المؤلفون: International Multiple Sclerosis Genetics Consortium, Ashley H. Beecham, Nikolaos A. Patsopoulos, Dionysia K. Xifara, Mary F. Davis, Anu Kemppinen, Chris Cotsapas, Tejas S. Shah, Chris Spencer, David Booth, An Goris, Annette Oturai, Janna Saarela, Bertrand Fontaine, Bernhard Hemmer, Claes Martin, Frauke Zipp, Sandra D'Alfonso, Filippo Martinelli Boneschi, Bruce Taylor, Hanne F. Harbo, Ingrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge R. Oksenberg, Rogier Hintzen, Barcellos Lf 2. Wellcome Trust Case Control Consortium, International Ibd Genetics Consortium, Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl Anderson, Robert Andrews, Helle Bach Søndergaard, Amie Baker, Gavin Band, Sergio E. Baranzini, Nadia Barizzone, Jeffrey Barrett, Celine Bellenguez, Laura Bergamaschi, Luisa Bernardinelli, Achim Berthele, Viola Biberacher, Thomas M. C. Binder, Hannah Blackburn, Izaura L. Bomfim, Paola Brambilla, Simon Broadley, Bruno Brochet, Lou Brundin, Dorothea Buck, Helmut Butzkueven, Stacy J. Caillier, William Camu, Wassila Carpentier, Paola Cavalla, Elisabeth G. Celius, Irene Coman, Giancarlo Comi, Lucia Corrado, Leentje Cosemans, Isabelle Cournu Rebeix, Bruce A. C. Cree, Daniele Cusi, Vincent Damotte, Gilles Defer, Silvia R. Delgado, Panos Deloukas, A. Di Sapio, Alexander T. Dilthey, Peter Donnelly, Benedicte Dubois, Martin Duddy, Sarah Edkins, Irina Elovaara, Federica Esposito, Nikos Evangelou, Barnaby Fiddes, Judith Field, Andre Franke, Colin Freeman, Irene Y. Frohlich, Daniela Galimberti, Christian Gieger, Pierre Antoine Gourraud, Christiane Graetz, Andrew Graham, Verena Grummel, Clara Guaschino, Athena Hadjixenofontos, Hakon Hakonarson, Christopher Halfpenny, Gillian Hall, Per Hall, Anders Hamsten, James Harley, Timothy Harrower, Clive Hawkins, Garrett Hellenthal, Charles Hillier, Jeremy Hobart, Muni Hoshi, Sarah E. Hunt, Maja Jagodic, Ilijas Jelcic, Angela Jochim, Brian Kendall, Allan Kermode, Trevor Kilpatrick, Keijo Koivisto, Ioanna Konidari, Thomas Korn, Helena Kronsbein, Cordelia Langford, Malin Larsson, Mark Lathrop, Christine Lebrun Frenay, Jeannette Lechner Scott, Michelle H. Lee, Maurizio A. Leone, Virpi Leppa, Giuseppe Liberatore, Benedicte A. Lie, Christina M. Lill, Magdalena Linden, Jenny Link, Felix Luessi, Jan Lycke, Fabio Macciardi, Satu Mannisto, Clara P. Manrique, Roland Martin, Vittorio Martinelli, Deborah Mason, Gordon Mazibrada, Cristin Mccabe, Inger Lise Mero, Julia Mescheriakova, Loukas Moutsianas, Kjell Morten Myhr, Guy Nagels, Richard Nicholas, Petra Nilsson, Fredrik Piehl, Matti Pirinen, Sian E. Price, Hong Quach, Mauri Reunanen, Wim Robberecht, Neil P. Robertson, Mariaemma Rodegher, David Rog, Nathalie C. Schnetz Boutaud, Finn Sellebjerg, Rebecca C. Selter, Catherine Schaefer, Sandip Shaunak, Ling Shen, Simon Shields, Volker Siffrin, Mark Slee, Per Soelberg Sorensen, Melissa Sorosina, Mireia Sospedra, Anne Spurkland, Amy Strange, Emilie Sundqvist, Vincent Thijs, John Thorpe, Anna Ticca, Pentti Tienari, Cornelia Van Duijn, Elizabeth M. Visser, Steve Vucic, Helga Westerlind, James S. Wiley, Alastair Wilkins, James F. Wilson, Juliane Winkelmann, John Zajicek, Eva Zindler, Jonathan L. Haines, Margaret A. Pericak Vance, Adrian J. Ivinson, Graeme Stewart, David Hafler, Stephen L. Hauser, Alastair Compston, Gil Mcvean, Philip De Jager, Stephen J. Sawcer, Jacob L. Mccauley, SALVETTI, Marco

المساهمون: International Multiple Sclerosis Genetics, Consortium, Ashley H., Beecham, Nikolaos A., Patsopoulo, Dionysia K., Xifara, Mary F., Davi, Anu, Kemppinen, Chris, Cotsapa, Tejas S., Shah, Chris, Spencer, David, Booth, An, Gori, Annette, Oturai, Janna, Saarela, Bertrand, Fontaine, Bernhard, Hemmer, Claes, Martin, Frauke, Zipp, Sandra, D'Alfonso, Filippo Martinelli, Boneschi, Bruce, Taylor, Hanne F., Harbo, Ingrid, Kockum, Jan, Hillert, Tomas, Olsson, Maria, Ban, Jorge R., Oksenberg, Rogier, Hintzen, Barcellos Lf 2., Wellcome Trust Case Control Consortium, International Ibd Genetics, Consortium, Cristina, Agliardi, Lars, Alfredsson, Mehdi, Alizadeh, Carl, Anderson, Robert, Andrew, Helle Bach, Søndergaard, Amie, Baker, Gavin, Band, Sergio E., Baranzini, Nadia, Barizzone, Jeffrey, Barrett, Celine, Bellenguez, Laura, Bergamaschi, Luisa, Bernardinelli, Achim, Berthele, Viola, Biberacher, Thomas M. C., Binder, Hannah, Blackburn, Izaura L., Bomfim, Paola, Brambilla, Simon, Broadley, Bruno, Brochet, Lou, Brundin, Dorothea, Buck, Helmut, Butzkueven, Stacy J., Caillier, William, Camu, Wassila, Carpentier, Paola, Cavalla, Elisabeth G., Celiu, Irene, Coman, Giancarlo, Comi, Lucia, Corrado, Leentje, Coseman, Isabelle Cournu, Rebeix, Bruce A. C., Cree, Daniele, Cusi, Vincent, Damotte, Gilles, Defer, Silvia R., Delgado, Panos, Delouka, A., Di Sapio, Alexander T., Dilthey, Peter, Donnelly, Benedicte, Duboi, Martin, Duddy, Sarah, Edkin, Irina, Elovaara, Federica, Esposito, Nikos, Evangelou, Barnaby, Fidde, Judith, Field, Andre, Franke, Colin, Freeman, Irene Y., Frohlich, Daniela, Galimberti, Christian, Gieger, Pierre Antoine, Gourraud, Christiane, Graetz, Andrew, Graham, Verena, Grummel, Clara, Guaschino, Athena, Hadjixenofonto, Hakon, Hakonarson, Christopher, Halfpenny, Gillian, Hall, Per, Hall, Anders, Hamsten, James, Harley, Timothy, Harrower, Clive, Hawkin

الوصف: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/24076602; info:eu-repo/semantics/altIdentifier/wos/WOS:000326384100016; volume:45; issue:11; firstpage:1353; lastpage:+; numberofpages:10; journal:NATURE GENETICS; http://hdl.handle.net/11573/557110Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84887058596

الإتاحة: https://doi.org/10.1038/ng.2770Test
http://hdl.handle.net/11573/557110Test

المؤلفون: Frans van Harskamp, Michiel L. Bots, Christine Van Broeckhoven, Monique M.B. Breteler, Diederick E. Grobbee, Alewijn Ott, Arjen J .C. Slooter, Albert Hofman, Cornelia van Duijn

المساهمون: Epidemiology, Neurology

المصدر: Lancet (UK), 349, 151-154. Elsevier Ltd.

مصطلحات موضوعية: Apolipoprotein E, Male, Pathology, medicine.medical_specialty, Genotype, Arteriosclerosis, Population, Rotterdam Study, Apolipoproteins E, Alzheimer Disease, Internal medicine, mental disorders, medicine, Prevalence, Dementia, Humans, education, Vascular dementia, Aged, Netherlands, Aged, 80 and over, education.field_of_study, business.industry, Vascular disease, Dementia, Vascular, General Medicine, Odds ratio, Middle Aged, medicine.disease, Cross-Sectional Studies, Female, Alzheimer's disease, business

الوصف: Summary Background Vascular disorders have been implicated in dementia, but whether atherosclerosis is related to the most frequent type of dementia, Alzheimer's disease, is not known. The apolipoprotein-E genotype has been associated with Alzheimer's disease, and we postulate that it plays a part, together with atherosclerosis, in the aetiology of Alzheimer's disease. We investigated the frequency of dementia and its subtypes in relation to atherosclerosis and apolipoprotein E. Methods We did a population-based study of 284 patients with dementia, 207 of whom had Alzheimer's disease, and 1698 individuals who were not demented. Indicators of atherosclerosis included vessel wall thickness and plaques of the carotid arteries, assessed by ultrasonography, and the ratio of ankle-to-brachial systolic blood pressure as a measure of generalised atherosclerosis. Based on these indicators participants were scored from 0 (no atherosclerosis) to 3 (severe atherosclerosis) for degree of atherosclerosis. Apolipoprotein-E polymorphisms were assessed in 246 patients and in 928 controls. Findings All indicators of atherosclerosis were associated with dementia (odds ratios ranging from 1·3 to 1·9) and its major subtypes Alzheimer's disease (odds ratios 1·3–1·8) and vascular dementia (odds ratios 1·9–3·2). The frequencies of all dementia, Alzheimer's disease, and vascular dementia increased with the degree of atherosclerosis. The odds ratio for Alzheimer's disease in those with severe atherosclerosis compared with those without atherosclerosis was 3·0 (95% CI 1·5–6·0; p=0·001). In participants with the apolipoprotein-E e4 genotype and an atherosclerosis score of 2 or 3 the odds ratio for all dementia was 4·5 (2·0–10·1; p≤0·001), for Alzheimer's disease was 3·9 (1·6–9·6; p=0·002), and for vascular dementia was 19·8 (4·1–95·0; p Interpretation These findings suggest that dementia and its two major subtypes Alzheimer's disease and vascular dementia are associated with atherosclerosis and that there is an interaction between apolipoprotein E and atherosclerosis in the aetiology of Alzheimer's disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::09266fea52c563d2d2b467fc427334b8Test
https://pure.eur.nl/en/publications/3b0fac3e-c207-4176-928f-9b9b402c5e1aTest

المؤلفون: Eleftheria Zeggini, Anna Gloyn, Michael Weedon, Torben Jørgensen, Amanda Bennett, Yurii Aulchenko, Lucia FRITTITTA, Andrew Hattersley, Peter P Pramstaller, Christian Dina, Ines Barroso, Colin Palmer, Sabrina Prudente, Claudia Langenberg, DIEGO BAILETTI, Vincenzo TRISCHITTA, Rafn Benediktsson, MASSIMILIANO COPETTI, Philippe Froguel, Cornelia Van Duijn, David Couper, Jana Van Vliet-Ostaptchouk, Winston Hide, Alessandro Doria, Francesco Andreozzi, Thomas Meitinger, Richard Bergman, Giorgio Sesti, Igor Rudan

المصدر: Europe PubMed Central

مصطلحات موضوعية: Adult, medicine.medical_specialty, obesity, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Type 2 diabetes, Polymorphism, Single Nucleotide, White People, sh2b1, snp, glucose homeostasis, type 2 diabetes, Impaired glucose tolerance, Insulin resistance, SH2B1, Internal medicine, medicine, Humans, Glucose homeostasis, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Glucose Metabolism Disorders, Genetics, Evidence-Based Medicine, Nutrition and Dietetics, biology, Tag SNP, medicine.disease, Impaired fasting glucose, Insulin receptor, Endocrinology, Genetic Loci, biology.protein, Cardiology and Cardiovascular Medicine

الوصف: Background/Aims The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association. Methods The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ ( n = 47,117) and four other published studies ( n = 39,448). Results Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89–1.04) or in the meta-analysis (OR = 1.01; 0.98–1.05). Conclusion Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fe71ed6b3d4c8f1252b5a067ece05d85Test
http://hdl.handle.net/11573/620992Test

المؤلفون: Benjamin Voight, Guillaume Pare, Ruth Loos, Michael Preuss, Åsa Johansson, Eco De Geus, Michael Weedon, Marjo-Riitta Jarvelin, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Mattias Lorentzon, Braxton Mitchell, Nicole Soranzo, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Marika Kaakinen, Carla Vogel, Jennie Hui, Elina Hypponen, ROBERTO ELOSUA, Amanda Bennett, Michael Stumvoll, Andrew Hattersley, Peter P Pramstaller, Lambertus Kiemeney, Sophie Visvikis-Siest, Vilmundur Gudnason, John Whittaker, Aroon Hingorani, Thor Aspelund, Dale Nyholt, Mary Feitosa, Vimal Karani, Mika Kähönen, Lachlan Coin, Malcolm Dunlop, Josee Dupuis, Terho Lehtimäki, Peter Visscher, Katja Aben, Daniel Witte, Cyrus Cooper, Stefan Pilz, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Evropi Theodoratou, Hana Lango Allen, Rosanda Mulic, Rui Li, Stephen Kritchevsky, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Andrew Wood, Chiara Lanzani, Tonu Esko, Sadaf Farooqi, Reedik Mägi, Gerard Waeber, Claes Ohlsson, André Scherag, Marcus Kleber, Thomas Meitinger, Lina Zgaga, Denise Houston, Karl Michaëlsson, Robert Weyant, Thomas Wang, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Gonneke Willemsen, Mark McCarthy, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Liesbeth Vandenput

