Variantes genéticas e fatores associados ao risco de hemorragia digestiva alta: um estudo de caso-controle
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Data
2021-05-07
Autores
Forgerini, Marcela [UNESP]
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Universidade Estadual Paulista (Unesp)
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INTRODUÇÃO: A hemorragia digestiva alta secundária à doença péptica complicada (HDA) é uma emergência digestiva associada à alta morbimortalidade e é considerada uma reação adversa a medicamento grave. A presença de variantes genéticas tem sido sugerida como um importante fator de risco para HDA, principalmente em genes envolvidos no metabolismo de medicamentos e em mecanismos fisiológicos de agregação plaquetária e proteção gástrica. OBJETIVO: Investigar a associação de variantes genéticas nos genes PTGS1, NOS3, CYP2C9, VKORC1 e ABCB1 e o risco de HDA. METODOLOGIA: Foi conduzido um estudo caso-controle pareado por gênero e idade (±5 anos) no complexo hospitalar do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Caso: pacientes com diagnóstico de HDA confirmado mediante endoscopia digestiva alta (EDA) ou intervenção cirúrgica. Controle: pacientes submetidos à cirurgia leve não relacionadas à problemas gastrointestinais. Os dados foram coletados por meio de entrevistas e coleta de sangue (5 mL). Variável dependente: HDA. Variável independente: variante genética. Variáveis de confusão: etnia, escolaridade, índice de massa corpórea, histórico familiar de úlcera, histórico pessoal de doenças gastrointestinais (úlcera, hemorragia, dispepsia), sorologia para Helicobacter pylori, comorbidades, farmacoterapia em uso, hábitos de vida (tabaco, álcool e café) e consistência da entrevista. Foi proposta a análise dos seguintes genes e variantes: PTGS1 (rs1330344, rs3842787, rs10306114, rs5788), NOS3 (rs2070744, rs1799983 e repetição em série de número variável (VNTR) no íntron 4 da eNOS), CYP2C9 (rs1057910 e rs1799853), VKORC1 (rs9923231) e ABCB1 (rs1045642). A genotipagem foi conduzida por meio da reação em cadeia da polimerase em tempo real com o ensaio TaqPath ProAmp (AppliedBiosystems, Foster City, USA) e a determinação da VNTR no íntron 4 da eNOS por meio da reação em cadeia da polimerase e análise de fragmentos (ABI3130, AppliedBiosystems, Foster City, USA). A sorologia por Helicobacter pylori foi determinada por concentração de IgG no plasma dos participantes, por meio da técnica de quimiluminescência. Os dados da entrevista, análise genética e laboratorial foram digitados na plataforma Research Electronic Data Capture. Como controle de qualidade, a frequência genotípica das variantes genéticas foi avaliada por meio do Equilíbrio de Hardy-Weinberg. Análise estatística: modelos de regressão logística não condicional (programa SPSS). RESULTADOS: Foram elegíveis 200 casos e 706 controles, sendo a maioria do gênero masculino [grupo caso: 145 (72,5%) e grupo controle: 512 (72,5%)], autodeclarados brancos [grupo caso: 134 (67,3%) e grupo controle: 516 (73,5%)] e com média de idade de 60,2 (±16,3) e 59,8 (±15,8) anos, respectivamente. A frequência de admissões hospitalares por HDA foi de 7,1% e estima-se que sete a cada cem pacientes submetidos à EDA foram diagnosticados com HDA. Todas as variantes atenderam ao Equilíbrio de Hardy-Weinberg. Foram identificados seis polimorfismos de nucleotídeo único (rs1330344, rs10306114, rs2070744, rs1799983, rs1045642 e rs9923231) e VNTR no íntron 4 da eNOS que podem modificar a magnitude de risco de HDA em usuários de ácido acetilsalicílico. Quando foram considerados os usuários de antiinflamatório não esteroidal, as onze variantes genéticas avaliadas neste estudo foram associadas ao risco de HDA. Como fatores de risco independentes para HDA foram identificadas as variáveis: histórico pessoal prévio de úlcera (p-valor: < 0,001); sorologia reagente para Helicobacter pylori (p-valor: 0,029); uso de anticoagulantes (p-valor: < 0,001), ácido acetilsalicílico (p-valor: < 0,001) e antiinflamatórios não esteroidais (p-valor: < 0,001); consumo > 15 cigarros/dia (p-valor: < 0,001) e consumo de > 30 gramas de álcool/dia (p-valor: < 0,001). CONCLUSÃO: Trata-se de um estudo inédito na população brasileira e que contribui com a análise de três variantes inéditas no escopo da HDA: rs1330344 (PTGS1), rs2070744 (NOS3) e rs1045642 (ABCB1). Os nossos achados evidenciam que a presença das variantes genéticas avaliadas pode modificar a magnitude do risco de HDA em usuários de ácido acetilsalicílico e/ou de anti-inflamatórios não esteroidais, além de outras variáveis de risco independente para HDA. Por fim, os nossos achados sugerem a necessidade de uma terapia individualizada, considerando o monitoramento do uso de medicamentos e identificação de fatores prévios de risco para HDA a fim de promover a segurança do paciente.
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.
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.
Descrição
Palavras-chave
Hemorragia gastrointestinal, Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos, Farmacogenética, Farmacovigilância, Úlcera péptica, Drug-Related Side Effects and Adverse Reactions, Gastrointestinal Hemorrhage, Peptic ulcer, Pharmacogenetics, Pharmacovigilance