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Science translational medicine · 2016

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Scott Robert A, Freitag Daniel F, Li Li, Chu Audrey Y, Surendran Praveen, Young Robin, Grarup Niels, Stancáková Alena, Chen Yuning, Varga Tibor V, Yaghootkar Hanieh, Luan Jian'an, Zhao Jing Hua, Willems Sara M, Wessel Jennifer, Wang Shuai, Maruthur Nisa, Michailidou Kyriaki, Pirie Ailith, van der Lee Sven J, Gillson Christopher, Al Olama Ali Amin, Amouyel Philippe, Arriola Larraitz, Arveiler Dominique, Aviles-Olmos Iciar, Balkau Beverley, Barricarte Aurelio, Barroso Inês, Garcia Sara Benlloch, Bis Joshua C, Blankenberg Stefan, Boehnke Michael, Boeing Heiner, Boerwinkle Eric, Borecki Ingrid B, Bork-Jensen Jette, Bowden Sarah, Caldas Carlos, Caslake Muriel, CVD50 consortium, Cupples L Adrienne, Cruchaga Carlos, Czajkowski Jacek, den Hoed Marcel, Dunn Janet A, Earl Helena M, Ehret Georg B, Ferrannini Ele, Ferrieres Jean, Foltynie Thomas, Ford Ian, Forouhi Nita G, Gianfagna Francesco, Gonzalez Carlos, Grioni Sara, Hiller Louise, Jansson Jan-Håkan, Jørgensen Marit E, Jukema J Wouter, Kaaks Rudolf, Kee Frank, Kerrison Nicola D, Key Timothy J, Kontto Jukka, Kote-Jarai Zsofia, Kraja Aldi T, Kuulasmaa Kari, Kuusisto Johanna, Linneberg Allan, Liu Chunyu, Marenne Gaëlle, Mohlke Karen L, Morris Andrew P, Muir Kenneth, Müller-Nurasyid Martina, Munroe Patricia B, Navarro Carmen, Nielsen Sune F, Nilsson Peter M, Nordestgaard Børge G, Packard Chris J, Palli Domenico, Panico Salvatore, Peloso Gina M, Perola Markus, Peters Annette, Poole Christopher J, Quirós J Ramón, Rolandsson Olov, Sacerdote Carlotta, Salomaa Veikko, Sánchez María-José, Sattar Naveed, Sharp Stephen J, Sims Rebecca, Slimani Nadia, Smith Jennifer A, Thompson Deborah J, Trompet Stella, Tumino Rosario, van der A Daphne L, van der Schouw Yvonne T, Virtamo Jarmo, Walker Mark, Walter Klaudia, GERAD_EC Consortium, Neurology Working Group of the Cohorts for Heart, Aging Research in Genomic Epidemiology (CHARGE), Alzheimer’s Disease Genetics Consortium, Pancreatic Cancer Cohort Consortium, European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD), EPIC-InterAct, Abraham Jean E, Amundadottir Laufey T, Aponte Jennifer L, Butterworth Adam S, Dupuis Josée, Easton Douglas F, Eeles Rosalind A, Erdmann Jeanette, Franks Paul W, Frayling Timothy M, Hansen Torben, Howson Joanna M M, Jørgensen Torben, Kooner Jaspal, Laakso Markku, Langenberg Claudia, McCarthy Mark I, Pankow James S, Pedersen Oluf, Riboli Elio, Rotter Jerome I, Saleheen Danish, Samani Nilesh J, Schunkert Heribert, Vollenweider Peter, O'Rahilly Stephen, CHARGE consortium, CHD Exome+ Consortium, CARDIOGRAM Exome Consortium, Deloukas Panos, Danesh John, Goodarzi Mark O, Kathiresan Sekar, Meigs James B, Ehm Margaret G, Wareham Nicholas J, Waterworth Dawn M

Аннотация

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты