Portal de Periódicos da CAPES

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

2022; Elsevier BV; Volume: 11; Issue: 1 Linguagem: Inglês

10.1016/s2213-8587(22)00340-0

2213-8595

Adem Y. Dawed, Andrea Mari, Andrew Brown, Timothy J. McDonald, Lin Li, Shuaicheng Wang, Mun‐Gwan Hong, Sapna Sharma, Neil R. Robertson, Anubha Mahajan, Xuan Wang, Mark Walker, Stephen Gough, Leen M. ‘t Hart, Kaixin Zhou, Ian Forgie, Hartmut Ruetten, Imre Pávó, Pallav Bhatnagar, Angus G. Jones, Ewan R. Pearson, Leen M. ‘t Hart, Mohamed Elhassan Abdalla, Jean‐Michel Adam, J. Adamski, Kofi P. Adragni, Kristine H. Allin, Manimozhiyan Arumugam, Naeimeh Atabaki Pasdar, Tania Baltauss, Kamil Banasik, Patrick Baum, Jimmy D. Bell, Mats Bergström, Joline W. J. Beulens, Susaana Bianzano, Roberto Bizzotto, Amelie Bonneford, Caroline Brorsson, A.A. Brown, S.B. Brunak, Louise Cabrelli, Robert Caïazzo, Mickaël Canouil, M.M. Dale, David Davtian, Adem Y. Dawed, F.M. De Masi, Nathalie de Préville, Koen F. Dekkers, E. T. Dermitzakis, Harshal Deshmukh, Christiane Dings, Louise Donnelly, Avirup Dutta, Beate Ehrhardt, Petra J. M. Elders, Cecilia Engel Thomas, Line Engelbrechtsen, R.G. Eriksen, R.E. Eriksen, Yong Fan, J. Fernandez, José Illnait Ferrer, Hugo Fitipaldi, Ian Forgie, Axel Forman, Paul W. Franks, Franco Frau, A. Fritsche, P. Froguel, Gary Frost, Johann Gassenhuber, Guillermo Giordano, Toni Giorgino, Stephen Gough, Ulrike Graefe‐Mody, H. Grallert, Rolf Grempler, Lenka Groeneveld, Leif Groop, V Gudmundsdottir, R.G. Gupta, Mark Haid, T. Hansen, Tue H. Hansen, Andrew T. Hattersley, Ragna S. Häussler, A.J. Heggie, Anita M. Hennige, Adrian V. S. Hill, Reinhard W. Holl, Mun‐Gwan Hong, Michelle Hudson, Bernd Jablonka, Christopher Jennison, Jian Jiao, Jon Johansen, Adam G. Jones, A. Jonsson, Tugce Karaderi, Jane Kaye, Maria Klintenberg, Robert W. Koivula, Tarja Kokkola, Anitra D.M. Koopman, A Kurbasic, T. Kuulasmaa, M. Laakso, Thorsten Lehr, Hannah Loftus, R.L.A Lundbye Allesøe, Anubha Mahajan, Andrea Mari, Gianluca Mazzoni, Mark I. McCarthy, Timothy J. McDonald, Donald McEvoy, Nicky McRobert, Ian McVittie, Miranda Mourby, PB Musholt, Pascal M. Mutie, Rachel Nice, Claudia Nicolay, Agnes Martine Nielsen, Birgitte Nilsson, Nicholette D. Palmer, François Pattou, Imre Pávó, Ewan R. Pearson, Oluf Pedersen, Helle K. Pedersen, Mandy H. Perry, Hugo Pomares‐Millan, Anna Ramisch, Sebastian Buhl Rasmussen, V. Raverdi, Martin Ridderstråle, N. Robertson, Ryland Roderick, M. Rodriquez, Hartmut Ruetten, Femke Rutters, Walter G. Sackett, N. Scherer, Jochen M. Schwenk, N. Jon Shah, Sapna Sharma, Iryna Sihinevich, Nadja B. Søndertoft, Hans‐Henrik Stærfeldt, Birgit Steckel-Hamann, Harriet Teare, Melissa K. Thomas, E. Louise Thomas, Henrik S. Thomsen, Barbara Thorand, Claire E. Thorne, J. Tillner, A.T.L. Troen Lundgaard, Mark Troll, Kostas Tsirigos, Andrea Tura, Mathias Uhlén, Nienke van Leeuwen, Sabine van Oort, Hélène Verkindt, Henrik Vestergaard, A. Viñuela, Josef Korbinian Vogt, P.W.S Wad Sackett, Deborah J. Wake, Mark Walker, Agata Wesolowska‐Andersen, Brandon Whitcher, Matthew White, Han Wu,

Genetic Associations and Epidemiology

In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment.In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests.4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04-0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10-5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10-8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10-6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response.This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists.Innovative Medicines Initiative and the Wellcome Trust.