The Pharmacogenomics Journal https://doi.org/10.1038/s41397-020-00185-6 REVIEW ARTICLE Genetic polymorphisms associated with upper gastrointestinal bleeding: a systematic review Marcela Forgerini 1 ● Rosa Camila Lucchetta 1 ● Gustavo Urbano 2 ● Tales Rubens de Nadai 3 ● Patrícia de Carvalho Mastroianni 1 Received: 6 April 2020 / Revised: 17 August 2020 / Accepted: 8 September 2020 © The Author(s), under exclusive licence to Springer Nature Limited 2020 Abstract Non-variceal upper gastrointestinal bleeding (non-variceal UGIB) is a frequent and severe adverse drug reaction. Idiosyncratic responses due to genetic susceptibility to non-variceal UGIB has been suggested. A systematic review was conducted to assess the association between genetic polymorphisms and non-variceal UGIB. Twenty-one publications and 7134 participants were included. Thirteen studies evaluated genetic polymorphism in patients exposed to non-steroidal anti- inflammatory drugs, low-dose aspirin, and warfarin. Eight studies present at least one methodological problem. Only six studies clearly defined that the outcome evaluated was non-variceal UGIB. Genetic polymorphisms involved in platelet activation and aggregation, angiogenesis, inflammatory process, and drug metabolism were associated with risk of non- variceal UGIB (NOS3, COX-1; COX-2; PLA2G7; GP1BA; GRS; IL1RN; F13A1; CDKN2B-AS1; DPP6; TBXA2R; TNF- alpha; VKORC1; CYP2C9; and AGT). Further well-designed studies are needed (e.g., clear restriction to non-variceal UGIB; proper selection of participants; and adjustment of confounding factors) to provide strong evidence for pharmacogenetic and personalized medicine. Introduction Upper or low gastrointestinal bleeding are the most com- mon cause of hospitalizations related to digestive diseases [1, 2] and they are associated with high morbimortality due to the need for surgical interventions, in-hospital mortality, and 30-day hospital readmissions [3]. The upper gastrointestinal bleeding (UGIB) has the highest incidence [4] and it is classified as non-variceal and variceal [5]. The incidence of non-variceal UGIB is five times higher than variceal UGIB [6] and the mortality ranging from 1.1 to 11% [7] and even 26% in inpatients [8]. Non variceal-UGIB is also one of the most frequent and serious adverse drug reactions [9] associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), platelet antiaggregant, and oral antic- oagulants [10, 11]. Furthermore, some studies have been observed idiosyncratic responses to drugs due the genetic susceptibility to non-variceal UGIB [12, 13]. In this context, analysis of genetic susceptibility can improve clinical drug outcomes, besides to contribute to patient safety and per- sonalized medicine [14]. After an extensive research on PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews, and the JBI Evidence Synthesis, we are not aware of any other sys- tematic review that identified the polymorphisms associated with non-variceal UGIB, regardless of exposure to drugs. However, there is a review that assessed the association of polymorphisms in CYP2C9 and gastrointestinal bleeding in patients exposed to NSAIDs [15]. This review identified six studies but was not possible to clearly assess the association between the polymorphisms and gastrointestinal bleeding due to methodological flaws pointed out in the included * Patrícia de Carvalho Mastroianni patricia.mastroianni@unesp.br 1 Department of Drugs and Medicines, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil 2 Department of Surgery, School of Medicine, University of São Paulo (USP), Ribeirão Preto, Brazil 3 Department of Public Health, Bauru School of Dentistry, University of São Paulo (USP), Bauru, Brazil Supplementary information The online version of this article (https:// doi.org/10.1038/s41397-020-00185-6) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: