Common Variants in 22 Genes Regulate Response to Metformin Intervention in Children with Obesity: A Pharmacogenetic Study of a Randomized Controlled Trial
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AuthorAnguita-Ruiz, Augusto; Pastor-Villaescusa, Belén; Gil Hernández, Ángel; Aguilera García, Concepción María
Anguita-Ruiz, A.; Pastor-Villaescusa, B.; Leis, R.; Bueno, G.; Hoyos, R.; Vázquez-Cobela, R.; Latorre-Millán, M.; Cañete, M.D.; Caballero-Villarraso, J.; Gil, Á.; Cañete, R.; Aguilera, C.M. Common Variants in 22 Genes Regulate Response to Metformin Intervention in Children with Obesity: A Pharmacogenetic Study of a Randomized Controlled Trial. J. Clin. Med. 2019, 8, 1471. [doi:10.3390/jcm8091471]
SponsorshipThis research was funded by the Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products (codes and beneficiaries: EC10-243, Ramón Cañete, Reina Sofía Hospital, Córdoba; EC10-056, Ángel Gil, University of Granada and Virgen de las Nieves University Hospital, Granada; EC10-281, Rosaura Leis, Clinic University Hospital of Santiago, Santiago de Compostela; and EC10-227, Gloria Bueno, Lozano Blesa University Clinical Hospital, Zaragoza)
Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin’s action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES).