol tertiles were not significantly related to all-cause or cardiovascular mortality. The data suggest that high absorption and low synthesis of cholesterol predict increased all-cause and cardiovascular mortality in LURIC participants.

Published
2021

37. Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Author

Graff, Mariaelisa, Scott, Robert A., Justice, Anne E., Young, Kristin L., Feitosa, Mary F., Barata, Llilda, Winkler, Thomas W., Chu, Audrey Y., Mahajan, Anubha, Hadley, David, Xue, Luting, Workalemahu, Tsegaselassie, Heard-Costa, Nancy L., den Hoed, Marcel, Ahluwalia, Tarunveer S., Qi, Qibin, Ngwa, Julius S., Renström, Frida, Quaye, Lydia, Eicher, John D., Hayes, James E., Cornelis, Marilyn, Kutalik, Zoltan, Lim, Elise, Luan, Jian'an, Huffman, Jennifer E., Zhang, Weihua, Zhao, Wei, Griffin, Paula J., Haller, Toomas, Ahmad, Shafqat, Marques-Vidal, Pedro M., Bien, Stephanie, Yengo, Loic, Teumer, Alexander, Smith, Albert Vernon, Kumari, Meena, Harder, Marie Neergaard, Justesen, Johanne Marie, Kleber, Marcus E., Hollensted, Mette, Lohman, Kurt, Rivera, Natalia V., Whitfield, John B., Zhao, Jing Hua, Stringham, Heather M., Lyytikainen, Leo-Pekka, Huppertz, Charlotte, Willemsen, Gonneke, Peyrot, Wouter J., Wu, Ying, Kristiansson, Kati, Demirkan, Ayse, Fornage, Myriam, Hassinen, Maija, Bielak, Lawrence F., Cadby, Gemma, Tanaka, Toshiko, Magl, Reedlk, Van der Most, Peter J., Jackson, Anne U., Bragg-Gresham, Jennifer L., Vitart, Veronique, Marten, Jonathan, Navarro, Pau, Bellis, Claire, Pasko, Dorota, Johansson, Asa, Snitker, Soren, Cheng, Yu-Ching, Eriksson, Joel, Lim, Unhee, Aadahl, Mette, Adair, Linda S., Amin, Najaf, Balkau, Beverley, Auvinen, Juha, Beilby, John, Bergman, Richard N., Bergmann, Sven, Bertoni, Alain G., Blangero, John, Bonnefond, Amelle, Bonnycastle, Lori L., Borja, Judith B., Brage, Soren, Busonero, Fabio, Buyske, Steve, Campbell, Harry, Chines, Peter S., Collins, Francis S., Corre, Tanguy, Smith, George Davey, Delgado, Graciela E., Dueker, Nicole, Doerr, Marcus, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tonu, Faul, Jessica D., Fu, Mao, Faerch, Kristine, Gieger, Christian, Glaeser, Sven, Gong, Jian, Gordon-Larsen, Penny, Grallert, Harald, Grammer, Tanja B., Grarup, Niels, van Grootheest, Gerard, Harald, Kennet, Hastie, Nicholas D., Havulinna, Aki S., Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J., Holmens, Oddgeir L., Holzapfel, Christina, Hottenga, Jouke Jan, Huang, Jie, Huang, Tao, Hui, Jennie, Huth, Cornelia, Hutri-Kahonen, Nina, James, Alan L., Jansson, John-Olov, Jhun, Min A., Juonala, Markus, Kinnunen, Leena, Koistinen, Heikki A., Kolcic, Ivana, Komulainen, Pirjo, Kuusisto, Johanna, Kvaloy, Kirsti, Kahonen, Mika, Lakka, Timo A., Launer, Lenore J., Lehne, Benjamin, Lindgren, Cecilia M., Lorentzon, Mattias, Luben, Robert, Marre, Michel, Milaneschi, Yuri, Monda, Keri L., Montgomery, Grant W., De Moor, Marleen H. M., Mulas, Antonella, Mueller-Nurasyid, Martina, Musk, A. W., Mannikko, Reija, Mannisto, Satu, Narisu, Narisu, Nauck, Matthias, Nettleton, Jennifer A., Nolte, Ilja M., Oldehinkel, Albertine J., Olden, Matthias, Ong, Ken K., Padmanabhan, Sandosh, Paternoster, Lavinia, Perez, Jeremiah, Perola, Markus, Peters, Annette, Peters, Ulrike, Peyser, Patricia A., Prokopenko, Inga, Puolijoki, Hannu, Raitakari, Olli T., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rawal, Rajesh, Ridker, Paul M., Rose, Lynda M., Rudan, Igor, Sarti, Cinzia, Sarzynski, Mark A., Savonen, Kai, Scott, William