Variantes genéticas localizadas no gene ptgs2 e o risco de hemorragia digestiva alta em usuários de ácido acetilsalicílico: um estudo caso-controle
Data
2022-12-13
Autores
Gini, Ana Luísa Rodriguez
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Universidade Estadual Paulista (Unesp)
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INTRODUÇÃO: Susceptibilidade genética para a ocorrência de hemorragia digestiva alta de etiologia não varicosa (HDA) em usuários de ácido acetilsalicílico (AAS) tem sido sugerida. Nesse sentido, até onde se sabe, o nosso grupo de pesquisa está conduzindo um estudo farmacogenético inédito na população brasileira e até o momento foi avaliada a influência de dez variantes genéticas no risco de HDA. OBJETIVO: Investigar a influência de duas variantes genéticas rs689466 e rs5275 localizadas no gene PTGS2 no risco de HDA em usuários de AAS. METODOLOGIA: Trata-se de um estudo genético experimental. Foram utilizadas amostras de DNA de 50 casos usuários de AAS, 50 controles usuários de AAS e 189 controles saudáveis não usuários de AAS, armazenadas em um biorrepositório, obtidas por meio de um estudo observacional do tipo caso-controle. Casos: usuários de AAS com diagnóstico de HDA. Controle¹: usuários de AAS sem o diagnóstico de HDA. Controle²: não usuários de AAS sem o diagnóstico de HDA. Definiu-se como variável dependente HDA em usuários de AAS e como variável independente a presença das variantes rs689466 e rs5275. As variáveis de confusão são: etnia, escolaridade, índice de massa corpórea, histórico familiar de úlcera, histórico pessoal de doenças gastrointestinais, sorologia para Helicobacter pylori, comorbidades, farmacoterapia em uso e hábitos de vida. As variantes genéticas foram analisadas por meio da reação em cadeia da polimerase em tempo real com o ensaio TaqPath ProAmp (AppliedBiosystems, Foster City, USA). Os dados foram tabulados e digitados na Research Electronic Data Capture (RedCap). A frequência do alelo menor foi analisada por meio do Equilíbrio de Hardy-Weinberg e os dados foram analisados por meio de modelos de regressão logística (Programa SPSS). Esse estudo foi aprovado pelo Comitê de Ética em Pesquisa (CAAE 53753115.4.0000.5440 e CAAE 53753115.4.3001.5426). RESULTADOS: Em relação ao perfil epidemiológico dos participantes, a maioria era homem [grupo caso: 36 (72,0%); grupo controle¹: 35 (70,0%); grupo controle²: 139 (73,5%)], com média de idade de 69,4 (±10,9) para o grupo caso, 68,8 (±10,6) para o grupo controle¹ e 67,7 (±10,8) para o grupo controle² e autodeclarados brancos [grupo caso: 39 (78,0%); grupo controle¹: 38 (76,0%); e grupo controle²: 139 (73,5%)]. A maioria dos participantes possuíam de 0 - 4 anos de escolaridade [grupo caso: 33 (66,0%); grupo controle¹: 35 (70,0%); e grupo controle²: 117 (61,9%)]. A variante rs5275 – genótipo heterozigoto + homozigoto para o alelo variante – foi identificada como fator de proteção para HDA em casos e controles usuários de AAS (OR: 0,283; IC95%: 0,082 – 0,972; p-valor: 0,045), enquanto foi identificado como fator de risco em carreadores do genótipo heterozigoto (OR: 5,140; IC95%: 1,560 – 16,934; p-valor: 0,007), bem como em carreadores dos genótipos heterozigoto + homozigoto para o alelo variante (OR: 5,161; IC95%: 1,583 – 16,829; p-valor: 0,006) em grupos casos usuários de AAS e controles saudáveis. A variante rs689466 não foi associada ao risco de HDA. Também foram identificados seis fatores de risco independentes para HDA, sendo: doença cardiovascular, hipertensão arterial, infecção por Helicobacter pylori, uso de anticoagulantes, uso de outros antiagregantes plaquetários e uso de AINEs. CONCLUSÃO: Nossos achados sugerem que a variante rs5275 pode ser promissora em usuários crônicos de AAS, especialmente os que possuem maior risco de HDA, a fim de promover no futuro uma terapia personalizada e a segurança do paciente.
