Mallah, Narmeen, Zapata-Cachafeiro, Maruxa, Aguirre, Carmelo, Ibarra-García, Eguzkiñe, Palacios-Zabalza, Itziar, Macías-García, Fernando, Piñeiro-Lamas, María, Ibáñez, Luisa, Vidal Guitart, Xavier, Vendrell Bosch, Lourdes, Martin-Arias, Luis, Sáinz-Gil, María, Velasco-González, Verónica, Bacariza-Cortiñas, Manuel, Salgado, Angel, Estany-Gestal, Ana, Figueiras, Adolfo, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Mallah N] Department of Preventive Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. WHO Collaborating Centre for Vaccine Safety, Santiago de Compostela, Spain. Genetics, Vaccines and Pediatric Infectious Diseases Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain. Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBER-ES), Carlos III Health Institute, Madrid, Spain. [Zapata-Cachafeiro M] Department of Preventive Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública-CIBERESP), Carlos III Health Institute, Madrid, Spain. [Aguirre C] Pharmacotherapy Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. Basque Country Pharmacovigilance Unit, University Hospital of Galdakao-Usansolo, Osakidetza, Spain. Pharmacology Department, Medicine and Nursing Faculty, University of the Basque Country, Barakaldo, Spain. [Ibarra-García E] Department of Preventive Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. Pharmacotherapy Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. Osakidetza Basque Health Service, Pharmacy Department, Urduliz Hospital, Urduliz, Spain. [Palacios-Zabalza I] Pharmacotherapy Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. Basque Country Pharmacovigilance Unit, University Hospital of Galdakao-Usansolo, Osakidetza, Spain. [Macías-García F] Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain. [Ibáñez L, Vidal X, Vendrell L] Catalonian Institute of Pharmacology, Barcelona, Spain. Servei de Farmacologia Clínica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
[EN] Background Interindividual genetic variations contribute to differences in patients' response to drugs as well as to the development of certain disorders. Patients who use non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal disorders, mainly upper gastrointestinal haemorrhage (UGIH). Studies about the interaction between NSAIDs and genetic variations on the risk of UGIH are scarce. Therefore, we investigated the effect of 16 single nucleotide polymorphisms (SNPs) involved in drug metabolism on the risk of NSAIDs-induced UGIH. Materials and methods We conducted a multicenter case-control study of 326 cases and 748 controls. Participants were sub-grouped into four categories according to NSAID exposure and genetic profile. We estimated odds ratios (ORs) and their 95% confidence intervals (CI) using generalized linear mixed models for dependent binomial variables and then calculated the measures of interaction, synergism index (S), and relative excess risk due to interaction (RERI). We undertook stratified analyses by the type of NSAID (aspirin, non-aspirin). Results We observed an excess risk of UGIH due to an interaction between any NSAID, non-aspirin NSAIDs or aspirin and carrying certain SNPs. The greatest excess risk was observed for carriers of: rs2180314:C>G [any NSAID: S = 3.30 (95%CI: 1.24-8.80), RERI = 4.39 (95%CI: 0.70-8.07); non-aspirin NSAIDs: S = 3.42 (95%CI: 1.12-10.47), RERI = 3.97 (95%CI: 0.44-7.50)], and rs4809957:A>G [any NSAID: S = 2.11 (95%CI: 0.90-4.97), RERI = 3.46 (95%CI: -0.40-7.31)]. Aspirin use by carriers of rs6664:C>T is also associated with increased risk of UGIH [ORaspirin(+),wild-type: 2.22 (95%CI: 0.69-7.17) vs. ORaspirin(+),genetic-variation: 7.72 (95%CI: 2.75-21.68)], yet larger sample size is needed to confirm this observation. Conclusions The joint effect of the SNPs s2180314:C>G and rs4809957:A>G and NSAIDs are more than three times higher than the sum of their individual effects. Personalized prescriptions based on genotyping would permit a better weighing of risks and benefits from NSAID consumption. KEY MESSAGES Multicenter case-control study of the effect of genetic variations involved in drug metabolism on upper gastrointestinal haemorrhage (UGIH) induced by NSAIDs (aspirin and non-aspirin). There is a statistically significant additive synergism interaction between certain genetic polymorphisms and NSAIDs on UGIH: rs2180314:C>G and rs4809957:A>G. The joint effect of each of these single nucleotide polymorphisms and NSAIDs on UGIH is more than three times higher than the sum of their individual effects. Genetic profiling and personalized prescriptions would be useful in managing the risks and benefits associated with NSAIDs. This study was supported by grants from: Carlos III Health Institute (P I12/02414, of the P E I+D+I 2012-2016); Fondo Europeo de Desarrollo Regional (FEDER); the Novartis, Pfizer and Dr Esteve pharmaceutical companies; the Health Research Fund/Fondo de Investigacio ~nn Sanitaria (P I021512, P I021364, P I020661, and P I021572); Ministry of Health & Consumer Affairs, Spain (SAF2002-04057); Galician Regional Authority, Spain (P GIDIT03P XIC20806P N); Department of Health of the Basque Country (03/11092 and 11/111103); Fundacion Vasca de innovacion e investigacion sanitarias (OSIBG19/002 and OSIBG18/105). The genotyping service was carried out at CEGEN-P RB3-ISCIII; Carlos III Health Institute and ERDF (P T17/0019, of the P E I+D+I 2013-2016). The funding sources do not have any role in the study design; data collection, analysis and interpretation; writing the manuscript; and in the decision to submit the article for publication.