R., Sanna, Serena, Shuldiner, Alan R., Sidney, Steve, Silbernagel, Guenther, Smith, Blair H., Smith, Jennifer A., Snieder, Harold, Stancakova, Alena, Sternfeld, Barbara, Swift, Amy J., Tammelin, Tuija, Tan, Sian-Tsung, Thorand, Barbara, Thuillier, Dorothee, Vandenput, Liesbeth, Vestergaard, Henrik, van Vliet-Ostaptchouk, Jana V., Vohl, Marie-Claude, Voelker, Uwe, Waeber, Gerard, Walker, Mark, Wild, Sarah, Wong, Andrew, Wright, Alan F., Zillikens, M. Carola, Zubair, Niha, Haiman, Christopher A., Lemarchand, Loic, Gyllensten, Ulf, Ohlsson, Claes, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Perusse, Louis, Wilson, James F., Hayward, Caroline, Polasek, Ozren, Cucca, Francesco, Hveem, Kristian, Hartman, Catharina A., Toenjes, Anke, Bandinelli, Stefania, Palmer, Lyle J., Kardia, Sharon L. R., Rauramaa, Rainer, Sorensen, Thorkild I. A., Tuomilehto, Jaakko, Salomaa, Veikko, Penninx, Brenda W. J. H., de Geus, Eco J. C., Boomsma, Dorret I., Lehtimaki, Terho, Mangino, Massimo, Laakso, Markku, Bouchard, Claude, Martin, Nicholas G., Kuh, Diana, Liu, Yongmei, Linneberg, Allan, Maerz, Winfried, Strauch, Konstantin, Kivimaki, Mika, Harris, Tamara B., Gudnason, Vilmundur, Voelzke, Henry, Qi, Lu, Jarvelin, Marjo-Riitta, Chambers, John C., Kooner, Jaspal S., Froguel, Philippe, Kooperberg, Charles, Vollenweider, Peter, Hallmans, Göran, Hansen, Torben, Pedersen, Oluf, Metspalu, Andres, Wareham, Nicholas J., Langenberg, Claudia, Weir, David R., Porteous, David J., Boerwinkle, Eric, Chasman, Daniel I., Abecasis, Goncalo R., Barroso, Ines, McCarthy, Mark I., Frayling, Timothy M., O'Connell, Jeffrey R., van Duijn, Cornelia M., Boehnke, Michael, Heid, Iris M., Mohlke, Karen L., Strachan, David P., Fox, Caroline S., Liu, Ching-Ti, Hirschhorn, Joel N., Klein, Robert J., Johnson, Andrew D., Borecki, Ingrid B., Franks, Paul W., North, Kari E., Cupples, L. Adrienne, Loos, Ruth J. F., Kilpelainen, Tuomas O., Graff, Mariaelisa, Scott, Robert A., Justice, Anne E., Young, Kristin L., Feitosa, Mary F., Barata, Llilda, Winkler, Thomas W., Chu, Audrey Y., Mahajan, Anubha, Hadley, David, Xue, Luting, Workalemahu, Tsegaselassie, Heard-Costa, Nancy L., den Hoed, Marcel, Ahluwalia, Tarunveer S., Qi, Qibin, Ngwa, Julius S., Renström, Frida, Quaye, Lydia, Eicher, John D., Hayes, James E., Cornelis, Marilyn, Kutalik, Zoltan, Lim, Elise, Luan, Jian'an, Huffman, Jennifer E., Zhang, Weihua, Zhao, Wei, Griffin, Paula J., Haller, Toomas, Ahmad, Shafqat, Marques-Vidal, Pedro M., Bien, Stephanie, Yengo, Loic, Teumer, Alexander, Smith, Albert Vernon, Kumari, Meena, Harder, Marie Neergaard, Justesen, Johanne Marie, Kleber, Marcus E., Hollensted, Mette, Lohman, Kurt, Rivera, Natalia V., Whitfield, John B., Zhao, Jing Hua, Stringham, Heather M., Lyytikainen, Leo-Pekka, Huppertz, Charlotte, Willemsen, Gonneke, Peyrot, Wouter J., Wu, Ying, Kristiansson, Kati, Demirkan, Ayse, Fornage, Myriam, Hassinen, Maija, Bielak, Lawrence F., Cadby, Gemma, Tanaka, Toshiko, Magl, Reedlk, Van der Most, Peter J., Jackson, Anne U., Bragg-Gresham, Jennifer L., Vitart, Veronique, Marten, Jonathan, Navarro, Pau, Bellis, Claire, Pasko, Dorota, Johansson, Asa, Snitker, Soren, Cheng, Yu-Ching, Eriksson, Joel, Lim, Unhee, Aadahl, Mette, Adair, Linda S., Amin, Najaf, Balkau, Beverley, Auvinen, Juha, Beilby, John, Bergman, Richard N., Bergmann, Sven, Bertoni, Alain G., Blangero, John, Bonnefond, Amelle, Bonnycastle, Lori L., Borja, Judith B., Brage, Soren, Busonero, Fabio, Buyske, Steve, Campbell, Harry, Chines, Peter