Genetic Variants in PTGS1 and NOS3 Genes Increase the Risk of Upper Gastrointestinal Bleeding: A Case–Control Study

Abstract

Objective: To assess the association between PTGS1 and NOS3 variant alleles and the risk to develop upper gastrointestinal bleeding (UGIB) secondary to complicated peptic disease.Methods: A case–control study was conducted in a Brazilian complex hospital from July 2016 to March 2020. Case: Patients with UGIB diagnosis. Control: Patients admitted for surgery not related to gastrointestinal disorders. Variables: UGIB (outcome), genetic variants in PTGS1 and NOS3 genes (independent), and sex, age, schooling, ethnicity, previous history of gastrointestinal disorders, Helicobacter pylori serology, comorbidity, drug therapy, and lifestyle (confounding). The single-nucleotide polymorphisms (SNPs) of the PTSG1 gene (rs1330344, rs3842787, rs10306114, and rs5788) and NOS3 gene (rs2070744 and rs1799983) were determined using the real-time polymerase chain reaction. Helicobacter pylori serology was determined through the chemiluminescence technique. Logistic regression models were built and deviations of allelic frequencies from Hardy–Weinberg equilibrium were verified.Results: 200 cases and 706 controls were recruited. Carriers of the AG genotype of rs10306114 (OR: 2.55, CI 95%: 1.13–5.76) and CA + AA genotypes of rs5788 (OR: 2.53, CI 95%: 1.14–5.59) were associated with an increased risk for the UGIB development. In nonsteroidal anti-inflammatory drugs (NSAIDs) users, the six variants evaluated modified the magnitude of the risk of UGIB, whereas in low-dose aspirin (LDA) users, an increased risk of UGIB was observed for four of them (rs1330344, rs10306114, rs2070744, and rs1799983). Personal ulcer history (p-value: < 0.001); Helicobacter pylori infection (p-value: < 0.011); NSAIDs, LDA, and oral anticoagulant use (p-value: < 0.001); and alcohol intake (p-value: < 0.001) were also identified as independent risk factors for UGIB.Conclusion: This study presents two unprecedented analyses within the scope of the UGIB (rs10306114 and rs2070744), and our findings showing an increased risk of UGIB in the presence of the genetic variants rs10306114 and rs5788, regardless of the drug exposure. Besides, the presence of the evaluated variants might modify the magnitude of the risk of UGIB in LDA/NSAIDs users. Therefore, our data suggest the need for a personalized therapy and drug use monitoring in order to promote patient safety.

Genetic Association Study and Machine Learning to Investigate Differences in Platelet Reactivity in Patients with Acute Ischemic Stroke Treated with Aspirin

“…Notably, the alleles of the PTGS1 and ADRA2A genes, associated with AR and/or high AA-induced aggregation in our study, correlated with a reduced risk of complications from the gastrointestinal tract when taking aspirin in other studies [ 61 , 62 , 63 ]. This may indicate a role in stimulating platelet activity in carriers of these alleles.…”

The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study

“…The inclusion and exclusion criteria for the participants are described in detail in our three previous studies (4,10,11).…”

“…One hypothesis for idiosyncratic responses to the use of NSAIDs and LDA is the presence of variants in genes involved in the drug metabolism of these drugs or in physiological functions in the gastrointestinal tract system and platelet aggregation cascade (3). In a previous study we evaluated six variants in PTGS1 and NOS3 genes and an increased magnitude of UGIB risk was observed in NSAIDs and LDA users (4). In order to continue this investigation, we identified other genetic variants potentially involved in the risk of gastric injury and UGIB and the *2 (Arg144Cys, rs1799853) and *3 alleles (Ile359Leu, rs10587910) of CYP2C9 gene stand out (3).…”

VNTR Polymorphism in Intron 4 of the eNOS Gene and the Risk of Gastrointestinal Bleeding: A Case-control Study

“…Both participants were recruited from the same hospital complex and the inclusion and exclusion criteria for the participants of case and control groups are described in detail in our two previous studies [6,13].…”

“…In our previous study, we evaluated in the Brazilian population the influence of rs2070744 and rs1799983 variants on the risk of upper gastrointestinal bleeding (UGIB) [6], a potential adverse drug reaction associated with high mortality, hospital readmissions, and the need for surgical intervention [7]. When the subgroups of LDA and NSAIDs users were considered, carriers of the variant alleles of rs2070744 and rs1799983 had a higher risk of developing UGIB [6], corroborating with a recent case-control study conducted with the Spanish population that also identified an increased risk of UGIB in LDA users carrying the variant allele of rs1799983 [8].…”