Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort

Shahabi, Payman; Lamothe, Félix; Dumas, S.; Rouleau-Mailloux, Étienne; Zada, Yassamin Feroz; Provost, Sylvie; Asselin, Géraldine; Mongrain, Ian; Valois, Diane; Marion, Marie-Josée Gaulin; Perreault, Louis‐Philippe Lemieux; Perreault, Sylvie; Dubé, Marie‐Pierre

doi:10.1038/s41397-017-0005-1

Cited by 6 publications

(4 citation statements)

References 53 publications

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“…Although it may not be possible to measure epigenetic factors, it seems likely that they make some contribution. For example, variants in the vitamin D receptor or pregnane X receptor genes have been associated with the variability in response to warfarin …”

Section: Discussionmentioning

confidence: 99%

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Shah

2020

J Clin Pharm Ther

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What is known and objective: Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so. Methods:Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. Results and discussion: Critical examination of major warfarin pharmacogenetic studies identified a number of methodological concerns such as marked variations in study designs with different variously-defined measures of outcome. Genotype testing involved only a limited number of CYP2C9/VKORC1 alleles. Claims of benefits of genotyping are based almost exclusively on INR-related parameters which are known to be highly time-labile and of limited value in predicting clinical risk orbenefit. This is evidenced by lack of any significant effect of genotyping on rates of bleeding or thromboembolic events. Neither have the effects of potential phenoconversion or medication non-adherence in study populations been adequately investigated. Although the effect of ethnicity/race is now better characterised, studies lack the power to determine whether any benefits claimed are indication-sensitive. What is new and conclusion:Since 60% of inter-individual variability in warfarin dose/ response is due to other factors (many of which are non-genetic), expectations of eliminating this variability simply by CYP2C9/VKORC1 genotyping are over-optimistic and efforts cost-ineffective. Real-world studies have not always corroborated trialsbased claims of clinical benefit. It is time to consider redirecting scarce resources away from the study of warfarin pharmacogenetics to pharmacogenetic research of potentially greater clinical relevance.

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Section: Discussionmentioning

confidence: 99%

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Shah

2020

J Clin Pharm Ther

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“…Interestingly, mutations located in GATA4-binding sites dramatically decreased this induction (Mwinyi et al, 2009[ 27 ]). A recent investigation described that polymorphisms in nuclear receptor genes are potentially associated with alteration in CYP2C9 expression and altered drug metabolism (Shahabi et al, 2018[ 39 ]). Genetics variations in GATA4 have been postulated to play a significant role in the inter-individual variability in drug response (Van Schie et al, 2012[ 47 ]).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous other genes including the microsomal epoxide hydroxylase ( EPHX1 ), γ-glutamyl carboxylase ( GGCX ), calumenin ( CALU ) and GATA binding protein 4 ( GATA4 ), also have been implicated to determine the inter-individual variability in warfarin response (Mwinyi et al, 2009[ 27 ]; Shahabi et al, 2018[ 39 ]). To our knowledge, few studies have directly investigated the effect of 3′-untranslated region (3′UTR) SNPs of warfarin-related genes on clinical outcomes such as the incidence of bleeding events due to warfarin therapy.…”

Section: Introductionmentioning

confidence: 99%

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications

Hosseindokht

Boroumand

Salehi

et al. 2019

EXCLI Journal; 18:Doc287; ISSN 1611-2156

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“…Anticoagulation is a key treatment for patients with VHD after valve replacement. Interestingly, long-term anticoagulation therapy with warfarin can influence DNA methylation of the BNP gene in RHD patients undergoing mechanical heart valve replacement therapy reported in our previous studies [ 16 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 88%

BMPR2 promoter methylation and its expression in valvular heart disease complicated with pulmonary artery hypertension

Zhu

et al. 2021

Aging

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Valvular heart disease (VHD) is a common heart disease that affects blood flow. It usually requires heart surgery. Valvular heart disease complicated with pulmonary artery hypertension (VHD-PAH) may be lethal due to heart failure that results from increased heart burden. It is important for these patients to seek early treatment in order to minimize the heart damage. However, there is no reliable diagnosis method in VHD. In this study, we found DNA methylation was increased at the promoter of BMPR2 gene in the VHD patients compared with the healthy controls. This finding was confirmed by an independent cohort study of VHD patients and healthy controls. In addition, BMPR2 mRNA levels were reduced in the plasma of the VHD patients. There is strong correlation between BMPR2 promoter DNA methylation and the severity of VHD. Indeed, we found that both BMPR2 promoter DNA methylation and BMPR2 mRNA levels in the plasma are good biomarkers of VHD by themselves, with the respective AUC value of 0.879 and 0.725, respectively. When they were used in combination, the diagnostic value was even better, with the AUC value of 0.93. Consistent with the results in the VHD patients, we observed decreased BMPR2 and increased fibrosis in the lung of a PAH model mouse. BMPR2 was also decreased in the hearts of the PAH mice, whereas BMP4 was increased. Furthermore, BMPR2 was reduced in the heart valve tissue samples of human VHD patients after valve replacement with moderate/severe PAH compared with those with mild PAH. There was also increased apoptosis in the hearts of the PAH mice. BMPR2 promoter DNA methylation and its expression appear to be good biomarkers for VHD. Our results also suggest that DNA methylation may cause PAH through deregulation of BMP signaling and increased apoptosis.

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Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort

Cited by 6 publications

References 53 publications

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications

BMPR2 promoter methylation and its expression in valvular heart disease complicated with pulmonary artery hypertension

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