S., Collins, Francis S., Corre, Tanguy, Smith, George Davey, Delgado, Graciela E., Dueker, Nicole, Doerr, Marcus, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tonu, Faul, Jessica D., Fu, Mao, Faerch, Kristine, Gieger, Christian, Glaeser, Sven, Gong, Jian, Gordon-Larsen, Penny, Grallert, Harald, Grammer, Tanja B., Grarup, Niels, van Grootheest, Gerard, Harald, Kennet, Hastie, Nicholas D., Havulinna, Aki S., Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J., Holmens, Oddgeir L., Holzapfel, Christina, Hottenga, Jouke Jan, Huang, Jie, Huang, Tao, Hui, Jennie, Huth, Cornelia, Hutri-Kahonen, Nina, James, Alan L., Jansson, John-Olov, Jhun, Min A., Juonala, Markus, Kinnunen, Leena, Koistinen, Heikki A., Kolcic, Ivana, Komulainen, Pirjo, Kuusisto, Johanna, Kvaloy, Kirsti, Kahonen, Mika, Lakka, Timo A., Launer, Lenore J., Lehne, Benjamin, Lindgren, Cecilia M., Lorentzon, Mattias, Luben, Robert, Marre, Michel, Milaneschi, Yuri, Monda, Keri L., Montgomery, Grant W., De Moor, Marleen H. M., Mulas, Antonella, Mueller-Nurasyid, Martina, Musk, A. W., Mannikko, Reija, Mannisto, Satu, Narisu, Narisu, Nauck, Matthias, Nettleton, Jennifer A., Nolte, Ilja M., Oldehinkel, Albertine J., Olden, Matthias, Ong, Ken K., Padmanabhan, Sandosh, Paternoster, Lavinia, Perez, Jeremiah, Perola, Markus, Peters, Annette, Peters, Ulrike, Peyser, Patricia A., Prokopenko, Inga, Puolijoki, Hannu, Raitakari, Olli T., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rawal, Rajesh, Ridker, Paul M., Rose, Lynda M., Rudan, Igor, Sarti, Cinzia, Sarzynski, Mark A., Savonen, Kai, Scott, William R., Sanna, Serena, Shuldiner, Alan R., Sidney, Steve, Silbernagel, Guenther, Smith, Blair H., Smith, Jennifer A., Snieder, Harold, Stancakova, Alena, Sternfeld, Barbara, Swift, Amy J., Tammelin, Tuija, Tan, Sian-Tsung, Thorand, Barbara, Thuillier, Dorothee, Vandenput, Liesbeth, Vestergaard, Henrik, van Vliet-Ostaptchouk, Jana V., Vohl, Marie-Claude, Voelker, Uwe, Waeber, Gerard, Walker, Mark, Wild, Sarah, Wong, Andrew, Wright, Alan F., Zillikens, M. Carola, Zubair, Niha, Haiman, Christopher A., Lemarchand, Loic, Gyllensten, Ulf, Ohlsson, Claes, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Perusse, Louis, Wilson, James F., Hayward, Caroline, Polasek, Ozren, Cucca, Francesco, Hveem, Kristian, Hartman, Catharina A., Toenjes, Anke, Bandinelli, Stefania, Palmer, Lyle J., Kardia, Sharon L. R., Rauramaa, Rainer, Sorensen, Thorkild I. A., Tuomilehto, Jaakko, Salomaa, Veikko, Penninx, Brenda W. J. H., de Geus, Eco J. C., Boomsma, Dorret I., Lehtimaki, Terho, Mangino, Massimo, Laakso, Markku, Bouchard, Claude, Martin, Nicholas G., Kuh, Diana, Liu, Yongmei, Linneberg, Allan, Maerz, Winfried, Strauch, Konstantin, Kivimaki, Mika, Harris, Tamara B., Gudnason, Vilmundur, Voelzke, Henry, Qi, Lu, Jarvelin, Marjo-Riitta, Chambers, John C., Kooner, Jaspal S., Froguel, Philippe, Kooperberg, Charles, Vollenweider, Peter, Hallmans, Göran, Hansen, Torben, Pedersen, Oluf, Metspalu, Andres, Wareham, Nicholas J., Langenberg, Claudia, Weir, David R., Porteous, David J., Boerwinkle, Eric, Chasman, Daniel I., Abecasis, Goncalo R., Barroso, Ines, McCarthy, Mark I., Frayling, Timothy M., O'Connell, Jeffrey R., van Duijn, Cornelia M., Boehnke, Michael, Heid, Iris M., Mohlke, Karen L., Strachan, David P., Fox, Caroline S., Liu, Ching-Ti, Hirschhorn, Joel N., Klein, Robert J., Johnson, Andrew D., Borecki, Ingrid B., Franks, Paul W., North, Kari E., Cupples, L. Adrienne, Loos, Ruth J. F., and Kilpelainen, Tuomas O.

Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017
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38. High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality

Author

Silbernagel, Guenther, Schöttker, Ben, Appelbaum, Sebastian, Scharnagl, Hubert, Kleber, Marcus E., Grammer, Tanja B., Ritsch, Andreas, Mons, Ute, Holleczek, Bernd, Goliasch, Georg, Niessner, Alexander, Boehm, Bernhard O., Schnabel, Renate B., Brenner, Hermann, Blankenberg, Stefan, Landmesser, Ulf, März, Winfried, Silbernagel, Guenther, Schöttker, Ben, Appelbaum, Sebastian, Scharnagl, Hubert, Kleber, Marcus E., Grammer, Tanja B., Ritsch, Andreas, Mons, Ute, Holleczek, Bernd, Goliasch, Georg, Niessner, Alexander, Boehm, Bernhard O., Schnabel, Renate B., Brenner, Hermann, Blankenberg, Stefan, Landmesser, Ulf, and März, Winfried

Abstract

Aims High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. Methods and results We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. Conclusion The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients

Published
2017

39. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author

Walford, Geoffrey A., Gustafsson, Stefan, Rybin, Denis, Stancakova, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A., Rice, Ken, Morris, Andrew P., Magi, Reedik, Toenjes, Anke, Prokopenko, Inga, Kleber, Marcus E., Delgado, Graciela, Silbernagel, Guenther, Jackson, Anne U., Appel, Emil V., Grarup, Niels, Lewis, Joshua P., Montasser, May E., Ladenvall, Claes, Staiger, Harald, Luan, Jian'an, Frayling, Timothy M., Weedon, Michael N., Xie, Weijia, Morcillo, Sonsoles, Teresa Martinez-Larrad, Maria, Biggs, Mary L., Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Faerch, Kristine, Miguel Gomez-Zumaquero, Juan, Goodarzi, Mark O., Kizer, Jorge R., Koistinen, Heikki A., Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K., Maria Martin-Nunez, Gracia, Rojo-Martinez, Gemma, Rotter, Jerome I., Siscovick, David S., Zmuda, Joseph M., Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jorgensen, Torben J., Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A., Wareham, Nicholas J., Fritsche, Andreas, Haering, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O'Connell, Jeff R., Boehnke, Michael, Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Maerz, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M., Kuusisto, Johanna, Laakso, Markku, Meigs, James B., Dupuis, Josee, Ingelsson, Erik, Florez, Jose C., Walford, Geoffrey A., Gustafsson, Stefan, Rybin, Denis, Stancakova, Alena, Chen, Han, Liu, Ching-Ti, Hong, Jaeyoung, Jensen, Richard A., Rice, Ken, Morris, Andrew P., Magi, Reedik, Toenjes, Anke, Prokopenko, Inga, Kleber, Marcus E., Delgado, Graciela, Silbernagel, Guenther, Jackson, Anne U., Appel, Emil V., Grarup, Niels, Lewis, Joshua P., Montasser, May E., Ladenvall, Claes, Staiger, Harald, Luan, Jian'an, Frayling, Timothy M., Weedon, Michael N., Xie, Weijia, Morcillo, Sonsoles, Teresa Martinez-Larrad, Maria, Biggs, Mary L., Chen, Yii-Der Ida, Corbaton-Anchuelo, Arturo, Faerch, Kristine, Miguel Gomez-Zumaquero, Juan, Goodarzi, Mark O., Kizer, Jorge R., Koistinen, Heikki A., Leong, Aaron, Lind, Lars, Lindgren, Cecilia, Machicao, Fausto, Manning, Alisa K., Maria Martin-Nunez, Gracia, Rojo-Martinez, Gemma, Rotter, Jerome I., Siscovick, David S., Zmuda, Joseph M., Zhang, Zhongyang, Serrano-Rios, Manuel, Smith, Ulf, Soriguer, Federico, Hansen, Torben, Jorgensen, Torben J., Linnenberg, Allan, Pedersen, Oluf, Walker, Mark, Langenberg, Claudia, Scott, Robert A., Wareham, Nicholas J., Fritsche, Andreas, Haering, Hans-Ulrich, Stefan, Norbert, Groop, Leif, O'Connell, Jeff R., Boehnke, Michael, Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Maerz, Winfried, Kovacs, Peter, Stumvoll, Michael, Psaty, Bruce M., Kuusisto, Johanna, Laakso, Markku, Meigs, James B., Dupuis, Josee, Ingelsson, Erik, and Florez, Jose C.

Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 x 10(-11)), rs12454712 (BCL2; P = 2.7 x 10(-8)), and rs10506418 (FAM19A2; P = 1.9 x 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci., Funding:This work was supported by National Institutes of Health grant DK099249 (to G.A.W.). Grant support was provided to cohorts. For METSIM, the study was funded by the Academy of Finland (grants 77299 and 124243). For Sorbs, the work was supported by grants from the German Research Council (DFG-SFB 1052, "Obesity mechanisms," A01, C01, B03, and SPP 1629 TO 718/2-1), the German Diabetes Association, and the Diabetes Hilfs-und Forschungsfonds Deutschland (DHFD). This work was further supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ (01EO1501, AD2-060E to P.K.), and by the Boehringer Ingelheim Foundation. For FHS, the study was supported by the National Heart, Lung, and Blood Institute (contract nos. N02-HL-6-4278 [supporting its contract with Affymetrix, Inc., for genotyping services], N01-HC-25195, HL084756, and HHSN268201500001I) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078616 to J.D., U01-DK085526 to H.C. and J.D., 2R01 DK078616 and K24 DK080140 to J.M.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. A.K.M. was supported by American Diabetes Association Research Foundation (grant 7-12-MN-02). For CHS, research was supported by National Heart, Lung, and Blood Institute contract nos. HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant nos. U01HL080295, HL105756, and HL120393, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). For ULSAM, the project was supported by the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), the European Research Council (ERC Starting Grant), the Swe

Published
2016
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40. LDL-Cholesterol: Standards of Treatment 2016: A German Perspective

Author

Maerz, Winfried, Scharnagl, Hubert, Gouni-Berthold, Ioanna, Silbernagel, Guenther, Dressel, Alexander, Grammer, Tanja B., Landmesser, Ulf, Dieplinger, Hans, Windler, Eberhard, Laufs, Ulrich, Maerz, Winfried, Scharnagl, Hubert, Gouni-Berthold, Ioanna, Silbernagel, Guenther, Dressel, Alexander, Grammer, Tanja B., Landmesser, Ulf, Dieplinger, Hans, Windler, Eberhard, and Laufs, Ulrich

Abstract

Decreasing low-density lipoprotein cholesterol (LDL-C) is one of the few established and proven principles for the prevention and treatment of atherosclerosis. The higher the individual cardiovascular risk, the higher the benefit of lipid-lowering pharmacotherapy. Therefore, treatment options are chosen based on a patient's total cardiovascular risk. The latter depends not only on the levels of LDL-C but also on the presence of cardiovascular disease (CVD) and on the number and severity of other risk factors. Current guidelines recommend the lowering of LDL-C to 115 mg/dl (3 mmol/l) in patients with low and moderate risk. The LDL-C treatment target is < 100 mg/dl (2.6 mmol/l) for patients at high risk and < 70 mg/dl (1.8 mmol/l) for patients at very high risk. Although lifestyle measures remain a fundamental part of treatment, many patients require drug therapy to achieve their LDL-C targets. Statins are the drugs of choice, with other options including ezetimibe and the newly available monoclonal antibodies against PCSK9 (proprotein convertase subtilisin/kexin type 9). In some cases, bile acid-binding sequestrants and fibrates can also be considered. Nicotinic acid is no longer available in Germany. PCSK9 antibodies decrease LDL-C about 50-60 % and are well tolerated. Their effects on clinical endpoints are being investigated in large randomized trials. The aim of the present review is to summarize the current guidelines and treatment options for hypercholesterolemia. Moreover, we provide an appraisal of PCSK9 antibodies and propose their use in selected patient populations, particularly in those at very high cardiovascular risk whose LDL-C levels under maximally tolerated lipid-lowering therapy are significantly over their treatment target.

Published
2016

41. LDL-Cholesterol: Standards of Treatment 2016: A German Perspective (vol 16, pg 323, 2016)

Author

Maerz, Winfried, Scharnagl, Hubert, Gouni-Berthold, Ioanna, Silbernagel, Guenther, Dressel, Alexander, Grammer, Tanja B., Landmesser, Ulf, Dieplinger, Hans, Windler, Eberhard, Laufs, Ulrich, Maerz, Winfried, Scharnagl, Hubert, Gouni-Berthold, Ioanna, Silbernagel, Guenther, Dressel, Alexander, Grammer, Tanja B., Landmesser, Ulf, Dieplinger, Hans, Windler, Eberhard, and Laufs, Ulrich

