Abstract
BackgroundDespite the wide benefits of aspirin and its cost-effectiveness, aspirin prescriptions have been reduced due to idiosyncratic responses in susceptible individuals. Low-dose aspirin and single-nucleotide polymorphisms (SNPs) are independently associated with increased risk of gastrointestinal hemorrhage; however, to-date, no studies investigated the SNP-aspirin interaction effect on upper gastrointestinal hemorrhage (UGIH). Therefore, we aimed to evaluate the role of 25 SNPs in multiple genes involved in platelet activation, angiogenesis and inflammatory response in aspirin-related UGIH.MethodsA multicenter, full case–control study was conducted in patients exposed and unexposed to aspirin. Three hundred twenty-six cases diagnosed with UGIH were matched with 748 controls (1:3) by age, gender, health center, and recruitment date. Only adults of European origin were included. Participants were stratified by aspirin exposure and genotype [(Aspirin(−), wild-type), (Aspirin(+), wild-type), (Aspirin(+), genetic variation), (Aspirin(−), genetic variation)]. For each SNP, the Odds Ratio of UGIH and their 95% confidence intervals were estimated in each subgroup by using the generalized linear mixed models for dependent binomial variables. SNP-aspirin interaction effect was estimated through Relative Excess Risk due to Interaction (RERI) measures.ResultsWe observed two categories of SNPs that might modify the risk magnitude of UGIH in aspirin consumers. Seven SNPs (rs1387180 A > G, rs2238631 T > C, rs1799964 T > C, rs5050 T > C/T > G, rs689466 T > C, rs1799983 T > A/T > G, and rs7756935 C > A) were “positive modifiers” associated with an excess of risk from aspirin exposure and carrying that genetic variation (1.75 ≤ RERI ≤ 4.95). On the contrary, the following nine SNPs (rs2243086 G > T, rs1131882 G > A, rs4311994 C > T, rs10120688 G > A, rs4251961 T > C, rs3778355 G > C, rs1330344 C > T, rs5275 A > G/A > T, and rs3779647 C > T) were “negative modifiers” and associated with a reduced risk in aspirin users (−2.74 ≤ RERI ≤ −0.95). ConclusionThis preliminary study suggests that polymorphisms in genes involved in platelets activity, angiogenesis and inflammatory response might modify the risk of aspirin-related UGIH. Further studies with larger sample size and in different populations are needed to confirm our findings. If confirmed, this might have great impact on public health, thanks to aspirin’s prophylactic properties in diseases of high incidence and severity.
Highlights
Aspirin is one of the most commonly used medicines worldwide due to its broad spectrum of health benefits such as analgesic, anti-inflammatory and antiplatelet properties (Thorat and Cuzick, 2015)
The controls were in equilibrium with respect to the corresponding single-nucleotide polymorphisms (SNPs) as confirmed by the manual inspection of the clusters’ plots and the Hardy-Weinberg equilibrium (HWE) analysis (p < 0.001)
No conclusive interpretation could be done about the following 8 SNPs due to the limited number of cases and controls who were aspirin users and carriers of these genetic variations (< 5 subjects in one of the groups): rs2502488, rs1800629, rs361525, rs1143627, rs16944, rs3842787, rs3842788 and rs5788. This is the first and largest case-control study that assesses the effect of a large number of SNPs in multiple genes involved in platelet aggregation angiogenesis and inflammatory response on the risk of aspirin-related upper gastrointestinal hemorrhage (UGIH), and that explores the excess of risk from SNPs-aspirin interaction
Summary
Aspirin is one of the most commonly used medicines worldwide due to its broad spectrum of health benefits such as analgesic, anti-inflammatory and antiplatelet properties (Thorat and Cuzick, 2015). Patients on aspirin treatment may manifest idiosyncratic reactions to this drug and may be at risk of bleeding, which limit the widespread use of aspirin as prophylactic of many diseases, despite its effectiveness and low cost (Thorat and Cuzick, 2015). Gastrointestinal bleeding is a frequent clinically relevant adverse effect in patients on low-dose aspirin treatment. Several cohort studies and meta-analyses have demonstrated that low-dose aspirin increases the risk of gastrointestinal bleeding between 37% and 85% (Sutcliffe et al, 2013; Whitlock et al, 2015; Whitlock et al, 2016; Raju et al, 2016; Luo et al, 2019; Haykal et al, 2019). We aimed to evaluate the role of 25 SNPs in multiple genes involved in platelet activation, angiogenesis and inflammatory response in aspirin-related UGIH
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