المساهمون: Vimaleswaran, K, Berry, Dj, Lu, C, Tikkanen, E, Pilz, S, Hiraki, Lt, Cooper, Jd, Dastani, Z, Li, R, Houston, Dk, Wood, Ar, Michaëlsson, K, Vandenput, L, Zgaga, L, YERGES ARMSTRONG, Lm, Mccarthy, Mi, Dupuis, J, Kaakinen, M, Kleber, Me, Jameson, K, Arden, N, Raitakari, O, Viikari, J, Lohman, Kk, Ferrucci, L, Melhus, H, Ingelsson, E, Byberg, L, Lind, L, Lorentzon, M, Salomaa, V, Campbell, H, Dunlop, M, Mitchell, Bd, Herzig, Kh, Pouta, A, Hartikainen, Al, Manunta, Paolo, Streeten, Ea, Theodoratou, E, Jula, A, Wareham, Nj, Ohlsson, C, Frayling, Tm, Kritchevsky, Sb, Spector, Td, Richards, Jb, Lehtimäki, T, Ouwehand, Wh, Kraft, P, Cooper, C, März, W, Power, C, Loos, Rj, Wang, Tj, Järvelin, Mr, Whittaker, Jc, Hingorani, Ad, Hyppönen, E., Council, Medical Research, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Vimaleswaran, Karani S, Berry, Diane J, Lu, Chen, Tikkanen, Emmi, Hyppönen, Elina, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, Hinney, Anke (Beitragende*r), Scherag, Susann (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Epidemiology and Data Science, Psychiatry, EMGO - Lifestyle, overweight and diabetes, Genetic Investigation of Anthropometric Traits-GIANT Consortium, Speliotes, E.K., Willer, C.J., Berndt, S.I., Monda, K.L., Thorleifsson, G., Jackson, A.U., Allen, H.L., Lindgren, C.M., Jian'an, L., Mägi, R., Randall, J.C., Vedantam, S., Winkler, T.W., Qi, L., Workalemahu, T., Heid, I.M., Steinthorsdottir, V., Stringham, H.M., Weedon, M.N., Wheeler, E., Wood, A.R., Ferreira, T., Weyant, R.J., Segrè, A.V., Estrada, K., Liang, L., Nemesh, J., Park, J.H., Gustafsson, S., Kilpeläinen, T.O., Yang, J., Bouatia-Naji, N., Tõnu, E., Feitosa, M.F., Kutalik, Z., Mangino, M., Raychaudhuri, S., Scherag, A., Smith, A.V., Welch, R., Zhao, J.H., Aben, K.K., Absher, D.M., Amin, N., Dixon, A.L., Fisher, E., Glazer, N.L., Goddard, M.E., Heard-Costa, N.L., Hoesel, V., Hottenga, J.J., Johansson, Å., Johnson, T., Ketkar, S., Lamina, C., Li, S., Moffatt, M.F., Myers, R.H., Narisu, N., Perry, J.R., Peters, M.J., Preuss, M., Ripatti, S., Rivadeneira, F., Sandholt, C., Scott, L.J., Timpson, N.J., Tyrer, J.P., van Wingerden, S., Watanabe, R.M., White, C.C., Wiklund, F., Barlassina, C., Chasman, D.I., Cooper, M.N., Jansson, J.O., Lawrence, R.W., Pellikka, N., Prokopenko, I., Shi, J., Thiering, E., Alavere, H., Alibrandi, M.T., Almgren, P., Arnold, A.M., Aspelund, T., Atwood, L.D., Balkau, B., Balmforth, A.J., Bennett, A.J., Ben-Shlomo, Y., Bergman, R.N., Bergmann, S., Biebermann, H., Blakemore, A.I., Boes, T., Bonnycastle, L.L., Bornstein, S.R., Brown, M.J., Buchanan, T.A., Busonero, F., Campbell, H., Cappuccio, F.P., Cavalcanti-Proença, C., Chen, Y.D., Chen, C.M., Chines, P.S., Clarke, R., Coin, L., Connell, J., Day, I.N., Heijer, M., Duan, J., Ebrahim, S., Elliott, P., Elosua, R., Eiriksdottir, G., Erdos, M.R., Eriksson, J.G., Facheris, M.F., Felix, S.B., Fischer-Posovszky, P., Folsom, A.R., Friedrich, N., Freimer, N.B., Fu, M., Gaget, S., Gejman, P.V., Geus, E.J., Gieger, C., Gjesing, A.P., Goel, A., Goyette, P., Grallert, H., Gräßler, J., Greenawalt, D.M., Groves, C.J., Gudnason, V., Guiducci, C., Hartikainen, A.L., Hassanali, N., Hall, A.S., Havulinna, A.S., Hayward, C., Heath, A.C., Hengstenberg, C., Hicks, A.A., Hinney, A., Hofman, A., Homuth, G., Hui, J., Igl, W., Iribarren, C., Isomaa, B., Jacobs, K.B., Jarick, I., Jewell, E., John, U., Jørgensen, T., Jousilahti, P., Jula, A., Kaakinen, M., Kajantie, E., Kaplan, L.M., Kathiresan, S., Kettunen, J., Kinnunen, L., Knowles, J.W., Kolcic, I., König, I.R., Koskinen, S., Kovacs, P., Kuusisto, J., Kraft, P., Kvaløy, K., Laitinen, J., Lantieri, O., Lanzani, C., Launer, L.J., Lecoeur, C., Lehtimäki, T., Lettre, G., Liu, J., Lokki, M.L., Lorentzon, M., Luben, R.N., Ludwig, B., Manunta, P., Marek, D., Marre, M., Martin, N.G., McArdle, W.L., McCarthy, A., McKnight, B., Meitinger, T., Melander, O., Meyre, D., Midthjell, K., Montgomery, G.W., Morken, M.A., Morris, A.P., Mulic, R., Ngwa, J.S., Nelis, M., Neville, M.J., Nyholt, D.R., O'Donnell, C.J., O'Rahilly, S., Ong, K.K., Oostra, B., Paré, G., Parker, A.N., Perola, M., Pichler, I., Pietiläinen, K.H., Platou, C.G., Polasek, O., Pouta, A., Rafelt, S., Raitakari, O., Rayner, N.W., Ridderstråle, M., Rief, W., Ruokonen, A., Robertson, N.R., Rzehak, P., Salomaa, V., Sanders, A.R., Sandhu, M.S., Sanna, S., Saramies, J., Savolainen, M.J., Scherag, S., Schipf, S., Schreiber, S., Schunkert, H., Silander, K., Sinisalo, J., Siscovick, D.S., Smit, J.H., Soranzo, N., Sovio, U., Stephens, J., Surakka, I., Swift, AJ., Tammesoo, M.L., Tardif, J.C., Teder-Laving, M., Teslovich, T.M., Thompson, J.R., Thomson, B., Tönjes, A., Tuomi, T., van Meurs, J.B., van Ommen, G.J., Vatin, V., Viikari, J., Visvikis-Siest, S., Vitart, V., Vogel, C.I., Voight, B.F., Waite, L.L., Wallaschofski, H., Walters, G.B., Widen, E., Wiegand, S., Wild, S.H., Willemsen, G., Witte, D.R., Witteman, J.C., Xu, J., Zhang, Q., Zgaga, L., Ziegler, A., Zitting, P., Beilby, J.P., Farooqi, I.S., Hebebrand, J., Huikuri, H.V., James, AL., Kähönen, M., Levinson, D.F., Macciardi, F., Nieminen, M.S., Ohlsson, C., Palmer, L.J., Ridker, P.M., Stumvoll, M., Beckmann, J.S., Boeing, H., Boerwinkle, E., Boomsma, D.I., Caulfield, M.J., Chanock, S.J., Collins, F.S., Cupples, L.A., Smith, G.D., Erdmann, J., Froguel, P., Grönberg, H., Gyllensten, U., Hall, P., Hansen, T., Harris, T.B., Hattersley, A.T., Hayes, R.B., Heinrich, J., Hu, F.B., Hveem, K., Illig, T., Jarvelin, M.R., Kaprio, J., Karpe, F., Khaw, K.T., Kiemeney, L.A., Krude, H., Laakso, M., Lawlor, D.A., Metspalu, A., Munroe, P.B., Ouwehand, W.H., Pedersen, O., Penninx, B.W., Peters, A., Pramstaller, P.P., Quertermous, T., Reinehr, T., Rissanen, A., Rudan, I., Samani, N.J., Schwarz, P.E., Shuldiner, A.R., Spector, T.D., Tuomilehto, J., Uda, M., Uitterlinden, A., Valle, T.T., Wabitsch, M., Waeber, G., Wareham, N.J., Watkins, H., Wilson, J.F., Wright, A.F., Zillikens, M.C., Chatterjee, N., McCarroll, S.A., Purcell, S., Schadt, E.E., Visscher, P.M., Assimes, T.L., Borecki, I.B., Deloukas, P., Fox, C.S., Groop, L.C., Haritunians, T., Hunter, D.J., Kaplan, R.C., Mohlke, K.L., O'Connell, J.R., Peltonen, L., Schlessinger, D., Strachan, D.P., van Duijn, C.M., Wichmann, H.E., Frayling, T.M., Thorsteinsdottir, U., Abecasis, G.R., Barroso, I., Boehnke, M., Stefansson, K., North, K.E., McCarthy, M.I., Hirschhorn, J.N., Ingelsson, E., Loos, R.J., Medical Research Council (MRC), National Institute for Health Research