INTRODUCTION: Genetic susceptibility to the occurrence of upper gastrointestinal bleeding of non-variceal etiology (UGIB) in aspirin (LDA) users has been suggested. In this sense, as far as is known, our research group is conducting an unprecedented pharmacogenetic study in the Brazilian population and so far the influence of ten genetic variants on the risk of UGIB has been evaluated. OBJECTIVE: To investigate the influence of two genetic variants rs689466 and rs5275 located in the PTGS2 gene on the risk of UGIB in LDA users. METHODOLOGY: This is an experimental genetic study. DNA samples from 50 LDA-using cases, 50 LDA-using controls and 189 healthy non-LDA-using controls, stored in a biorepository, obtained through a case-control observational study were used. Cases: LDA users diagnosed with UGIB. Control¹: LDA users without UGIB diagnostics. Control²: Non-LDA users without UGIB diagnostics. The UGIB dependent variable was defined in LDA users and the presence of the rs689466 and rs5275 variants was defined as an independent variable. Confounding variables are: ethnicity, schooling, body mass index, family history of ulcer, personal history of gastrointestinal diseases, serology for Helicobacter pylori, comorbidities, pharmacotherapy in use, and lifestyle. Genetic variants were analyzed by real-time polymerase chain reaction with the TaqPath ProAmp assay (AppliedBiosystems, Foster City, USA). Data were tabulated and entered into Research Electronic Data Capture (RedCap). The minor allele frequency was analyzed using the Hardy-Weinberg Equilibrium and the data were analyzed using logistic regression models (SPSS Program). This study was approved by the Research Ethics Committee (CAAE 53753115.4.0000.5440 and CAAE 53753115.4.3001.5426) RESULTS: Regarding the epidemiological profile of the participants, the majority were men [case group: 36 (72,0%); control group¹: 35 (70,0%); control group²: 139 (73,5%)], with a mean age of 69.4 (±10.9) for the case group, 68.8 (±10.6) for the control group¹ and 67.7 (±10.8) for the control group² and self-reported whites [case group: 39 (78,0%); control group¹: 38 (76,0%); and control group²: 139 (73,5%)]. Most participants had 0 - 4 years of schooling [case group: 33 (66,0%); control group¹: 35 (70,0%); and control group²: 117 (61,9%)]. The rs5275 variant – genotype heterozygous + homozygous for the variant allele – was identified as a protective factor for UGIB in LDA users cases and controls (OR: 0.283; 95%CI: 0.082 – 0.972; p-value: 0,045), while it was identified as a risk factor in carriers of the heterozygous genotype (OR: 5.140; 95%CI: 1.560 – 16.934; p-value: 0,007), as well as in carriers of the heterozygous + homozygous genotypes for the variant allele (OR: 5.161; 95%CI: 1.583 – 16.829; p-value: 0,006) in LDA-using case groups and healthy controls. The rs689466 variant was not associated with risk of UGIB. Six independent risk factors for UGIB were also identified, namely: cardiovascular disease, arterial hypertension, Helicobacter pylori infection, use of anticoagulants, use of other antiplatelet agents and use of NSAIDs. CONCLUSION: Our findings suggest that the rs5275 variant may hold promise in chronic LDA users, especially those at higher risk of UGIB, in order to promote personalized therapy and patient safety in the future.
INTRODUCTION: Genetic susceptibility to the occurrence of upper gastrointestinal bleeding of non-variceal etiology (UGIB) in aspirin (LDA) users has been suggested. In this sense, as far as is known, our research group is conducting an unprecedented pharmacogenetic study in the Brazilian population and so far the influence of ten genetic variants on the risk of UGIB has been evaluated. OBJECTIVE: To investigate the influence of two genetic variants rs689466 and rs5275 located in the PTGS2 gene on the risk of UGIB in LDA users. METHODOLOGY: This is an experimental genetic study. DNA samples from 50 LDA-using cases, 50 LDA-using controls and 189 healthy non-LDA-using controls, stored in a biorepository, obtained through a case-control observational study were used. Cases: LDA users diagnosed with UGIB. Control¹: LDA users without UGIB diagnostics. Control²: Non-LDA users without UGIB diagnostics. The UGIB dependent variable was defined in LDA users and the presence of the rs689466 and rs5275 variants was defined as an independent variable. Confounding variables are: ethnicity, schooling, body mass index, family history of ulcer, personal history of gastrointestinal diseases, serology for Helicobacter pylori, comorbidities, pharmacotherapy in use, and lifestyle. Genetic variants were analyzed by real-time polymerase chain reaction with the TaqPath ProAmp assay (AppliedBiosystems, Foster City, USA). Data were tabulated and entered into Research Electronic Data Capture (RedCap). The minor allele frequency was analyzed using the Hardy-Weinberg Equilibrium and the data were analyzed using logistic regression models (SPSS Program). This study was approved by the Research Ethics Committee (CAAE 53753115.4.0000.5440 and CAAE 53753115.4.3001.5426) RESULTS: Regarding the epidemiological profile of the participants, the majority were men [case group: 36 (72,0%); control group¹: 35 (70,0%); control group²: 139 (73,5%)], with a mean age of 69.4 (±10.9) for the case group, 68.8 (±10.6) for the control group¹ and 67.7 (±10.8) for the control group² and self-reported whites [case group: 39 (78,0%); control group¹: 38 (76,0%); and control group²: 139 (73,5%)]. Most participants had 0 - 4 years of schooling [case group: 33 (66,0%); control group¹: 35 (70,0%); and control group²: 117 (61,9%)]. The rs5275 variant – genotype heterozygous + homozygous for the variant allele – was identified as a protective factor for UGIB in LDA users cases and controls (OR: 0.283; 95%CI: 0.082 – 0.972; p-value: 0,045), while it was identified as a risk factor in carriers of the heterozygous genotype (OR: 5.140; 95%CI: 1.560 – 16.934; p-value: 0,007), as well as in carriers of the heterozygous + homozygous genotypes for the variant allele (OR: 5.161; 95%CI: 1.583 – 16.829; p-value: 0,006) in LDA-using case groups and healthy controls. The rs689466 variant was not associated with risk of UGIB. Six independent risk factors for UGIB were also identified, namely: cardiovascular disease, arterial hypertension, Helicobacter pylori infection, use of anticoagulants, use of other antiplatelet agents and use of NSAIDs. CONCLUSION: Our findings suggest that the rs5275 variant may hold promise in chronic LDA users, especially those at higher risk of UGIB, in order to promote personalized therapy and patient safety in the future.
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Efeitos Colaterais e Reações Adversas Relacionadas a Medicamentos, Farmacogenética, Polimorfismo genético, Segurança do Paciente, Úlcera péptica