The Implication of the Polymorphisms of COX-1, UGT1A6, and CYP2C9 among Cardiovascular Disease (CVD) Patients Treated with Aspirin

Abstract

PURPOSE: Enzymes potentially responsible for the pharmacokinetic variations of aspirin include cyclooxygenase-1 (COX-1), UDP-glucuronosyltransferase (UGT1A6) and P450 (CYP) (CYP2C9). We therefore aimed to determine the types and frequencies of variants of COX-1 (A-842G), UGT1A6 (UGT1A6*2; A541G and UGT1A6*3; A522C) and CYP2C9 (CYP2C9*3; A1075C) in the three major ethnic groups in Malaysia. In addition, the role of these polymorphisms on aspirin-induced gastritis among the patients was investigated. METHODS: A total of 165 patients with cardiovascular disease who were treated with 75-150 mg daily dose of aspirin and 300 healthy volunteers were recruited. DNA was extracted from the blood samples and genotyped for COX-1 (A-842G), UGT1A6 (UGT1A6*2 and UGT1A6*3) and CYP2C9 (CYP2C9*3; A1075C) using allele specific polymerase chain reaction (AS-PCR). RESULTS: Variants UGT1A6*2,*3 and CYP2C9*3 were detected in relatively high percentage of 22.83%, 30.0% and 6.50%, respectively; while COX-1 (A-842G) was absent. The genotype frequencies for UGT1A6*2 and *3 were significantly different between Indians and Malays or Chinese. The level of bilirubin among patients with different genotypes of UGT1A6 was significantly different (p-value < 0.05). In addition, CYP2C9*3 was found to be associated with gastritis with an odd ratio of 6.8 (95 % Cl OR: 1.39 – 33.19; P = 0.033). CONCLUSION: Screening of patients with defective genetic variants of UGT1A6 and CYP2C9*3 helps in identifying patients at risk of aspirin induced gastritis. However, a randomised clinical study of bigger sample size would be needed before it is translated to clinical use.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…For a more in-depth understanding of these DEGs, we analyzed the selected genes for GO and REACTOME pathway enrichment analyses and found that GO terms and signaling pathways were significant. [106], FCN1 [107], CARNS1 [108], AMH (anti-Mullerian hormone) [109], E2F1 [110], PF4 [111], RPL3L [112], TRIM72 [113], HOXB4 [114], TP73 [115], KCNH2 [116], (advanced glycosylation end-product specific receptor) [117], SMPD3 [118], TYMP (thymidine phosphorylase) [119], RIPPLY3 [120], GREM1 [121], CYP11B2 [122], MYLK2 [123], WNT3A [124], MSX1 [125], COMP (cartilage oligomeric matrix protein) [126], FLI1 [127], ACTA1 [128], TCAP (titincap) [129], TUBB1 [130], TNNI3 [131], HSPB7 [132], DES (desmin) [133], RAP1B [134], TNNT1 [135], BHMT (betaine--homocysteine S-methyltransferase) [136], ANGPTL3 [137], CYP3A5 [138], KMO (kynurenine 3-monooxygenase) [139], HMGCS2 [140], AGXT2 [141], FABP1 [142], SLC22A12 [143], CUBN (cubilin) [144], MIOX (myo-inositol oxygenase) [145], FBP1 [146], ARG2 [147], FGF1 [148], CRY1 [149], PPARGC1A [150], UGT1A6 [151], ECHDC3 [152], CYP2C8 [153], ACOX2…”

Cilostazol combined with P2Y12 receptor inhibitors: A substitute antiplatelet regimen for aspirin‐intolerant patients undergoing percutaneous coronary stent implantation

“…Polymorphisms of enzymes like UDP-glycolaldehyde transferase, cytochrome P450, and heterologous/medium-chain fatty acid CoA ligase were thought to be the underlying mechanism of aspirin intolerance. 32,33 Cilostazol is a specific and strong inhibitor of PDE3 in platelets and smooth muscle cells, where it diminishes intracellular calcium.…”

“…The mechanism of aspirin intolerance has not been well explained yet. Polymorphisms of enzymes like UDP‐glycolaldehyde transferase, cytochrome P450, and heterologous/medium‐chain fatty acid CoA ligase were thought to be the underlying mechanism of aspirin intolerance 32,33 …”

Genetic Testing for Opioid Pain Management: A Primer

“…CYP2C9 metabolism primarily involves NSAIDs and aspirin, though it is also the system that metabolizes phenytoin and warfarin. A recent study noted that the genetic screening of patients for defective variants of UGT1A6 (see below) and CYP2C9 helped identify those patients at risk for gastritis from aspirin use [ 37 ]. Up to 31 defective variants of the CYP2C9 have been found to cause reduced clearance of diclofenac [ 38 ], potentially increasing the risk of GI and renal adverse events.…”