TABLE 2.
Notable genetic associations in NSAID-induced upper GI toxicity.
| Genetic loci | Therapy | Phenotype | Association | p-value | Or (95%CI) | References |
|---|---|---|---|---|---|---|
| CYP2C9 | NSAIDs—various | Endoscopically confirmed UGIB | CYP2C9*2 genotype (in heterozygosity or | p = 0.009 | Crude OR = 1.92 (95% CI = 1.14–3.25) | Martínez et al. (2004) |
| homozygosity) increases risk of GI bleeding | ||||||
| CYP2C9 | CYP2C9-metabolised | Endoscopically confirmed UGIB | Using CYP2C9*1/*1 wild type as control, significantly | Pilotto et al. (2007) | ||
| NSAIDs | higher frequencies of bleeding observed in | |||||
| CYP2C9*1/*3 | p = < 0.001 | OR = 12.9 (95% CI = 2.917–57.922) | ||||
| CYP2C9*1/*2 | p = 0.036 | OR = 3.8 (95% CI = 1.090–13.190) | ||||
| CYP2C9*3 allele carriers have significant risk of bleeding | Adjusted OR = 7.3 (95% CI = 2.058–26.004) | |||||
| CYP2C9 | Non-aspirin NSAIDs | Endoscopically confirmed | CYP2C9*3 loss-of-function allele associated with acute | p = 0.0002 | OR = 7.2 (95% CI = 2.6–20.3) | Carbonell et al. (2010) |
| ulcers/bleeding erosions | UGIB in NSAIDs other than aspirin | |||||
| CYP2C9 | CYP2C9-metabolised | Endoscopically confirmed | CYP2C9*3 variant increases risk of UGIB for defined daily doses >0.5 | CYP2C9*3 OR = 18.07 (95% CI = 6.34–51.53) | Figueiras et al. (2016) | |
| NSAIDs | erosions/lesions/UGIB | Adjusted OR | ||||
| CYP2C8 and CYP2C9 | CYP2C8/2C9-metabolised | Endoscopically confirmed UGIB | CYP2C8*3 and CYP2C9*2 exist in LD | Blanco et al. (2008) | ||
| NSAIDs | Combined CYP2C8*3 + CYP2C9*2 genotype associated with increased risk of bleeding | p = 0.003 | OR = 3.73 (95% CI = 1.57–8.88) | |||
| CYP2C19 | NSAIDs—various | Endoscopically confirmed UGIB | CYP2C19*17 associated with PUD, but not UGIB | p = 0.024 | OR (additive model) = 1.47 (95% CI = 1.12–1.92) | Musumba et al. (2013) |
| PUD distribution varied according to CYP2C19*17 genotype | ||||||
| *1/*1, 64.3%; *1/*17, 71.7%; *17/*17, 73.8% | ||||||
| COX-1 | Aspirin and ethanol | SNPs A-842G and C50T in complete LD | Halushka et al. (2003) | |||
| pre-treatment | Heterozygous A-842G/C50T haplotype shows significantly | p = 0.01 | ||||
| greater PG H (2) inhibition | ||||||
| COX-1 | Not stated | Endoscopically confirmed | A-842/C50T polymorphism has lower (yet non-significant) | OR = 0.5 (95% CI = 0.18–1.34) | van Oijen et al. (2006) | |
| bleeding GU or DU | Risk of PU bleeding compared to wild type | Adjusted* OR = 0.75 (95% CI = 0.19–3.01) | ||||
| Adjusted for: sex, age, smoking, NSAID/aspirin use, H. pylori infection | ||||||
| COX-2 | Aspirin (ASA) | Surgical or endoscopic UGIB | rs689466 T > C increases risk magnitude of UGIB in ASA users | Mallah et al. (2020) | ||
| diagnosis | Variant carriers taking ASA v wild-type carriers NOT taking ASA | p = 0.0022 | OR = 8.22 (95% CI = 2.14–31.59) | |||
| Variant carriers taking ASA v wild-type carriers taking ASA | p = 0.3036 | OR = 2.98 (95% CI = 0.37–23.96) | ||||
| OR adjusted as per Mallah et al. (2020) |
Abbreviations: ASA, (acetylsalicylic acid) aspirin; CI, confidence interval; DU, duodenal ulcer; GI, gastrointestinal; GU, gastric ulcer; LD, linkage disequilibrium; NSAID, non-steroidal anti-inflammatory drug; OR, odds ratio; PG H(2), prostaglandin H(2); PU, peptic ulcer; PUD, peptic ulcer disease; UGIB, upper gastrointestinal bleeding; SNP, single nucleotide polymorphism.