المصدر: Plos Medicine, 10, e1001383
PLoS Medicine
Vimaleswaran, K S, Berry, D J, Lu, C, Tikkanen, E, Pilz, S, Hiraki, L T, Cooper, J D, Dastani, Z, Li, R, Houston, D K, Wood, A R, Michaëlsson, K, Vandenput, L, Zgaga, L, Yerges-Armstrong, L M, McCarthy, M I, Dupuis, J, Kaakinen, M, Kleber, M E, Jameson, K, Arden, N, Raitakari, O, Viikari, J, Lohman, K K, Ferrucci, L, Melhus, H, Ingelsson, E, Byberg, L, Lind, L, Lorentzon, M, Salomaa, V, Campbell, H, Dunlop, M, Mitchell, B D, Herzig, K H, Pouta, A, Hartikainen, A L, Hottenga, J J, de Geus, E J C, Willemsen, G, Boomsma, D I, Penninx, B W J H, Uitterlinden, A G, Visscher, P M, van Duijn, C M, Streeten, E A, Theodoratou, E, Jula, A, Wareham, N J, Ohlsson, C, Frayling, T M, Kritchevsky, S B, Spector, T D, Richards, J B, Lehtimäki, T, Ouwehand, W H, Kraft, P, Cooper, C, März, W, Power, C, Loos, R J, Wang, T J, Järvelin, M R, Whittaker, J C, Hingorani, A D & Hyppönen, E 2013, ' Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts ', PLoS Medicine, vol. 10, no. 2, e1001383 . https://doi.org/10.1371/journal.pmed.1001383Test
Scopus-Elsevier
PLoS Medicine, 10(2):e1001383. Nature Publishing Group
PLoS Medicine, Vol 10, Iss 2, p e1001383 (2013)
Plos Medicine, 10, 2, pp. e1001383
PLoS Medicine, 10(2):e1001383. Public Library of Science
PLoS Med. 10:e1001383 (2013)
PLOS Medicine, vol. 10, no. 2, pp. e1001383
Vimaleswaran, K S, Berry, D J, Lu, C, Tikkanen, E, Pilz, S, Hiraki, L T, Cooper, J D, Dastani, Z, Li, R, Houston, D K, Wood, A R, Michaëlsson, K, Vandenput, L, Zgaga, L, Yerges-Armstrong, L M, McCarthy, M I, Dupuis, J, Kaakinen, M, Kleber, M E, Jameson, K, Arden, N, Raitakari, O, Viikari, J, Lohman, K K, Ferrucci, L, Melhus, H, Ingelsson, E, Byberg, L, Lind, L, Lorentzon, M, Salomaa, V, Campbell, H, Dunlop, M, Mitchell, B D, Herzig, K-H, Pouta, A, Hartikainen, A-L, Streeten, E A, Theodoratou, E, Jula, A, Wareham, N J, Ohlsson, C, Frayling, T M, Kritchevsky, S B, Spector, T D, Richards, J B, Lehtimäki, T, Ouwehand, W H & Kraft, P & Cooper, C 2013, ' Causal Relationship between Obesity and Vitamin D Status : Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts ', PLoS Medicine, vol. 10, no. 2, e1001383, pp. e1001383 . https://doi.org/10.1371/journal.pmed.1001383Test

مصطلحات موضوعية: Male, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, obesity, 25-HYDROXYVITAMIN D, D INSUFFICIENCY, Epidemiology, Medizin, vitamin D, Aetiology, screening and detection [ONCOL 5], Medical and Health Sciences, Gastroenterology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, Medicine, 030212 general & internal medicine, Vitamin D, 2. Zero hunger, Genetics, Aged, 80 and over, Evidence-Based Medicine, Confounding, 11 Medical And Health Sciences, General Medicine, Middle Aged, 3. Good health, PREVALENCE, Europe, Phenotype, Genetic Epidemiology, Biological Markers, Female, Life Sciences & Biomedicine, Research Article, Vitamin, Adult, medicine.medical_specialty, vitamin D deficiency, genetic variants, Genetic Investigation of Anthropometric Traits-GIANT Consortium, European Continental Ancestry Group, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, body mass index, Polymorphism, Single Nucleotide, Risk Assessment, White People, COMMON OBESITY, 03 medical and health sciences, D DEFICIENCY, Medicine, General & Internal, SDG 3 - Good Health and Well-being, General & Internal Medicine, Internal medicine, Mendelian randomization, Vitamin D and neurology, INSTRUMENTAL VARIABLES, Humans, Genetic Predisposition to Disease, Obesity, GENOME-WIDE ASSOCIATION, Biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, Science & Technology, Population Biology, business.industry, CARDIOVASCULAR-DISEASE RISK, ta3121, Mendelian Randomization Analysis, medicine.disease, Vitamin D Deficiency, BODY-MASS INDEX, chemistry, Genetic epidemiology, 3121 General medicine, internal medicine and other clinical medicine, Multivariate Analysis, North America, Genetic Polymorphism, Linear Models, business, Body mass index, Population Genetics, Biomarkers

