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Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms

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Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms Journal of Personalized Medicine Article Influence of SH2B3, MTHFD1L, GGCX, and ITGB3 Gene Polymorphisms on theVariability on Warfarin Dosage Requirements and Susceptibility to CVD in the Jordanian Population Laith N. AL-Eitan 1,2,* , Ayah Y. Almasri 1, Rame H. Khasawneh 3 and Mansour A. Alghamdi 4,5 1 Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; [email protected] 2 Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan 3 Department of Hematopathology, King Hussein Medical Center (KHMC), Jordan Royal Medical Services (RMS), Amman 11118, Jordan; [email protected] 4 Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia; [email protected] 5 Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia * Correspondence: [email protected]; Tel.: +962-2-7201000 (ext. 23464); Fax: +962-2-7201071 Received: 10 August 2020; Accepted: 7 September 2020; Published: 9 September 2020 Abstract: The purpose of this study was to investigate the effects of the SH2B3, MTHFD1L, GGCX, and ITGB3 gene variants on the efficacy of warfarin treatment and its effects on the risk of cardiovascular disorders in Jordanian patients. The selected genes and their polymorphisms are involved in many Genome-Wide Association Study (GWAS) associated with cardiovascular disease and the variability of warfarin therapy. The current study conducted a genetic association and pharmacogenetics study in (212) Jordanian cardiovascular patients treated with warfarin and (213) healthy controls. DNA extraction and the Mass ARRAY™ system were used to genotype ten selected polymorphisms within four genes (SH2B3, MTHFD1L, GGCX, and ITGB3). This study confirmed a genetic association of MTHFD1L rs6922269 Single Nucleotide Polymorphism (SNP) with warfarin sensitivity during the initial and stabilization phases of treatment. Moreover, this SNP showed significant differences in the initial and maintenance doses of warfarin. This study also found an association between the genetic haplotypes (AGC and GAT) within the SH2B3 gene and responsiveness to warfarin. However, possession of an MTHFD1L rs491552 variant allele was found to affect the outcome measure of the international normalized ratio (INR) during the stabilization phase of warfarin treatment. In contrast, there was no association between all selected SNPs and susceptibility to cardiovascular disorders. This study extends the current understanding of the high variability of the warfarin response, including variability in dose requirements and susceptibility to cardiovascular disease in the Jordanian-Arab population. Other studies on a larger sample and in different ethnic groups could help to better understand the pharmacogenetics of warfarin and its application in personalized medicine. Keywords: warfarin; warfarin dose; cardiovascular disease; pharmacogenetics; INR; MTHFD1L; SH2B3 1. Introduction The term “pharmacogenetics” was developed in 1959 and defined as “the study of the variability of genome structure in response to drugs due to heredity”; since that time, numerous studies have J. Pers. Med. 2020, 10, 117; doi:10.3390/jpm10030117 www.mdpi.com/journal/jpm J. Pers. Med. 2020, 10, 117 2 of 14 been conducted to investigate the effects of genetic variants in the drug responses among individuals. However, warfarin is one of the best-known drugs for having a high variability in responses due to individual genetic variants [1,2]. Although it is the most commonly prescribed anticoagulant drug for the treatment of many cardiovascular diseases, including deep vein thrombosis, arterial thromboembolism, and heart valve replacement [3], the adjustment of warfarin doses has been complicated, due to its narrow therapeutic range, which was associated with bleeding or thrombosis in high or low doses, respectively [4]. Thus, regular monitoring of the anticoagulation status should be performed for each patient by measuring the international normalized ratio (INR) [5]. In addition to the environmental factors that include age, body mass index, smoking, gender, vitamin inducers, concomitant medication, and diet, genetic factors and ethnic characteristics affect the pharmacokinetics and pharmacodynamics of warfarin and lead to changes in the efficacy and safety between individuals [6]. Consequently, several studies on the pharmacogenetics of warfarin have been carried out, and it has been shown that the polymorphisms of some genes play an important role in predicting the warfarin dose. However, the most commonly studied genes were the VKORC1 gene (encoding vitamin K epoxide reductase complex subunit 1), which is the target of warfarin, and