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

Marcela Forgerini; Gustavo Urbano; Tales Rubens de Nadai; Cleslei Fernando Zanelli; Sandro Roberto Valentini; Patrícia de Carvalho Mastroianni

doi:10.15403/jgld-4226

May 14, 2022Journal of Gastrointestinal and Liver DiseasesOpen Access

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

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Why the study?

The influence of the 4b/4a VNTR polymorphism in intron 4 of the eNOS gene on drug response and upper gastrointestinal bleeding risk was not known.

Does the 4b/4a VNTR polymorphism in the eNOS gene increase the risk of upper gastrointestinal bleeding in users of low-dose aspirin or NSAIDs?

Key Points

To evaluate whether the 4b/4a VNTR polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene influences the risk of upper gastrointestinal bleeding, alone or via interaction with aspirin and NSAIDs.
Conducted a hospital-based case-control study in Brazil including 200 patients diagnosed with upper gastrointestinal bleeding and 706 surgical controls without gastrointestinal problems.
Genotyped the eNOS 4b/4a VNTR using PCR and fragment analysis, estimating upper gastrointestinal bleeding risk through conditional logistic regression.
Calculated additive gene-drug interactions for low-dose aspirin and nonsteroidal anti-inflammatory drugs using Cox regression via the Synergism index and Relative Excess Risk Due to Interaction.
Carriage of the homozygous 4a/4a genotype (OR=0.37, 95% CI: 0.09–1.45) or the 4a variant allele (OR=0.91, 95% CI: 0.55–1.51) showed no significant increase in upper gastrointestinal bleeding risk.
Bleeding risk was elevated by low-dose aspirin in wild-type carriers (OR=4.96, 95% CI: 2.04–2.06) and 4a carriers (OR=3.49, 95% CI: 1.18–10.38), as well as by NSAIDs in wild-type carriers (OR=5.73, 95% CI: 2.61–12.60) and 4a carriers (OR=5.51, 95% CI: 1.42–15.82).
No additive interaction on bleeding risk was detected between the 4a allele and low-dose aspirin (RERI: -1.44, 95% CI: -6.02–3.14; S: 0.63, 95% CI: -1.97–1.15) or NSAIDs (RERI: -0.13, 95% CI: -6.79–6.53; S: 0.97, 95% CI: -0.23–4.19).

Structured PICO

Does the 4b/4a VNTR polymorphism in the eNOS gene increase the risk of upper gastrointestinal bleeding in users of low-dose aspirin or NSAIDs?

P

Population

906 participants (200 cases with upper gastrointestinal bleeding diagnosis, 706 controls admitted for surgical procedures not related to gastrointestinal problems) in a Brazilian hospital complex.

I

Intervention

Presence of the 4b/4a VNTR variant (allele '4a') of the eNOS gene, and use of low-dose aspirin (LDA) or NSAIDs

C

Comparator

Wild genotype (4b/4b) and non-users of LDA/NSAIDs

O

Outcome

Risk of upper gastrointestinal bleeding (UGIB)hard clinical

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Implication

The 4b/4a VNTR polymorphism in the eNOS gene does not appear to modify the risk of upper gastrointestinal bleeding associated with low-dose aspirin or NSAID use.

Abstract

BACKGROUND AND AIMS: Considering the lack of knowledge regarding the influence of the variable number of repeats of 27 pb in intron 4 (4b/4a VNTR - rs61722009) of the endothelial nitric oxide synthase (eNOS) on the drug response, we assessed the influence of this polymorphism for the risk of upper gastrointestinal bleeding (UGIB). METHODS: A case-control study, including 200 cases and 706 controls, was conducted in a Brazilian hospital complex. Cases were participants with UGIB diagnosis. Controls were participants admitted to surgical procedures not related to gastrointestinal problems. The 4b/4a VNTR was determined through polymerase chain reaction followed by fragment analysis. Conditional logistic regression models were designed. The additive interaction between the presence of the 4b/4a VNTR variant and the use of low-dose aspirin (LDA) and nonsteroidal anti-inflammatory drugs (NSAIDs) was calculated by fitting the Cox regression model through the parameters of Synergism index (S) and Relative Excess Risk Due To Interaction (RERI). RESULTS: The presence of the 4b/4a VNTR variant did not increase the risk of UGIB: carriers of the 4a/4a genotype (OR=0.37, 95%CI: 0.09-1.45) and of the variant allele "4a" (OR=0.91, 95%CI: 0.55-1.51). The risk of UGIB in LDA users carriers of the wild genotype (OR=4.96, 95%CI: 2.04- 2.06) and the variant allele "4a" (OR=3.49, 95%CI: 1.18-10.38) is similar, as well as for NSAID users carriers of the wild genotype (OR=5.73, 95%CI: 2.61-12.60) and variant allele "4a" (OR=5.51, 95%CI: 1.42-15.82). No additive interaction was identified between the presence of the genetic variant and the use of LDA [RERI: -1.44 (95%CI: -6.02-3.14; S: 0.63 (95%CI: -1.97-1.15)] and NSAIDs [RERI: -0.13 (95%CI: -6.79-6.53; S: 0.97 (95%CI: -0.23-4.19)] on the UGIB risk. CONCLUSION: Our data suggests that there is no increase in the magnitude of UGIB risk in LDA and NSAIDs users' carrying the variant allele "4a".

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Cite This Study

Forgerini et al. (2022) studied this question.

synapsesocial.com/papers/6a718b0478a11c550e0b97c9 https://doi.org/10.15403/jgld-4226

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

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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