Published
2016

45. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

Author

Kilpelaeinen, Tuomas O., Qi, Lu, Brage, Soren, Sharp, Stephen J., Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S., Hyppoenen, Elina, Cauchi, Stephane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancakova, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T., Mangino, Massimo, Timpson, Nicholas J., Song, Yiqing, Zillikens, M. Carola, Jablonski, Kathleen A., Garcia, Melissa E., Johansson, Stefan, Bragg-Gresham, Jennifer L., Wu, Ying, van Vliet-Ostaptchouk, Jana V., Onland-Moret, N. Charlotte, Zimmermann, Esther, Rivera, Natalia V., Tanaka, Toshiko, Stringham, Heather M., Silbernagel, Guenther, Kanoni, Stavroula, Feitosa, Mary F., Snitker, Soren, Ruiz, Jonatan R., Metter, Jeffery, Martinez Larrad, Maria Teresa, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proenca, Christine, Grontved, Anders, Hallmans, Goran, Jansson, John-Olov, Kuusisto, Johanna, Kahonen, Mika, Lutsey, Pamela L., Nolan, John J., Palla, Luigi, Pedersen, Oluf, Perusse, Louis, Renstrom, Frida, Scott, Robert A., Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H., Ronnemaa, Tapani, Lakka, Timo A., Uusitupa, Matti, Serrano Rios, Manuel, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B., Dedoussis, George V., Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M., Ebrahim, Shah, Lawlor, Debbie A., Gudnason, Vilmundur, Harris, Tamara B., Sorensen, Thorkild I. A., Mohlke, Karen L., Hofman, Albert, Uitterlinden, Andre G., Tuomilehto, Jaakko, Lehtimaki, Terho, Raitakari, Olli, Isomaa, Bo, Njolstad, Pal R., Florez, Jose C., Liu, Simin, Ness, Andy, Spector, Timothy D., Tai, E. Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L., Illig, Thomas, Jarvelin, Marjo-Riitta, Wareham, Nicholas J., Hu, Frank B., Groop, Leif, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul, Loos, Ruth J. F., Kilpelaeinen, Tuomas O., Qi, Lu, Brage, Soren, Sharp, Stephen J., Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S., Hyppoenen, Elina, Cauchi, Stephane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stancakova, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T., Mangino, Massimo, Timpson, Nicholas J., Song, Yiqing, Zillikens, M. Carola, Jablonski, Kathleen A., Garcia, Melissa E., Johansson, Stefan, Bragg-Gresham, Jennifer L., Wu, Ying, van Vliet-Ostaptchouk, Jana V., Onland-Moret, N. Charlotte, Zimmermann, Esther, Rivera, Natalia V., Tanaka, Toshiko, Stringham, Heather M., Silbernagel, Guenther, Kanoni, Stavroula, Feitosa, Mary F., Snitker, Soren, Ruiz, Jonatan R., Metter, Jeffery, Martinez Larrad, Maria Teresa, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proenca, Christine, Grontved, Anders, Hallmans, Goran, Jansson, John-Olov, Kuusisto, Johanna, Kahonen, Mika, Lutsey, Pamela L., Nolan, John J., Palla, Luigi, Pedersen, Oluf, Perusse, Louis, Renstrom, Frida, Scott, Robert A., Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H., Ronnemaa, Tapani, Lakka, Timo A., Uusitupa, Matti, Serrano Rios, Manuel, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B., Dedoussis, George V., Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M., Ebrahim, Shah, Lawlor, Debbie A., Gudnason, Vilmundur, Harris, Tamara B., Sorensen, Thorkild I. A., Mohlke, Karen L., Hofman, Albert, Uitterlinden, Andre G., Tuomilehto, Jaakko, Lehtimaki, Terho, Raitakari, Olli, Isomaa, Bo, Njolstad, Pal R., Florez, Jose C., Liu, Simin, Ness, Andy, Spector, Timothy D., Tai, E. Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, Marmot, Michael, Bergmann, Sven, Power, Chris, Khaw, Kay-Tee, Chasman, Daniel, Ridker, Paul, Hansen, Torben, Monda, Keri L., Illig, Thomas, Jarvelin, Marjo-Riitta, Wareham, Nicholas J., Hu, Frank B., Groop, Leif, Orho-Melander, Marju, Ekelund, Ulf, Franks, Paul, and Loos, Ruth J. F.