the CYP2C9 gene (cytochrome P450 superfamily) responsible for S-warfarin metabolism and clearance [7–9]. Recent studies have shown that polymorphisms in various genes are responsible for the variability of warfarin response and, therefore, have a significant effect on the warfarin required dose [10,11]. Among them, GGCX (gamma-glutamyl carboxylase), CYP4F2 (cytochrome P450, family 4, subfamily F, polypeptide 2), ApoE (apolipoprotein E), and FVII (blood clotting factor VII) are genes that can help predict a stable therapeutic dose of warfarin [11–15]. Recently, several algorithms have been proposed to predict the appropriate warfarin dose for each patient by combining the CYP2C9 and VKORC1 variants with other clinical and environmental factors [16,17].In fact, there are many complications and challenges in the exchange of personal medicine into clinical settings, especially in the Arab population [18,19]. Therefore, it is necessary to expand studies on candidate genes involved in the pharmacokinetics and pharmacodynamics of warfarin to improve both the efficacy and safety of drugs. Examining several genes that affect warfarin metabolism and are involved in cardiovascular disease (CVD) may help to provide more accurate treatment by reducing the side effects [18,20]. For this reason, four genes (SH2B3, MTHFD1L, GGCX, and ITGB3) were analyzed to determine their influence on CVD risk, warfarin sensitivity, and responsiveness. The SH2B3 gene belongs to the SH2B adaptors family. This gene is located on chromosome 12 (12k24) and encodes the SH2B3 protein, which is responsible for the negative regulation of cytokine signaling [21]. However, it has been shown that genetic variability in this region is associated with multiple symptoms, including type one diabetes, risk of coronary heart disease, and myocardial infarction [22,23]. The methylene-tetrahydrofolate dehydrogenase (NADP + -dependent) 1-like gene (MTHFD1L) is involved in the mitochondrial metabolism of tetrahydrofolate [24]. However, the polymorphism of this gene is closely related to the development of coronary heart disease (CHD), as found in a recent meta-analysis [25]. Moreover, a family study reported that a significant association was found between MTHFD1L polymorphism and the risk of myocardial infarction (MI) [26]. The γ-glutamyl carboxylase (GGCX) gene encodes the main enzyme responsible for carboxylation of the glutamic acid residue in the vitamin K-dependent coagulation factor to obtain its activity. Thus, polymorphisms, including this gene, can affect the coagulation factor cascade, and, therefore, it can lead to variability on an individual’s susceptibility to stroke disease [27]. The ITGB3 gene encodes the beta integrin subunit; this subunit, together with the alpha subunit encoding by ITGA2B, are involved in some of the specific platelet receptors for fibrinogen, a protein that regulates platelet aggregation, thrombosis, and hemostasis [28,29]. However, it was discovered that the ITGB3 gene was a highly polymorphic region, and some of these polymorphisms were associated with cardiovascular diseases [30]. The objective of the present study was to demonstrate the impacts of SH2B3, MTHFD1L, GGCX, and ITGB3 polymorphisms on the risk of CVD and the warfarin sensitivity and responsiveness in Jordanian patients. J. Pers. Med. 2020, 10, 117 3 of 14 2. Materials and Methods 2.1. Study Population The study population included 425 subjects, of whom 212 were irrelevant warfarin outpatients recruited from the Anticoagulation Clinic at the Queen Alia Heart Institute (QAHI) in Amman, Jordan, and the remaining 213 were healthy noncardiovascular control groups. All participants accompanied the written consent of the Arab-Jordanian population. This study was approved by the Human Research Committees of the Jordan University of Science and Technology in Irbid and the Royal Medical Services of Amman. The enrolled patients met the following inclusion criteria: (1) patients who received warfarin for at least three months, (2) who undergo the anticoagulation clinic regularly, and (3) are older than 18 years. The most important exclusion criteria included: (1) patients without written consent or registered clinical data, (2) the use of CYP2C9 inhibitors or induction drugs, (3) get concomitant medications that are interacting with warfarin, (4) alcohol consumption, and (5) pregnant women. 2.2. Data Collection and Follow-Up Time Blood samples were taken to obtain the INR value and to genotype the selected SNPs. The medical records include the average weekly warfarin dose and INR values, indication for warfarin, bleeding events, and concomitant medication and demographic information (gender, smoking status, age, and body mass index) reported during
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