VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

Misasi, Silvia; Martini, Giuliana; Paoletti, Oriana; Calza, Stefano; Scovoli, Giovanni; Marengoni, Alessandra; Testa, Sophie; Caimi, Luigi; Marchina, Eleonora

doi:10.1097/md.0000000000005451

Cited by 13 publications

(15 citation statements)

References 40 publications

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“…For example, in addition to clinical variables, genetic variation of cytochrome P450 2C9 (a warfarin metabolism enzyme, has also been strongly associated with warfarin-resistant phenotype. 57 The general consistency of our MD-simulation results, along with the cell-based experimental data, not only help us to understand the mechanism of warfarin inhibition of VKOR, but also provide important clues to help explain warfarin-resistant clinical phenotypes and design safer anticoagulant drugs for treating disorders involving vitamin K metabolism.…”

Section: Discussionmentioning

confidence: 58%

Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition

Chen

Jin

et al. 2018

Blood

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Vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K-dependent carboxylation, a posttranslational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant, warfarin. However, the topological structure of VKOR and the mechanism of warfarin's inhibition of VKOR remain elusive. Additionally, it is not clear why warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin's binding affinity, but have only a minor effect on vitamin K binding. Here, we used immunofluorescence confocal imaging of VKOR in live mammalian cells and PEGylation of VKOR's endogenous cytoplasmic-accessible cysteines in intact microsomes to probe the membrane topology of human VKOR. Our results show that the disputed loop sequence between the first and second transmembrane (TM) domain of VKOR is located in the cytoplasm, supporting a 3-TM topological structure of human VKOR. Using molecular dynamics (MD) simulations, a T-shaped stacking interaction between warfarin and tyrosine residue 139, within the proposed TYA warfarin-binding motif, was observed. Furthermore, a reversible dynamic warfarin-binding pocket opening and conformational changes were observed when warfarin binds to VKOR. Several residues (Y25, A26, and Y139) were found essential for warfarin binding to VKOR by MD simulations, and these were confirmed by the functional study of VKOR and its mutants in their native milieu using a cell-based assay. Our findings provide new insights into the dynamics of the binding of warfarin to VKOR, as well as into warfarin's mechanism of anticoagulation.

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Section: Discussionmentioning

confidence: 58%

Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition

Chen

Jin

et al. 2018

Blood

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“…They did not find any effect of using genetic algorithms on a reduction in the risk of thromboembolic events 12 . However, one candidate-gene study found that variants in VKORC1 and CYP2C9 were associated with thrombotic events, such as stroke, TIA, and venous thromboembolism, among others 13 . Furthermore, two studies that included patients from the Chinese Han population found that VKORC1 mutations were associated with a higher risk of cardiovascular diseases, including stroke 14,15 .…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain

Cullell

Carrera

Muiño³

et al. 2020

Sci Rep

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fàbregas 9 , Luis prats-Sánchez 9 , pol camps-Renom 9 , francisco purroy 10 , Serafi cambray 11 , María del Mar freijo 12 , cristòfol Vives-Bauzá 13 , Silvia tur 14 , Maria-Àngels font 15 , elena López-cancio 16,17 , Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (icH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In A p-value of <0.001 was considered statistically significant after correcting for the 49 polymorphisms evaluated (Bonferroni test).We also evaluated which SNPs were in linkage disequilibrium (R 2 > 0.8). For the SNPs significantly associated with ICH events, rs7197475, rs4889490 and rs10871454 were independents. For the SNPs significantly associated with stroke recurrence, rs8046001, rs741810 and rs4086116 were independents and for acenocoumarol maintenance dose analysis: rs17790434, rs10871454, rs8046001, rs11642466 and rs9332169 were independents.Moreover, we have generated weighted polygenic risk scores (GRS) based on the independent polymorphisms (R 2 < 0.8) from the Teichert et al. GWAs 6 and analysed it for association with acenocoumarol maintenance dose, ischemic stroke recurrence and ICH events. Each value was obtained as described in the Supplemental Information and in Cullell N et al. 28 , for weighted GRS.Survival analysis. We used the Survival package 29 in R (Version 3.5.1) to perform survival analysis using Cox regression curves. We included age as a covariate in the Cox regression analysis. Scientific RepoRtS |(2020) 10:2806 | https://doi.

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“…1 , Table 1 ). Further, genetic variation in the VKORC1 gene also predicts warfarin dosing and response 39 . A low activity T allele of rs9923231 in the VKORC1 is very common in East Asians (0.95; EAS) compared to Europeans (0.40; NFE) and South Asians [0.20 (Sikhs and SAS) and 0.19 (GIH)], and was lowest (0.06) in African (YRI).…”

Section: Discussionmentioning

confidence: 99%

Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin

Sanghera

Bejar

Sapkota

et al. 2018

Sci Rep

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Diversity in drug response is attributed to both genetic and non-genetic factors. However, there is paucity of pharmacogenetics information across ethnically and genetically diverse populations of India. Here, we have analyzed 21 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Indian origin (N = 1,616), as part of the Sikh Diabetes Study (SDS). We compared the allele frequency of poor metabolism (PM) phenotype among Sikhs across other major global populations from the Exome Aggregation Consortium and 1000 Genomes. The PM phenotype of CYP1A2*1 F for slow metabolism of caffeine and carcinogens was significantly higher in Indians (SDS 42%, GIH [Gujarati] 51%, SAS [Pakistani] 45%) compared to Europeans 29% (pgenotype = 5.3E-05). Similarly, South Asians had a significantly higher frequency of CYP2C9*3 (12% SDS, 13% GIH, 11% SAS) vs. 7% in Europeans (pgenotype = <1.0E-05) and ‘T’ allele of CYP4F2 (36%) SDS, (43%) GIH, 40% (SAS) vs. (29%) in Europeans (pgenotype = <1.0E-05); both associated with a higher risk of bleeding with warfarin. All South Asians –the Sikhs (0.36), GIH (0.34), and SAS (0.36) had a higher frequency of the NAT2*6 allele (linked with slow acetylation of isoniazid) compared to Europeans (0.29). Additionally, the prevalence of the low activity ‘C’ allele of MTHFR (rs1801131) was highest in Sikhs compared to all other ethnic groups [SDS (44%), GIH (39%), SAS (42%) and European (32%) (pgenotype = <1.0E-05)]. SNPs in MTHFR affect metabolism of statins, 5-fluorouracil and methotrexate-based cancer drugs. These findings underscore the need for evaluation of other endogamous ethnic groups of India and beyond for establishing a global benchmark for pre-emptive genotyping in drug metabolizing genes before beginning therapeutic intervention.

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VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients

Cited by 13 publications

References 40 publications

Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition

Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition

Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain

Frequencies of poor metabolizer alleles of 12 pharmacogenomic actionable genes in Punjabi Sikhs of Indian Origin

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