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

Abstract

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.

Genome-Wide Studies in Ischaemic Stroke: Are Genetics Only Useful for Finding Genes?

“…Paré et al investigated whether some genetic component accounted for the concentration of the active dabigatran metabolite and whether these genes were also implicated in the efficacy and safety of the drug using GWAS [ 137 ]. Polymorphisms in CES1 were associated with trough and peak metabolite concentration, while ABCB1 was found to be associated with peak concentration only.…”

“…Polymorphisms in CES1 were associated with trough and peak metabolite concentration, while ABCB1 was found to be associated with peak concentration only. ABCB1 is important for the entry of dabigatran-etexilate (prodrug form) into the blood and CES1 metabolizes dabigatran-etexilate to dabigatran to activate the drug [ 137 ]. In this GWAS, the CES1 polymorphism, which is associated with a 15% reduction in the trough metabolite concentration, was also linked with a decrease in any bleeding risk.…”

Genetics of Spontaneous Intracerebral Hemorrhage: Risk and Outcome

“…Actually, evidence has emerged that several genetic variants modulate certain pharmacological drugs which prevent stroke, such as antiplatelet agents and anticoagulants. Cullell et al (2020) found that several variants in CYP2C9 (encoding cytochrome P450 2C9) and VKORC1 (encoding vitamin K epoxide reductase complex subunit 1) associated with acenocoumarol (an oral anticoagulant) maintenance dose were also associated with ICH risk. Moreover, Falcone et al (2014) demonstrated that APOE ε2 and APOE ε4 were associated with warfarin related LICH ( Falcone et al, 2014 ).…”

Independent and Interactive Effects of Sex and CYP2C9 Variant rs4918758 on Ischemic Stroke Risk in Taiwan Biobank

“… 8 Additionally, there is evidence that polymorphisms in the CYP2CP gene are associated with stroke occurrence and recurrence in Spanish and Chinese populations. 9 , 10 …”