Deep sequencing of prostaglandin‐endoperoxide synthase (<i>PTGE)</i> genes reveals genetic susceptibility for cross‐reactive hypersensitivity to NSAID

García‐Martín, Elena; García-Menaya, Jesús Miguel; Esguevillas, Gara; Cornejo-García, J.A.; Doña, Inmaculada; Jurado‐Escobar, Raquel; Torres, Marı́a José; Blanca‐López, Natalia; Cantó, Gabriela; Blanca, Miguel; Laguna, José Julio; Bartra, Joan; Rosado, A.; Fernández, J.; Cordobés, Concepción; Agúndez, José A. G.

doi:10.1111/bph.15366

Cited by 9 publications

(5 citation statements)

References 74 publications

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“…The role of COX-1 inhibition in the etiopathogenesis of crosshypersensitivity to NSAIDs has been the object of controversy for years (Kowalski et al, 2007;Doña et al, 2018;Mastalerz et al, 2019). Supporting this hypothesis, it has been shown that COX-2 inhibitors are well tolerated among patients with crosshypersensitivity to NSAIDs (Morales et al, 2014;Bakhriansyah et al, 2019) and that patients with PTGS1 gene variants related to a decreased activity (Agúndez et al, 2014;Agúndez et al, 2015b;Lucena et al, 2019) are at increased risk of developing crosshypersensitivity to NSAIDs (García-Martín et al, 2021). Interestingly, preliminary evidence suggests that crosshypersensitivity to NSAIDs is dose-dependent (Palmer, 2005;Kong et al, 2007;Kowalski et al, 2013;Blumenthal et al, 2017) and, therefore, it could be speculated that individuals with impaired NSAID clearance (and therefore increased drug exposure) might have increased risk of developing cross-hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs

Macías¹,

García-Menaya

Martí³

et al. 2021

Front. Pharmacol.

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Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.

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Section: Discussionmentioning

confidence: 99%

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs

Macías¹,

García-Menaya

Martí³

et al. 2021

Front. Pharmacol.

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“…Most studies have focused on evaluating AA pathway-related variants or immune cell activation. 115,116 In NERD, variants in genes associated with LT production (5-Lipoxygenase, 5-LOX) and LTC4 synthase and PGs production (COX) pathways were reported. 115 Available data show that NECD and NIUA share similar genetic backgrounds; nevertheless, different gene polymorphisms have been reported.…”

Section: B I Omark Er S In N Saids Cross -Hyper Sen Sit Ivit Ymentioning

confidence: 99%

“…Genetic variants have been associated with NSAID hypersensitivity, being distinct in patients experiencing respiratory or cutaneous symptoms although most of them have not been replicated. Most studies have focused on evaluating AA pathway‐related variants or immune cell activation 115,116 . In NERD, variants in genes associated with LT production (5‐Lipoxygenase, 5‐LOX) and LTC4 synthase and PGs production (COX) pathways were reported 115 .…”

Section: Biomarkers In Nsaids Cross‐hypersensitivitymentioning

confidence: 99%

Biomarkers of immediate drug hypersensitivity

Mayorga,

Ariza,

Muñoz‐Cano

et al. 2023

Allergy

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Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the health systems. This problem increases when taking into account that only a small proportion of patients initially labelled as allergic are finally confirmed after an allergological workup. The diverse nature of drugs involved will imply different interactions with the immunological system. Therefore, IDHRs can be produced by a wide array of mechanisms mediated by the drug interaction with specific antibodies or directly on effector target cells. These heterogeneous mechanisms imply an enhanced complexity for an accurate diagnosis and the identification of the phenotype and endotype at early stages of the reaction is of vital importance. Currently, several endophenotypic categories (type I IgE/non‐IgE, cytokine release, Mast‐related G‐protein coupled receptor X2 (MRGPRX2) or Cyclooxygenase‐1 (COX‐1) inhibition and their associated biomarkers have been proposed. A precise knowledge of endotypes will permit to discriminate patients within the same phenotype, which is crucial in order to personalise diagnosis, future treatment and prevention to improve the patient's quality of life.

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“…However, it shares with NSAIDs their antipyretic and analgesic properties as well as adverse drug events, such as hypersensitivity events in their two main clinical forms (selective hypersensitivity and cross-hypersensitivity) [ 4 , 5 , 6 , 7 ]. In addition, acetaminophen causes idiosyncratic drug-induced liver injury (iDILI) [ 8 , 9 , 10 ], as NSAIDs do, and it has been hypothesized that functional genetic variations in the COX-enzymes are related to iDILI risk and cross-hypersensitivity to COX-inhibitors [ 11 , 12 , 13 , 14 , 15 ], thus suggesting that patients with impaired COX activity are more prone to developing adverse drug events when using COX inhibitors [ 14 , 15 ]. Acetaminophen is also related to dose-dependent acute liver failure.…”

Section: Introductionmentioning

confidence: 99%

Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

Cerezo-Arias

Gómez-Tabales

Martí

et al. 2022

JPM

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Acetaminophen (paracetamol) is a widely used drug that causes adverse drug events that are often dose-dependent and related to plasma drug concentrations. Acetaminophen metabolism strongly depends on UGT1A enzymes. We aimed to investigate putative factors influencing acetaminophen pharmacokinetics. We analyzed acetaminophen pharmacokinetics after intravenous administration in 186 individuals, and we determined the effect of sex; body mass index (BMI); previous and concomitant therapy with UGT1A substrates, inhibitors, and inducers; as well as common variations in the genes coding for UGT1A1, UGT1A6, and UGT1A9. We identified sex and UGT1A6 genetic variants as major factors influencing acetaminophen pharmacokinetics, with women showing lower clearance (p < 0.001) and higher area under the plasma drug concentration-time curve (AUC) values than men (p < 0.001). UGT1A6 genetic variants were related to decreased acetaminophen biodisposition. Individuals who were homozygous or double-heterozygous for variant UGT1A6 alleles showed a 22.5% increase in t1/2 values and a 22.8 increase in drug exposure (p < 0.001, and 0.006, respectively) after correction by sex. The effect is related to the UGT1A6*2 and UGT1A6*4 variant alleles, whereas no effect of UGT1A6*3 and UGT1A9*3 alleles, BMI, or drug–drug interaction was identified in this study. We conclude that sex and UGT1A6 variants determine acetaminophen pharmacokinetics, thus providing evidence to eventually developing pharmacogenomics procedures and recommendations for acetaminophen use.

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Deep sequencing of prostaglandin‐endoperoxide synthase (PTGE) genes reveals genetic susceptibility for cross‐reactive hypersensitivity to NSAID

Cited by 9 publications

References 74 publications

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs

Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs

Biomarkers of immediate drug hypersensitivity

Common UGT1A6 Variant Alleles Determine Acetaminophen Pharmacokinetics in Man

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