الوصف: A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Background Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). Conclusions On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors' Summary
Editors' Summary Background Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements. Why Was This Study Done? Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations. What Did the Researchers Do and Find? The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium. What Do These Findings Mean? These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383Test. The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population The World Health Organization provides information on obesity (in several languages) The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D The International Obesity Taskforce provides information about the global obesity epidemic The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish) The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish) MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits

وصف الملف: application/pdf; application/octet-stream

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::114ff45c9f3c5ccc860e181b421b1f0eTest

المؤلفون: Muhammad Zafar Hydrie, Eleftheria Zeggini, Anna Gloyn, Michael Weedon, Chidambaram Manickam, Torben Jørgensen, Amanda Bennett, Yurii Aulchenko, Andrew Hattersley, Christian Dina, Shahrad Taheri, Claudia Langenberg, SRIKANTH BELLARY, Rafn Benediktsson, Nabi Shah, Prasad Katulanda, Philippe Froguel, Cornelia Van Duijn, David Couper, Jana Van Vliet-Ostaptchouk, Winston Hide, Thomas Meitinger, Sudhesh Kumar, Richard Bergman, Cecilia Lindgren, Igor Rudan

المصدر: PLoS ONE
PLoS ONE, Vol 7, Iss 4, p e32670 (2012)

مصطلحات موضوعية: Male, Genotyping Techniques, Clinical Research Design, lcsh:Medicine, Single-nucleotide polymorphism, Pilot Projects, Disease, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Endocrinology, Gene Frequency, Polymorphism (computer science), Risk Factors, Diabetes mellitus, medicine, Genetics, Humans, Genetic Predisposition to Disease, Circadian rhythm, lcsh:Science, QH426, Genetic Association Studies, Diabetic Endocrinology, Multidisciplinary, Circadian Rhythm Signaling Peptides and Proteins, Cancer Risk Factors, lcsh:R, Computational Biology, Cancers and Neoplasms, Human Genetics, medicine.disease, Genitourinary Tract Tumors, Diabetes Mellitus, Type 2, Oncology, Medicine, lcsh:Q, Female, Metabolic syndrome, TCF7L2, Population Genetics, Research Article, RC

الوصف: Background\ud Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants.\ud \ud Methodology/Principal Findings\ud The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66–0.86], p = 3.18×10−5), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07–1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01–1.08], p = 0.008 and OR = 0.95 [0.91–0.99], p = 0.015 respectively).\ud \ud Conclusions/significance\ud None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e8052f1bf9d6587c4137a819ec8bb8fbTest
http://wrap.warwick.ac.uk/44387/1/jWRAP_Kumar_ournal.pone.0032670.pdfTest

المؤلفون: Amelie Bonnefond, Nancy Heard-Costa, Eleftheria Zeggini, Anna Gloyn, LAURA CRISPONI, Eco De Geus, Michael Weedon, Torben Jørgensen, Jaakko Kaprio, Iva Miljkovic, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Christian Dina, Sophie Visvikis-Siest, Udo Seedorf, Vilmundur Gudnason, Michael Marmot, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Cyrus Cooper, Meena Kumari, Peter Kovacs, Debbie A Lawlor, Inga Prokopenko, Rafn Benediktsson, Stephen Kritchevsky, Philippe Froguel, Cornelia Van Duijn, Nita Forouhi, Anne B. Newman, Ko Willems van Dijk, John Carr, Reedik Mägi, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, L. Adrienne Cupples, Paul Franks, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Kirsten Ohm Kyvik, Manuel Serrano Ríos, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Igor Rudan

المساهمون: Human genetics, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Institute for Molecular Medicine Finland, Research Group Ripatti Samuli, Hjelt Institute (-2014), Department of Public Health, Biostatistics Helsinki, Complex Disease Genetics, Genetic Epidemiology, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, GIANT Consortium, MAGIC Consortium, GLGC Consortium, Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, AU., Wheeler, E., Glazer, NL., Bouatia-Naji, N., Gloyn, AL., Lindgren, CM., Mägi, R., Morris, AP., Randall, J., Johnson, T., Elliott, P., Rybin, D., Thorleifsson, G., Steinthorsdottir, V., Henneman, P., Grallert, H., Dehghan, A., Hottenga, JJ., Franklin, CS., Navarro, P., Song, K., Goel, A., Perry, JR., Egan, JM., Lajunen, T., Grarup, N., Sparsø, T., Doney, A., Voight, BF., Stringham, HM., Li, M., Kanoni, S., Shrader, P., Cavalcanti-Proença, C., Kumari, M., Qi, L., Timpson, NJ., Gieger, C., Zabena, C., Rocheleau, G., Ingelsson, E., An, P., O'Connell, J., Luan£££Jian'an£££ J., Elliott, A., McCarroll, SA., Payne, F., Roccasecca, RM., Pattou, F., Sethupathy, P., Ardlie, K., Ariyurek, Y., Balkau, B., Barter, P., Beilby, JP., Ben-Shlomo, Y., Benediktsson, R., Bennett, AJ., Bergmann, S., Bochud, M., Boerwinkle, E., Bonnefond, A., Bonnycastle, LL., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, SJ., Charpentier, G., Chen, YD., Chines, P., Clarke, R., Coin, LJ., Cooper, MN., Cornelis, M., Crawford, G., Crisponi, L., Day, IN., de Geus EJ., Delplanque, J., Dina, C., Erdos, MR., Fedson, AC., Fischer-Rosinsky, A., Forouhi, NG., Fox, CS., Frants, R., Franzosi, MG., Galan, P., Goodarzi, MO., Graessler, J., Groves, CJ., Grundy, S., Gwilliam, R., Gyllensten, U., Hadjadj, S., Hallmans, G., Hammond, N., Han, X., Hartikainen, AL., Hassanali, N., Hayward, C., Heath, SC., Hercberg, S., Herder, C., Hicks, AA., Hillman, DR., Hingorani, AD., Hofman, A., Hui, J., Hung, J., Isomaa, B., Johnson, PR., Jørgensen, T., Jula, A., Kaakinen, M., Kaprio, J., Kesaniemi, YA., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, KO., Lathrop, GM., Lawlor, DA., Le Bacquer, O., Lecoeur, C., Li, Y., Lyssenko, V., Mahley, R., Mangino, M., Manning, AK., Martínez-Larrad£££María Teresa£££ MT., McAteer, JB., McCulloch, LJ., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, BD., Morken, MA., Mukherjee, S., Naitza, S., Narisu, N., Neville, MJ., Oostra, BA., Orrù, M., Pakyz, R., Palmer, CN., Paolisso, G., Pattaro, C., Pearson, D., Peden, JF., Pedersen, NL., Perola, M., Pfeiffer, AF., Pichler, I., Polasek, O., Posthuma, D., Potter, SC., Pouta, A., Province, MA., Psaty, BM., Rathmann, W., Rayner, NW., Rice, K., Ripatti, S., Rivadeneira, F., Roden, M., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, AA., Scheet, P., Scott, LJ., Seedorf, U., Sharp, SJ., Shields, B., Sigurðsson, G., Sijbrands, EJ., Silveira, A., Simpson, L., Singleton, A., Smith, NL., Sovio, U., Swift, A., Syddall, H., Syvänen, AC., Tanaka, T., Thorand, B., Tichet, J., Tönjes, A., Tuomi, T., Uitterlinden, AG., van Dijk KW., van Hoek, M., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, PJ., Walley, A., Walters, GB., Ward, KL., Watkins, H., Weedon, MN., Wild, SH., Willemsen, G., Witteman, JC., Yarnell, JW., Zeggini, E., Zelenika, D., Zethelius, B., Zhai, G., Zhao, JH., Zillikens, MC., Borecki, IB., Loos, RJ., Meneton, P., Magnusson, PK., Nathan, DM., Williams, GH., Hattersley, AT., Silander, K., Salomaa, V., Smith, GD., Bornstein, SR., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, AR., Cooper, C., Dedoussis, GV., Serrano-Ríos, M., Morris, AD., Lind, L., Palmer, LJ., Hu, FB., Franks, PW., Ebrahim, S., Marmot, M., Kao, WH., Pankow, JS., Sampson, MJ., Kuusisto, J., Laakso, M., Hansen, T., Pedersen, O., Pramstaller, PP., Wichmann, HE., Illig, T., Rudan, I., Wright, AF., Stumvoll, M., Campbell, H., Wilson, JF., Hamsten, A., Bergman, RN., Buchanan, TA., Collins, FS., Mohlke, KL., Tuomilehto, J., Valle, TT., Altshuler, D., Rotter, JI., Siscovick, DS., Penninx, BW., Boomsma, ID., Deloukas, P., Spector, TD., Frayling, TM., Ferrucci, L., Kong, A., Thorsteinsdottir, U., Stefansson, K., van Duijn CM., Aulchenko, YS., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, MR., Waterworth, DM., Vollenweider, P., Peltonen, L., Mooser, V., Abecasis, RG., Wareham, NJ., Sladek, R., Froguel, P., Watanabe, RM., Meigs, JB., Groop, L., Boehnke, M., McCarthy, MI., Florez, JC., Barroso£££Inês£££ I., Feitosa, Mary [0000-0002-0933-2410], Heard-Costa, Nancy [0000-0001-9730-0306], Newman, Anne B [0000-0002-0106-1150], Miljkovic, Iva [0000-0002-3155-9777], Kritchevsky, Stephen B [0000-0003-3336-6781], Carr, J Jeffrey [0000-0002-4398-8237], Gudnason, Vilmunder [0000-0001-5696-0084], Cupples, L Adrienne [0000-0003-0273-7965], Apollo - University of Cambridge Repository, Medical Research Council (MRC)