Abstract

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Published
2011

49. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Justice, Anne E., Winkler, Thomas W., Feitosa, Mary F., Graff, Misa, Fisher, Virginia A., Young, Kristin, Barata, Llilda, Deng, Xuan, Czajkowski, Jacek, Hadley, David, Ngwa, Julius S., Ahluwalia, Tarunveer S., Chu, Audrey Y., Heard-Costa, Nancy L., Lim, Elise, Perez, Jeremiah, Eicher, John D., Kutalik, Zoltán, Xue, Luting, Mahajan, Anubha, Renström, Frida, Wu, Joseph, Qi, Qibin, Alfred, Tamuno, Amin, Najaf, Bielak, Lawrence F., Bonnefond, Amelie, Bragg, Jennifer, Cadby, Gemma, Chittani, Martina, Coggeshall, Scott, Corre, Tanguy, Direk, Nese, Eriksson, Joel, Fischer, Krista, Gorski, Mathias, Neergaard Harder, Marie, Horikoshi, Momoko, Huffman, Jennifer E., Jackson, Anne U., Justesen, Johanne Marie, Kanoni, Stavroula, Kinnunen, Leena, Kleber, Marcus E., Komulainen, Pirjo, Kumari, Meena, Lim, Unhee, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Middelberg, Rita P. S., Müller-Nurasyid, Martina, Navarro, Pau, Pérusse, Louis, Pervjakova, Natalia, Sarti, Cinzia, Smith, Albert Vernon, Smith, Jennifer A., Stančáková, Alena, Strawbridge, Rona J., Stringham, Heather M., Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W., van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Vedantam, Sailaja L., Verweij, Niek, Vink, Jacqueline M., Vitart, Veronique, Wu, Ying, Yengo, Loic, Zhang, Weihua, Hua Zhao, Jing, Zimmermann, Martina E., Zubair, Niha, Abecasis, Gonçalo R., Adair, Linda S., Afaq, Saima, Afzal, Uzma, Bakker, Stephan J. L., Bartz, Traci M., Beilby, John, Bergman, Richard N., Bergmann, Sven, Biffar, Reiner, Blangero, John, Boerwinkle, Eric, Bonnycastle, Lori L., Bottinger, Erwin, Braga, Daniele, Buckley, Brendan M., Buyske, Steve, Campbell, Harry, Chambers, John C., Collins, Francis S., Curran, Joanne E., de Borst, Gert J., de Craen, Anton J. M., de Geus, Eco J. C., Dedoussis, George, Delgado, Graciela E., den Ruijter, Hester M., Eiriksdottir, Gudny, Eriksson, Anna L., Esko, Tõnu, Faul, Jessica D., Ford, Ian, Forrester, Terrence, Gertow, Karl, Gigante, Bruna, Glorioso, Nicola, Gong, Jian, Grallert, Harald, Grammer, Tanja B., Grarup, Niels, Haitjema, Saskia, Hallmans, Göran, Hamsten, Anders, Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas D., Heath, Andrew C., Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Homuth, Georg, Jan Hottenga, Jouke, Huang, Jie, Hung, Joseph, Hutri-Kähönen, Nina, Ingelsson, Erik, James, Alan L., Jansson, John-Olov, Jarvelin, Marjo-Riitta, Jhun, Min A., Jørgensen, Marit E., Juonala, Markus, Kähönen, Mika, Karlsson, Magnus, Koistinen, Heikki A., Kolcic, Ivana, Kolovou, Genovefa, Kooperberg, Charles, Krämer, Bernhard K., Kuusisto, Johanna, Kvaløy, Kirsti, Lakka, Timo A., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lee, Nanette R., Lind, Lars, Lindgren, Cecilia M., Linneberg, Allan, Lobbens, Stephane, Loh, Marie, Lorentzon, Mattias, Luben, Robert, Lubke, Gitta, Ludolph-Donislawski, Anja, Lupoli, Sara, Madden, Pamela A. F., Männikkö, Reija, Marques-Vidal, Pedro, Martin, Nicholas G., McKenzie, Colin A., McKnight, Barbara, Mellström, Dan, Menni, Cristina, Montgomery, Grant W., Musk, AW (Bill), Narisu, Narisu, Nauck, Matthias, Nolte, Ilja M., Oldehinkel, Albertine J., Olden, Matthias, Ong, Ken K., Padmanabhan, Sandosh, Peyser, Patricia A., Pisinger, Charlotta, Porteous, David J., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rasmussen-Torvik, Laura J., Rawal, Rajesh, Rice, Treva, Rose, Lynda M., Bien, Stephanie A., Rudan, Igor, Sanna, Serena, Sarzynski, Mark A., Sattar, Naveed, Savonen, Kai, Schlessinger, David, Scholtens, Salome, Schurmann, Claudia, Scott, Robert A., Sennblad, Bengt, Siemelink, Marten A., Silbernagel, Günther, Slagboom, P Eline, Snieder, Harold, Staessen, Jan A., Stott, David J., Swertz, Morris A., Swift, Amy J., Taylor, Kent D., Tayo, Bamidele O., Thorand, Barbara, Thuillier, Dorothee, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vandenput, Liesbeth, Vohl, Marie-Claude, Völzke, Henry, Vonk, Judith M., Waeber, Gérard, Waldenberger, Melanie, Westendorp, R. G. J., Wild, Sarah, Willemsen, Gonneke, Wolffenbuttel, Bruce H. R., Wong, Andrew, Wright, Alan F., Zhao, Wei, Zillikens, M Carola, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Böger, Carsten A., Boomsma, Dorret I., Bouchard, Claude, Bruinenberg, Marcel, Chen, Yii-DerIda, Chines, Peter S., Cooper, Richard S., Cucca, Francesco, Cusi, Daniele, Faire, Ulf de, Ferrucci, Luigi, Froguel, Philippe, Gordon-Larsen, Penny, Grabe, Hans- Jörgen, Gudnason, Vilmundur, Haiman, Christopher A., Hayward, Caroline, Hveem, Kristian, Johnson, Andrew D., Wouter Jukema, J, Kardia, Sharon L. R., Kivimaki, Mika, Kooner, Jaspal S., Kuh, Diana, Laakso, Markku, Lehtimäki, Terho, Marchand, Loic Le, März, Winfried, McCarthy, Mark I., Metspalu, Andres, Morris, Andrew P., Ohlsson, Claes, Palmer, Lyle J., Pasterkamp, Gerard, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Psaty, Bruce M., Rauramaa, Rainer, Smith, Blair H., Sørensen, Thorkild I. A., Strauch, Konstantin, Tiemeier, Henning, Tremoli, Elena, van der Harst, Pim, Vestergaard, Henrik, Vollenweider, Peter, Wareham, Nicholas J., Weir, David R., Whitfield, John B., Wilson, James F., Tyrrell, Jessica, Frayling, Timothy M., Barroso, Inês, Boehnke, Michael, Deloukas, Panagiotis, Fox, Caroline S., Spector, Tim D., Strachan, David P., van Duijn, Cornelia M., Heid, Iris M., Mohlke, Karen L., Marchini, Jonathan, Loos, Ruth J. F., Kilpeläinen, Tuomas O., Liu, Ching-Ti, Borecki, Ingrid B., North, Kari E., Cupples, L Adrienne, Ahmad, Shafqat, Huang, Tao, Ridker, Paul, Chasman, Daniel, Franks, Paul, Qi, Lu, Hirschhorn, Joel, and Hunter, David

