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Genetic variants and factors associated with the risk of upper gastrointestinal bleeding: a case-control study

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Author(s):
Marcela Forgerini
Total Authors: 1
Document type: Doctoral Thesis
Press: Araraquara. 0000-00-00.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
Defense date:
Advisor: Patricia de Carvalho Mastroianni; Maria Teresa Herdeiro
Abstract

INTRODUCTION: Upper gastrointestinal bleeding secondary to complicated peptic disease (UGIB) is a digestive emergency associated with high morbidity and mortality and is considered a serious adverse drug reaction. The presence of genetic variants has been suggested as an important risk factor for UGIB, mainly in genes involved in drug metabolism and in physiological mechanisms of platelet aggregation and gastric protection. OBJECTIVE: To investigate the association of genetic variants in the PTGS1, NOS3, CYP2C9, VKORC1 and ABCB1 genes and the risk of UGIB. METHODOLOGY: A case-control study paired by sex and age (± 5 years) was conducted in the the hospital complex of Clinical Hospital of the Ribeirão Preto Medical School of the University of São Paulo. Case: patients diagnosed with UGIB confirmed by upper digestive endoscopy (UDE) or surgical intervention. Control: patients undergoing mild surgery not related to gastrointestinal problems. Data were collected through interviews and blood collection (5 mL). Dependent variable: UGIB. Independent variable: genetic variant. Confounding variables: ethnicity, schooling, body mass index, family history of ulcer, personal history of gastrointestinal diseases (ulcer, hemorrhage, dyspepsia), serology for Helicobacter pylori, comorbidities, drug therapy in use, lifestyle (tobacco, alcohol and coffee) and consistency of the interview. The analysis of the following genes and variants were proposed: PTGS1 (rs1330344, rs3842787, rs10306114, rs5788), NOS3 (rs2070744, rs1799983 and variable number tandem repeats (VNTR) in intron 4), CYP2C9 (rs1057910 and rs1799853), VKORC1 (rs9923231). The genotyping were carried out through the real-time polymerase chain reaction with the TaqPath ProAmp assay (AppliedBiosystems, Foster City, USA) and the determination of VNTR in intron 4 of eNOS through polymerase chain reaction and fragment analysis (ABI3130, AppliedBiosystems, Foster City, USA). Helicobacter pylori serology was determined by IgG concentration in the participants' plasma, using the chemiluminescence technique. The interview data, genetic and laboratory analysis were entered into the Research Electronic Data Capture platform. For genotyping control, the genotypic frequency of the genetic variants was assessed using the Hardy- Weinberg Equilibrium. Statistical analysis: unconditional logistic regression models (SPSS program). RESULTS: 200 cases and 706 controls were eligible. Most participants were male [case group: 145 (72.5%) and control group: 512 (72.5%)], self-declared white [case group: 134 (67.3%) and control group: 516 (73.5%)] and with a mean age of 60.2 (± 16.3) and 59.8 (± 15.8) years, respectively. The frequency of hospital admissions for UGIB was 7.1% and it is estimated that seven out of every hundred patients undergoing UDE were diagnosed with UGIB. All the genetic variants attend the Hardy-Weinberg Equilibrium. Six single nucleotide polymorphisms (rs1330344, rs10306114, rs2070744, rs1799983, rs1045642 and rs9923231) and VNTR in intron 4 of eNOS can modify the UGIB risk magnitude in users of low-dose aspirin. When considering users of non-steroidal antiinflammatory drugs, the eleven genetic variants evaluated in this study were associated with the risk of UGIB. As independent risk factors for UGIB were identified the following variables: previous personal history of ulcer (p-value: <0.001); reagent serology for Helicobacter pylori (p-value: 0.029); use of anticoagulants (p-value: <0.001), low-dose aspirin (p-value: <0.001) and non-steroidal antiinflammatory drugs (p-value: <0.001); consumption > 15 cigarettes/day (p-value: <0.001) and consumption of > 30 grams of alcohol/day (p-value: <0.001). CONCLUSION: This is an unprecedented study in the Brazilian population and which contributes to the analysis of three new variants within the scope of UGIB: rs1330344 (PTGS1), rs2070744 (NOS3) and rs1045642 (ABCB1). Our findings show that the presence of the evaluated genetic variants can modify the magnitude of the risk of UGIB in low-dose aspirin users and/or non-steroidal anti-inflammatory drugs, in addition to other independent risk variables for UGIB. Finally, our findings suggest the need for individualized therapy, considering the monitoring of drug therapy use and the identification of previous risk factors for UGIB in order to promote patient safety. (AU)

FAPESP's process: 18/07501-9 - Genetic determinants of gastrointestinal bleeding associated with the use of ASA as an antiplalet agent: a case-control study
Grantee:Marcela Forgerini
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)