المصدر: PLoS Genet. 8:e1002695 (2012)
Fox, C S, Liu, Y, White, C C, Feitosa, M, Smith, A V, Heard-Costa, N, Lohman, K, Johnson, A D, Foster, M C, Greenawalt, D M, Griffin, P, Ding, J, Newman, A B, Tylavsky, F, Miljkovic, I, Kritchevsky, S B, Launer, L, Garcia, M, Eiriksdottir, G, Carr, J J, Gudnason, V, Harris, T B, Cupples, L A, Borecki, I B & Hayward, C 2012, ' Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women ', PLoS Genetics, vol. 8, no. 5, pp. e1002695 . https://doi.org/10.1371/journal.pgen.1002695Test
PLoS Genetics, 8(5):e1002695. Public Library of Science
Fox, C S, Liu, Y, White, C C, Feitosa, M, Smith, A V, Heard-Costa, N, Lohman, K, Hottenga, J J, de Geus, E J C, Willemsen, G, Boomsma, D I, Johnson, A D, Foster, M C, Greenawalt, D M, Griffin, P, Ding, J, Newman, A B, Tylavsky, F, Miljkovic, I, Kritchevsky, S B, Launer, L, Garcia, M, Eiriksdottir, G, Posthuma, D, Carr, J J, Gudnason, V, Harris, T B, Cupples, L A & Borecki, I B 2012, ' Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women ', PLoS Genetics, vol. 8, no. 5, e1002695, pp. e1002695 . https://doi.org/10.1371/journal.pgen.1002695Test
PLoS Genetics
Fox, C S, Liu, Y, White, C C, Feitosa, M, Smith, A V, Heard-Costa, N, Lohman, K, Johnson, A D, Foster, M C, Greenawalt, D M, Griffin, P, Ding, J, Newman, A B, Tylavsky, F, Miljkovic, I, Kritchevsky, S B, Launer, L, Garcia, M, Eiriksdottir, G, Carr, J J, Gudnason, V, Harris, T B, Cupples, L A, Borecki, I B, GIANT Consortium & Kyvik, K O 2012, ' Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women ', P L o S Genetics, vol. 8, no. 5, pp. e1002695 . https://doi.org/10.1371/journal.pgen.1002695Test
PLoS Genetics, 8(5)
PLoS Genetics, Vol 8, Iss 5, p e1002695 (2012)
Plos Genetics, vol. 8, no. 5, pp. e1002695
Fox, C S, Liu, Y, White, C C, Feitosa, M, Smith, A V, Heard-Costa, N, Lohman, K, Johnson, A D, Foster, M C, Greenawalt, D M, Griffin, P, Ding, J, Newman, A B, Tylavsky, F, Miljkovic, I, Kritchevsky, S B, Launer, L, Garcia, M, Eiriksdottir, G, Carr, J J, Gudnason, V, Harris, T B, Cupples, L A, Borecki, I B, GIANT Consortium & Sandbæk, A 2012, ' Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women ', PLoS genetics, vol. 8, no. 5, pp. e1002695 . https://doi.org/10.1371/journal.pgen.1002695Test

مصطلحات موضوعية: Male, Netherlands Twin Register (NTR), Cancer Research, Adipose tissue, Genome-wide association study, QH426-470, FTO gene, Body Mass Index, 0302 clinical medicine, Genetics (clinical), TISSUE DISTRIBUTION, GENE-EXPRESSION, 2. Zero hunger, ATHEROSCLEROSIS MESA, 0303 health sciences, INSULIN-RESISTANCE, Sex Characteristics, MAGIC Consortium, Adult, Aged, Cytokines/genetics, European Continental Ancestry Group, Female, Genome-Wide Association Study, HapMap Project, Humans, Intra-Abdominal Fat, Lysophospholipase/genetics, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proteins/genetics, Subcutaneous Fat, Abdominal, 3142 Public health care science, environmental and occupational health, CARDIOVASCULAR-DISEASE, OBESITY, Cytokines, Medicine, Lysophospholipase, Research Article, medicine.medical_specialty, Waist, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, HIP RATIO, Biology, White People, GLGC Consortium, 03 medical and health sciences, Insulin resistance, Internal medicine, GIANT Consortium, medicine, Genetics, CORONARY-HEART-DISEASE, ddc:610, Molecular Biology, PERICARDIAL FAT, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0604 Genetics, Proteins, nutritional and metabolic diseases, medicine.disease, Obesity, Endocrinology, RISK-FACTORS, Body mass index, Developmental Biology

الوصف: Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.
Author Summary Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. We quantified subcutaneous and visceral fat in more than 10,000 women and men who also had genome-wide association data available. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, near the THNSL2 gene. These findings were not observed in men. We also interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed for 7 of these loci, most notably for VAT/SAT ratio. We conclude that genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not uncovered in large-scale GWAS of anthropometric traits.