Abstract

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution., Version of Record

Published
2017
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50. Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children

Author

Kilpeläinen, Tuomas O., Qi, Lu, Brage, Soren, Sharp, Stephen J., Sonestedt, Emily, Demerath, Ellen, Ahmad, Tariq, Mora, Samia, Kaakinen, Marika, Sandholt, Camilla Helene, Holzapfel, Christina, Autenrieth, Christine S., Hyppönen, Elina, Cauchi, Stéphane, He, Meian, Kutalik, Zoltan, Kumari, Meena, Stančáková, Alena, Meidtner, Karina, Balkau, Beverley, Tan, Jonathan T., Mangino, Massimo, Timpson, Nicholas J., Song, Yiqing, Zillikens, M. Carola, Jablonski, Kathleen A., Garcia, Melissa E., Johansson, Stefan, Bragg-Gresham, Jennifer L., Wu, Ying, van Vliet-Ostaptchouk, Jana V., Onland-Moret, N. Charlotte, Zimmermann, Esther, Rivera, Natalia V., Tanaka, Toshiko, Stringham, Heather M., Silbernagel, Günther, Kanoni, Stavroula, Feitosa, Mary F., Snitker, Soren, Ruiz, Jonatan R., Metter, Jeffery, Larrad, Maria Teresa Martinez, Atalay, Mustafa, Hakanen, Maarit, Amin, Najaf, Cavalcanti-Proença, Christine, Grøntved, Anders, Hallmans, Göran, Jansson, John-Olov, Kuusisto, Johanna, Kähönen, Mika, Lutsey, Pamela L., Nolan, John J., Palla, Luigi, Pedersen, Oluf, Pérusse, Louis, Renström, Frida, Scott, Robert A., Shungin, Dmitry, Sovio, Ulla, Tammelin, Tuija H., Rönnemaa, Tapani, Lakka, Timo A., Uusitupa, Matti, Rios, Manuel Serrano, Ferrucci, Luigi, Bouchard, Claude, Meirhaeghe, Aline, Fu, Mao, Walker, Mark, Borecki, Ingrid B., Dedoussis, George V., Fritsche, Andreas, Ohlsson, Claes, Boehnke, Michael, Bandinelli, Stefania, van Duijn, Cornelia M., Ebrahim, Shah, Lawlor, Debbie A., Gudnason, Vilmundur, Harris, Tamara B., Sørensen, Thorkild I. A., Mohlke, Karen L., Hofman, Albert, Uitterlinden, André G., Tuomilehto, Jaakko, Lehtimäki, Terho, Raitakari, Olli, Isomaa, Bo, Njølstad, Pål R., Florez, Jose C., Liu, Simin, Ness, Andy, Spector, Timothy D., Tai, E. Shyong, Froguel, Philippe, Boeing, Heiner, Laakso, Markku, and Marmot, Michael

Abstract

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity., Version of Record

Published
2011

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