&lt;p&gt;Influence of PSRC1, CELSR2, and SORT1 Gene Polymorphisms on the Variability of Warfarin Dosage and Susceptibility to Cardiovascular Disease&lt;/p&gt;

AL-Eitan, Laith N.; Elsaqa, Barakat Z; Almasri, Ayah Y; Aman, Hatem A; Khasawneh, Rame; Alghamdi, Mansour A.

doi:10.2147/pgpm.s274246

Cited by 11 publications

(8 citation statements)

References 37 publications

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“…The involvement of SORT1 in the regulation of LDL has been widely reported in various nonruminant models (Ai et al, 2012;Uesaka et al, 2018;Al-Eitan et al, 2020;Zhang et al, 2020b). In mice, overexpression of SORT1 reduced VLDL-TAG synthesis and newly synthesized ApoB100, thereby decreasing plasma concentrations of APOB-containing lipoproteins and cholesterol (Strong et al, 2012).…”

Section: Discussionmentioning

confidence: 97%

Role of sortilin 1 (SORT1) on fatty acid–mediated cholesterol metabolism in primary calf hepatocytes

Wang

Jiang

Loor

et al. 2022

Journal of Dairy Science

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Ketosis is a common metabolic disorder in peripartal dairy cows that is caused by excessive mobilization of fat and incomplete hepatic metabolism of fatty acids (FFA). Recent data in nonruminant models revealed that sortilin 1 (SORT1) is involved in a variety of lipid metabolism-related diseases. It plays important roles in the regulation of triglyceride (TAG) and total cholesterol (TC) levels. In this study, we first used liver biopsies from healthy cows (serum β-hydroxybutyrate concentration <0.6 mM) and cows diagnosed with clinical ketosis (serum β-hydroxybutyrate concentration >3.0 mM) to assess alterations in cholesterol synthesis, transport, and excretion. Then, to assess mechanistic links between SORT1 and fatty acid-mediated cholesterol metabolism, hepatocytes isolated from 4 healthy female calves (1 d old, 35-45 kg) were challenged with or without a mixture of free fatty acids (FFA; 1.2 mM) to induce metabolic stress. Hepatocytes were then treated with empty adenovirus vectors (with green fluorescent protein; Ad-GFP) or with SORT1-overexpressing adenovirus (Ad-SORT1) for 6 h or with SORT1 inhibitor (SORT1i) for 2 h, followed by a challenge with (Ad-GFP+FFA, Ad-SORT1+FFA, or SORT1i+FFA) or without (Ad-GFP, Ad-SORT1, or SORT1i) 1.2 mM FFA mixture for 12 h. Data analysis of calf hepatocyte treatment comparisons were assessed by 2-way ANO-VA, and multiplicity for each experiment was adjusted using the Bonferroni procedure. Expression levels of factors related to cholesterol synthesis, transport, and excretion in liver tissue of cows with ketosis was lower. Hepatocytes challenged with FFA had lower concentrations of TC and mRNA and protein abundances of sterol regulatory element-binding protein 2 (SREBF2), acetyl acyl coenzyme A-cholesterol acyltransferase 2 (ACAT2), ATP-binding cassette transporter A1 (ABCA1), ABC subfamily G member 5 (ABCG5), and ABC subfamily G member 8 (ABCG8). Compared with FFA challenge alone, SORT1i + FFA led to greater protein abundance of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), ACAT2, and ABCG5, and greater mRNA abundance of ABCG5. Compared with FFA challenge alone, SORT1 overexpression led to lower protein abundance of SREBF2. In contrast, protein abundance of ABCA1 was greater. Overall, our data suggested that exogenous FFA induced abnormal cholesterol metabolism in hepatocytes, whereas a high abundance of SORT1 affected cholesterol esterification and potentially influx into bile. Thus, downregulation of hepatic SORT1 might be a cholesterol-regulated protective mechanism in the presence of a marked increase in FFA.

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Section: Discussionmentioning

confidence: 97%

Role of sortilin 1 (SORT1) on fatty acid–mediated cholesterol metabolism in primary calf hepatocytes

Wang

Jiang

Loor

et al. 2022

Journal of Dairy Science

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“…Regarding the pharmacogenetic part of this study, numerous warfarin pharmacogenetic studies indicated that the common polymorphisms of VKORC1 and CYP2C9 together with environmental and clinical factors account for more than half of the variation in the required warfarin dose 37 , 38 . We have recently published a study examining the effects of genetic polymorphism of CYP2C9 , VKORC1, FVII, PSRC1, CELSR2, and SORT1 on the sensitivity and responsiveness to warfarin treatment during the initiation and stabilization phase of therapy in Jordanian Arab cardiovascular patients 26 , 27 , 39 , 40 . In this study, our goal was to expand our knowledge and identify other genetic factors associated with warfarin sensitivity and response, including the CYP4F2, ApoE, and CYP2A6 genes.…”

Section: Discussionmentioning

confidence: 99%

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

AL-Eitan¹,

Almasri²,

Alnaamneh³

et al. 2021

Int. J. Med. Sci.

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“…Finally, out of the remaining 212 patients, 139 only reached the stabilization phase. Pharmacogenetics analysis was conducted based on two phases: the initiation phase relies on data of 212 patients and the stabilization phase depends on 139 patients who have reached the maintenance phase of treatments as previously described by AL-Eitan et al 29 …”

Section: Methodsmentioning

confidence: 99%

Variants in CDHR3, CACNAC1, and LTA Genes Predisposing Sensitivity and Response to Warfarin in Patients with Cardiovascular Disease

Alghamdi¹,

AL-Eitan²,

Alkhatib³

et al. 2021

IJGM

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Introduction Warfarin has been in use for more than 60 years; however, it has serious side effects including major bleeding. The high interpatient variability in the required dose impacts the sensitivity and responsiveness to warfarin in different patients. This study aims to assess the influence of CDHR3, CACNAC1 , and LTA gene polymorphisms on the variability of warfarin dose requirements and susceptibility to coronary heart disease in the Jordanian population. Methods This study was conducted in the anti-coagulation clinic in Queen Alia Heart Institute in Amman, with 212 patients in total. Three SNPs were genotyped within CDHR3 (rs10270308), CACNAC1 (rs216013), and LTA (rs1041981) genes. Results Our findings revealed that patients with LTA polymorphism are more prone to warfarin sensitivity than others. Furthermore, carriers of the LTA polymorphism needed a lower initial dose of warfarin and are associated with less variation in doses required to achieve target INR. Conclusion The current study could help in understanding the role of genetic variability in warfarin dosing and matching patients to different treatment options. Clinical applications of these findings for warfarin treatment may also contribute to improving the efficacy and safety of warfarin treatment in Jordanian patients with cardiovascular disease.

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<p>Influence of PSRC1, CELSR2, and SORT1 Gene Polymorphisms on the Variability of Warfarin Dosage and Susceptibility to Cardiovascular Disease</p>

Cited by 11 publications

References 37 publications

Role of sortilin 1 (SORT1) on fatty acid–mediated cholesterol metabolism in primary calf hepatocytes

Role of sortilin 1 (SORT1) on fatty acid–mediated cholesterol metabolism in primary calf hepatocytes

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

Variants in CDHR3, CACNAC1, and LTA Genes Predisposing Sensitivity and Response to Warfarin in Patients with Cardiovascular Disease

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