وصف الملف: application/pdf; application/octet-stream

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f51745aee40c86958d5af210e8d2dd9bTest
https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=8204Test

المؤلفون: Jacqueline M. Vink1, August B. Smit, Eco J.C. de Geus, Patrick Sullivan, Gonneke Willemsen, Jouke-Jan Hottenga, Johannes H. Smit, Witte J. Hoogendijk, Frans G. Zitman, Leena Peltonen, Jaakko Kaprio, Nancy L. Pedersen, Patrik K. Magnusson, Tim D. Spector, Kirsten Ohm Kyvik, Katherine I. Morley, Andrew C. Heath, Nicholas G. Martin, Rudi G.J. Westendorp, P. Eline Slagboom, Henning Tiemeier, Albert Hofman, Andre G. Uitterlinden, Yurii S. Aulchenko, Najaf Amin, Cornelia van Duijn, Brenda W. Penninx, Dorret I. Boomsma

المساهمون: Cynthia C Morton, Emilie Marcus

مصطلحات موضوعية: Genetics & Heredity, C1

الوصف: For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n ¼ 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and cell-adhesion molecules (e.g., CDH23). We conclude that a networkbased genome-wide association approach can identify genes influencing smoking behavior.

العلاقة: orcid:0000-0003-4069-8020; MH077139

الإتاحة: https://doi.org/10.1016/j.ajhg.2009.02.001Test
https://espace.library.uq.edu.au/view/UQ:200588Test

المؤلفون: Mariano Senti, Michael Preuss, ROBERTO ELOSUA, Vilmundur Gudnason, Gavin Lucas, Cornelia Van Duijn, Annette Peters, Jeanette Erdmann, Marcus Kleber, Tanja Zeller, Thomas Meitinger, Olle Melander

مصطلحات موضوعية: Adult, Male, Candidate gene, Population, Genome-wide association study, Coronary Artery Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Risk Factors, Genetic variation, Genetics, Humans, 1000 Genomes Project, education, Genetics (clinical), Genetic association, Aged, education.field_of_study, Framingham Risk Score, Estrogen Receptor alpha, Middle Aged, Female, Cardiology and Cardiovascular Medicine, Imputation (genetics), Genome-Wide Association Study

الوصف: Background— After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α ( ESR1 ) have shown conflicting results, although only a limited range of variation in the gene has been investigated. Methods and Results— We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1 's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87 000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1 . In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. Conclusions— We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aee6768fa4737b63b37f5081fa6f202eTest
https://europepmc.org/articles/PMC3260440Test/

المؤلفون: Marcel Den Hoed, Ruth Loos, Eco De Geus, Marjo-Riitta Jarvelin, Elina Hypponen, Amanda Bennett, Yurii Aulchenko, Andrew Hattersley, Craig Pennell, Gerard Koppelman, David Evans, Soren Brage, Rachel Freathy, Stavroula Kanoni, Lachlan Coin, George Davey Smith, Inga Prokopenko, Tuomas Kilpeläinen, Philippe Froguel, Cornelia Van Duijn, Anders Grøntved, Struan Grant, Reedik Mägi, Lyle John Palmer, Paul O'Reilly, Julie Marsh, Fernando Rivadeneira, Paul Elliott, Adaikalavan Ramasamy, Gonneke Willemsen, Mark McCarthy, Cecilia Lindgren, Nicole Warrington

المساهمون: Faculty of Behavioural and Movement Sciences, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, University of Groningen, Kilpeläinen, Tuomas O, den Hoed, Marcel, Ong, Ken K, Grøntved, Anders, Hypponen, Elina, Loos, Ruth JF

المصدر: The American Journal of Clinical Nutrition, 93(4), 851-860. Oxford University press
Am. J. Clin. Nutr. 93, 851-860 (2011)
American Journal of Clinical Nutrition, 93(4), 851-860. Oxford University Press
Kilpelaeinen, T O, den Hoed, M, Ong, K K, Grontved, A, Brage, S, Jameson, K, Cooper, C, Khaw, K T, Ekelund, U, Wareham, N J, Loos, R J F & Early Growth Genetics, C 2011, ' Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals ', American Journal of Clinical Nutrition, vol. 93, no. 4, pp. 851-860 . https://doi.org/10.3945/ajcn.110.000828Test
Kilpelaïnen, T O, van den Hoed, M, Ong, K K, Grøntved, A, Brage, S, Hottenga, J J, Willemsen, G, de Geus, E J C, Boomsma, D I, Jameson, K, Cooper, C, Khaw, K T, Ekelund, U, Wareham, N J & Loos, R J 2011, ' Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals ', The American Journal of Clinical Nutrition, vol. 93, no. 4, pp. 851-860 . https://doi.org/10.3945/ajcn.110.000828Test

مصطلحات موضوعية: Male, Netherlands Twin Register (NTR), obesity, Medicine (miscellaneous), Genome-wide association study, MC4R, Mitochondrial Membrane Transport Proteins, FTO gene, Body Mass Index, ADULT OBESITY, Birth Weight, body mass index (BMI), GESTATIONAL-AGE, Aged, 80 and over, Genetics, Nutrition and Dietetics, Middle Aged, European Prospective Investigation into Cancer and Nutrition, FAT MASS, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, loci, Genome-wide association, Body-mass index, Gestational-age, Common variant, Adult obesity, Fetal-growth, Fat mass, Adiposity, Female, Adult, medicine.medical_specialty, Birth weight, Biology, Mitochondrial Proteins, Young Adult, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, COHORT, Obesity, GENOME-WIDE ASSOCIATION, Allele, FTO GENE, Alleles, Aged, Membrane Transport Proteins, Proteins, birth weight, medicine.disease, COMMON VARIANT, BODY-MASS INDEX, Endocrinology, Genetic Loci, FETAL-GROWTH, Body mass index, Genome-Wide Association Study

الوصف: Background: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. Objective: The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. Design: A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623); and 3) all published data (n(max) = 14,837). Results: Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (beta +/- SE: 213 +/- 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (beta +/- SE: 11 +/- 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing. Conclusions: Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity. Am J Clin Nutr 2011;93:851-60.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e768ebd60ee8cc17d2967cd4177757cTest
https://research.vu.nl/en/publications/fe3435f9-c7fe-4360-b3ce-e9b339ad4afbTest

