Influence of  CYP4F2 ,  ApoE , and  CYP2A6  gene polymorphisms on the variability of Warfarin dosage requirements and susceptibility to cardiovascular disease in Jordan

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Abstract

Cardiovascular diseases are among the leading causes of death worldwide. Many of those diseases require treatment with warfarin, an anticoagulant that has a large high inter and intra-variability in the required doses. The aim of this study is to find if there are any associations between rs2108622 of CYP4F2, rs7412 and rs405509 of ApoE, and rs1801272 of CYP2A6, and CVD and warfarin dose variability. The selected genes and their polymorphisms are involved in many GWAS associated with cardiovascular disease and variability in warfarin treatment. The study sample consisted of 212 Jordanian Cardiovascular patients and 213 healthy controls. DNA was extracted and the Mass ARRAY™ system was used to genotype four selected SNPs within three genes ( CYP4F2, ApoE, and CYP2A6). Only one out of the four selected SNPs ( ApoE rs7412 SNP) was found to be associated with the risk of cardiovascular disease. Also, this SNP showed significant differences in warfarin initial doses. CYP2A6 rs1801272 SNP was found to be associated with warfarin sensitivity during the initiation phase of therapy and with warfarin responsiveness and INR measurement during the stabilization phase of therapy. This study improves the current understanding of the high inter and intra-variabilities in response to warfarin, including the variety of dosing requirements and the susceptibility to cardiovascular disease in the Jordanian Arab population. Further study on a larger sample and in different ethnic groups could help in improving our understanding of warfarin's pharmacogenetics and its application in personalized medicine.

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Large-scale association analysis identifies new risk loci for coronary artery disease.

Panos Deloukas, Stavroula Kanoni, Christina Willenborg … (2013)

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

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Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

Mitchell Higashi (2002)

Warfarin is a commonly used anticoagulant that requires careful clinical management to balance the risks of overanticoagulation and bleeding with those of underanticoagulation and clotting. The principal enzyme involved in warfarin metabolism is CYP2C9, and 2 relatively common variant forms with reduced activity have been identified, CYP2C9*2 and CYP2C9*3. Patients with these genetic variants have been shown to require lower maintenance doses of warfarin, but a direct association between CYP2C9 genotype and anticoagulation status or bleeding risk has not been established. To determine if CYP2C9*2 and CYP2C9*3 variants are associated with overanticoagulation and bleeding events during warfarin therapy. Retrospective cohort study conducted at 2 anticoagulation clinics based in Seattle, Wash. Two hundred patients receiving long-term warfarin therapy for various indications during April 3, 1990, to May 31, 2001. Only patients with a complete history of warfarin exposure were included. Anticoagulation status, measured by time to therapeutic international normalized ratio (INR), rate of above-range INRs, and time to stable warfarin dosing; and time to serious or life-threatening bleeding events. Among 185 patients with analyzable data, 58 (31.4%) had at least 1 variant CYP2C9 allele and 127 (68.6%) had the wild-type (*1/*1) genotype. Mean maintenance dose varied significantly among the 6 genotype groups (*1/*1 [n = 127], *1/*2 [n = 28], *1/*3 [n = 18], *2/*2 [n = 4], *2/*3 [n = 3], *3/*3 [n = 5]) (by Kruskall-Wallis test, chi(2)(5) = 37.348; P<.001). Compared with patients with the wild-type genotype, patients with at least 1 variant allele had an increased risk of above-range INRs (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.03-1.90). The variant group also required more time to achieve stable dosing (HR, 0.65; 95% CI, 0.45-0.94), with a median difference of 95 days (P =.004). In addition, although numbers were small for some genotypes, representing potentially unstable estimates, patients with a variant genotype had a significantly increased risk of a serious or life-threatening bleeding event (HR, 2.39; 95% CI, 1.18-4.86). The results of our study suggest that the CYP2C9*2 and CYP2C9*3 polymorphisms are associated with an increased risk of overanticoagulation and of bleeding events among patients in a warfarin anticoagulation clinic setting, although small numbers in some cases would suggest the need for caution in interpretation. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving warfarin.

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Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

Jack Ansell, Elaine Hylek, Sandra A. Jacobson … (2008)

This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the antithrombotic effect of the VKAs, the monitoring of anticoagulation intensity, and the clinical applications of VKA therapy and provides specific management recommendations. Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh the risks, burdens, and costs. Grade 2 recommendations suggest that the individual patient's values may lead to different choices. (For a full understanding of the grading, see the "Grades of Recommendation" chapter by Guyatt et al, CHEST 2008; 133:123S-131S.) Among the key recommendations in this article are the following: for dosing of VKAs, we recommend the initiation of oral anticoagulation therapy, with doses between 5 mg and 10 mg for the first 1 or 2 days for most individuals, with subsequent dosing based on the international normalized ratio (INR) response (Grade 1B); we suggest against pharmacogenetic-based dosing until randomized data indicate that it is beneficial (Grade 2C); and in elderly and other patient subgroups who are debilitated or malnourished, we recommend a starting dose of < or = 5 mg (Grade 1C). The article also includes several specific recommendations for the management of patients with nontherapeutic INRs, with INRs above the therapeutic range, and with bleeding whether the INR is therapeutic or elevated. For the use of vitamin K to reverse a mildly elevated INR, we recommend oral rather than subcutaneous administration (Grade 1A). For patients with life-threatening bleeding or intracranial hemorrhage, we recommend the use of prothrombin complex concentrates or recombinant factor VIIa to immediately reverse the INR (Grade 1C). For most patients who have a lupus inhibitor, we recommend a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. We recommend that physicians who manage oral anticoagulation therapy do so in a systematic and coordinated fashion, incorporating patient education, systematic INR testing, tracking, follow-up, and good patient communication of results and dose adjustments [Grade 1B]. In patients who are suitably selected and trained, patient self-testing or patient self-management of dosing are effective alternative treatment models that result in improved quality of anticoagulation management, with greater time in the therapeutic range and fewer adverse events. Patient self-monitoring or self-management, however, is a choice made by patients and physicians that depends on many factors. We suggest that such therapeutic management be implemented where suitable (Grade 2B).

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Author and article information

Journal

Journal ID (nlm-ta): Int J Med Sci

Journal ID (iso-abbrev): Int J Med Sci

Journal ID (publisher-id): ijms

Title: International Journal of Medical Sciences

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1449-1907

Publication date Collection: 2021

Publication date (Electronic): 1 January 2021

Volume: 18

Issue: 3

Pages: 826-834

Affiliations

[1 ]Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan.

[2 ]Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan.

[3 ]Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan.

[4 ]Department of Hematopathology, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman 11118, Jordan.

[5 ]Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabi.

[6 ]Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia.

Author notes

✉ Corresponding author: Laith N. AL-Eitan; Department of Biotechnology & Genetic Engineering/Faculty of Science and Arts/Jordan University of Science and Technology; P.O.Box 3030, Irbid 22110, Jordan; Tel.: +962-2-7201000 ext.: 23464; E-mail: lneitan@ 123456just.edu.jo .

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: ijmsv18p0826

DOI: 10.7150/ijms.51546

PMC ID: 7797549

PubMed ID: 33437219

SO-VID: 84451c45-8ecf-49fb-b0f9-2c6c2eaa6ff0

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This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Influence of CYP4F2, ApoE, and CYP2A6 gene polymorphisms on the variability of Warfarin dosage requirements and susceptibility to cardiovascular disease in Jordan

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Most cited references 55

Large-scale association analysis identifies new risk loci for coronary artery disease.

Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.

Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

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