المؤلفون: Benjamin Voight, Amelie Bonnefond, Mark Caulfield, Guillaume Pare, Manal Abdelmalek, Eleftheria Zeggini, Jeffrey Schwimmer, Anna Gloyn, Michael Preuss, Åsa Johansson, LAURA CRISPONI, Eco De Geus, Michael Weedon, Jeanne Clark, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Nicole Glazer, Jaakko Kaprio, Alan Shuldiner, Braxton Mitchell, Patricia Munroe, Ozren Polasek, Elisabeth Thiering, Carla Vogel, Jennie Hui, ROBERTO ELOSUA, Amanda Bennett, Yurii Aulchenko, Michael Stumvoll, Andrew Hattersley, Alexander Doney, Peter P Pramstaller, Christian Dina, Lambertus Kiemeney, Sophie Visvikis-Siest, ANGELO SCUTERI, Udo Seedorf, Vilmundur Gudnason, Peter Kraft, Aroon Hingorani, Michael Marmot, Dale Nyholt, Mika Kivimaki, Mary Feitosa, Danielle Posthuma, Claudia Langenberg, Stavroula Kanoni, Mika Kähönen, David Hillman, Lachlan Coin, Eric Brunner, Terho Lehtimäki, Man Li, John Beilby, Peter Visscher, Anette P Gjesing, James Pankow, Ruben Hernaez, Taina Lajunen, Katja Aben, Daniel Witte, Willem Ouwehand, Eleanor Wheeler, Peter Kovacs, Debbie A Lawlor, Kevin Jacobs, Jianjun Liu, Joseph Massaro, Hana Lango Allen, Inga Prokopenko, Rafn Benediktsson, Philippe Froguel, Soumya Raychaudhuri, Cornelia Van Duijn, Annette Peters, Nita Forouhi, Chiara Lanzani, Tonu Esko, Ko Willems van Dijk, Sadaf Farooqi, John Carr, Reedik Mägi, David Melzer, Gerard Waeber, Sutapa Mukherjee, Lyle John Palmer, Francois Pattou, Claes Ohlsson, Perry Elliott, André Scherag, Inke König, Stephen O'rahilly, Thomas Meitinger, Michael Goddard, Lina Zgaga, Robert Weyant, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Avan Aihie Sayer, Richard Bergman, Gonneke Willemsen, Cecilia Lindgren, Olle Melander, Igor Rudan, Maris Teder-Laving, Hugh Watkins, Ulrich John

المساهمون: Epidemiology, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C. I. (Beitragende*r), Hebebrand, Johannes (Beitragende*r), Functional Genomics, Biological Psychology, Neuroscience Campus Amsterdam - integrative Analysis & Modeling, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, McCarthy, Mark I, Apollo - University of Cambridge Repository, Medical Research Council (MRC), Speliotes, Ek, YERGES ARMSTRONG, Lm, Wu, J, Hernaez, R, Kim, Lj, Palmer, Cd, Gudnason, V, Eiriksdottir, G, Garcia, Me, Launer, Lj, Nalls, Ma, Clark, Jm, Mitchell, Bd, Shuldiner, Ar, Butler, Jl, Tomas, M, Hoffmann, U, Hwang, Sj, Massaro, Jm, O'Donnell, Cj, Sahani, Dv, Salomaa, V, Schadt, Ee, Schwartz, Sm, Siscovick, D, Nash, Crn, Manunta, Paolo, Giant, Consortium, Magic, Investigator, Voight, Bf, Carr, Jj, Feitosa, Mf, Harris, Tb, Fox, C, Smith, Av, Kao, Wh, Hirschhorn, Jn, Borecki, Ib, Gold, Consortium, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Genetic Epidemiology, O', Donnell, Cj, Giant, Paolisso, Giuseppe

المصدر: PLoS Genetics (print), 7(3). Public Library of Science
PLoS Genetics, 7(3):e1001324. Public Library of Science
Speliotes, E K, Yerges-Armstrong, L M, Wu, J, Hernaez, R, Kim, L J, Palmer, C D, Gudnason, V, Eiriksdottir, G, Garcia, M E, Launer, L J, Nalls, M A, Clark, J M, Mitchell, B D, Shuldiner, A R, Butler, J L, Tomas, M, Hoffmann, U, Hwang, S J, Massaro, J M, O'Donnell, C J, Sahani, D V, Salomaa, V, Schadt, E E, Schwartz, S M, Siscovick, D S, Posthuma, D, Voight, B F, Carr, J J, Feitosa, M F, Harris, T B, Fox, C S, Smith, A V, Kao, W H L, Hottenga, J J, Willemsen, G, de Geus, E J C, Boomsma, D I, Hirschhorn, J N & Borecki, I B 2011, ' Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits ', PLoS Genetics, vol. 7, no. 3, e1001324 . https://doi.org/10.1371/journal.pgen.1001324Test
PLoS genetics, vol 7, iss 3
PLoS Genetics, Vol 7, Iss 3, p e1001324 (2011)
PLoS Genetics
PLoS Genetics, 7(3)

مصطلحات موضوعية: Blood Glucose, Male, Netherlands Twin Register (NTR), Cancer Research, Medizin, Genome-wide association study, Hepatitis, Diabetes and Endocrinology/Obesity, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Lectins, Nonalcoholic fatty liver disease, 80 and over, Insulin, 2.1 Biological and endogenous factors, Aetiology, Tomography, Adaptor Proteins, Signal Transducing/genetics Adult Aged Aged, 80 and over Blood Glucose/analysis Case-Control Studies Chondroitin Sulfate Proteoglycans/genetics Cohort Studies Fatty Liver/*genetics/metabolism/radiography Genome-Wide Association Study Humans Insulin/blood Lectins, C-Type/genetics Lipase/genetics Male Membrane Proteins/genetics Middle Aged Mutation, Missense Nerve Tissue Proteins/genetics Polymorphism, Single Nucleotide Quantitative Trait Loci Tomography, X-Ray Computed, Genetics (clinical), Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Framingham Risk Score, C-Type, Liver Disease, Fatty liver, Adaptor Proteins, Single Nucleotide, Middle Aged, X-Ray Computed, 3. Good health, GOLD Consortium, 030211 gastroenterology & hepatology, Research Article, Adult, lcsh:QH426-470, Quantitative Trait Loci, Chronic Liver Disease and Cirrhosis, Mutation, Missense, genome-wide, fatty liver, metabolic, Nerve Tissue Proteins, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, Gastroenterology and Hepatology/Hepatology, MAGIC Investigators, 03 medical and health sciences, Clinical Research, GIANT Consortium, medicine, Humans, Lectins, C-Type, Adiponutrin, NASH CRN, ddc:610, Polymorphism, education, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Adaptor Proteins, Signal Transducing, Aged, 030304 developmental biology, 0604 Genetics, Genetic heterogeneity, Prevention, Human Genome, Signal Transducing, Membrane Proteins, Lipase, medicine.disease, 3141 Health care science, Fatty Liver, lcsh:Genetics, Chondroitin Sulfate Proteoglycans, Case-Control Studies, Mutation, Missense, Steatosis, Steatohepatitis, Tomography, X-Ray Computed, Digestive Diseases, Neurocan, Genome-Wide Association Study, Developmental Biology

الوصف: Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p
Author Summary NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, we show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. Our findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da6a087b46b57b1d80a3ac0f6f2a0890Test
https://pure.eur.nl/en/publications/2db8f511-49f4-4120-8115-915411e3636aTest