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ABCB1 polymorphism in clopidogrel-treated Montenegrin patients

  • Snezana Mugosa , Zoran Todorovic , Jelena Cukic , Majda Sahman-Zaimovic and Natasa Djordjevic EMAIL logo
Published/Copyright: February 18, 2021
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Open Life Sciences
From the journal Open Life Sciences Volume 16 Issue 1

Abstract

Clopidogrel is an antiplatelet drug that displays significant interindividual variability in treatment response. Its bioavailability depends on the function of P-glycoprotein (P-gp), which is coded by a highly polymorphic ABCB1 gene. Thus, the aim of this study was to investigate the effect of ABCB1 genetic polymorphism on clopidogrel efficacy and safety and to determine the frequency distribution of its most common single nucleotide polymorphisms (SNPs) in 106 Montenegrin cardiology patients. Clopidogrel efficacy and safety were followed up during 1 year after hospitalization, with the lack of efficacy and adverse drug reactions observed in 11 (10.4%) and 8 patients (7.5%), respectively. Genotyping for ABCB1 SNPs rs1128503 (1236C > T), rs2032582 (2677G > A/T), and rs1045642 (3435C > T) was performed by the real-time PCR method, and the variant alleles were detected with the frequencies of 42.9, 44.8, and 52.8%, respectively. No significant association was observed between any of the examined genotypes and clopidogrel efficacy (p = 0.253) or safety (p = 0.424). Due to small sample size, co-treatment with other drugs, and other genetic factors not taken into account, we believe the absence of correlation between ABCB1 genotypes and indicators of clopidogrel efficacy and safety in this study should be apprehended conditionally, and that larger and better-controlled studies are warranted.

Keywords: ABCB1 ; P-glycoprotein; clopidogrel; single nucleotide polymorphism

1 Introduction

Clopidogrel is an antiplatelet drug that inhibits platelet activation and aggregation by blocking adenosine diphosphate P2Y12 receptor [1]. Along with aspirin, it represents the mainstay in the management of patients suffering from myocardial infarction, ischemic stroke, acute coronary syndrome, and atrial fibrillation [2]. However, clopidogrel therapy is not always efficient or safe since the possible outcomes range from complete resistance to treatment to major bleeding events [3].

The observed interindividual variability in response to clopidogrel is multifactorial [4], but it mainly results from the heterogeneity of the achieved active drug plasma level [5]. Since clopidogrel is taken orally, its bioavailability depends on its absorption in the intestine and its metabolism in the liver, the former being partly regulated by an efflux transporter known as P-glycoprotein (P-gp) [6]. P-gp is encoded by a highly polymorphic ABCB1 (ATP binding cassette subfamily B member 1, a.k.a. MDR1, i.e., multidrug resistance 1) gene [7], whose variations have been frequently, but not consistently, associated with altered overall P-gp transporting activity [8]. In the coding region of ABCB1, the most common and the most frequently studied single nucleotide polymorphisms (SNPs) are two synonymous and one non-synonymous variant, namely, 1236C > T, 2677G > A/T, and 3435C > T [8]. In spite of numerous investigations involving many P-gp substrates, the role of these SNPs in protein expression and functional integrity, as well as their importance for drug therapy, is still stirring up controversy. Contradictory results include studies that have reported lower P-gp expression, higher drug levels, or more pronounced effects in carriers of variant alleles [9], as opposed to others, where the observed effects were partly or entirely inverse [10], or not detected at all [11]. Clopidogrel studies yielded conflicting conclusions too, with observations of lower drug plasma concentration, impaired response to therapy, and a higher risk of bleeding in carriers of variant 3435T allele [12], counterbalanced by the opposite findings lacking any significant association of ABCB1 polymorphism with clopidogrel pharmacokinetics or platelet response [13].

The frequency distribution of ABCB1 SNPs displays pronounced interethnic variations [10], which could at least in part explain the discrepancies in the reported effects of ABCB1 polymorphism. In Montenegro, clopidogrel is widely prescribed [14], but rarely followed through as recommended, usually due to increased risk of bleeding or the lack of therapeutic effects [4,15]. The importance of pharmacogenetic polymorphism for clopidogrel response in Montenegrins has already been reported [4]. However, as to our best knowledge, ABCB1 variations have not been studied in this population. Thus, the main aim of this study was to investigate the frequency distribution of the most common ABCB1 SNPs, and their potential effect on clopidogrel efficacy and safety, in Montenegrin cardiology patients.

2 Materials and methods

2.1 Study participants

The study involved 106 clopidogrel-treated inpatients from the Cardiology Department of the Clinical Centre of Montenegro, Podgorica. The exclusion criteria were age younger than 18 and older than 80, pregnancy or breastfeeding, and known contraindication for clopidogrel (including hypersensitivity, severe hepatic impairment, and active pathological bleeding). Clopidogrel was prescribed for approved indications (including acute coronary syndrome and atrial fibrillation) at 75 mg daily dose to all the patients. All the patients were co-prescribed with acetylsalicylic acid, which is not a substrate for P-gp [16].

Clopidogrel treatment was considered efficient if acute coronary syndrome, stent thrombosis, stroke, percutaneous coronary intervention, or death did not occur within 1 year after initial hospitalization. Clopidogrel safety was assessed based on the occurrence of common adverse reactions, i.e., bleeding complications. The relevant data were collected through interviews and questionnaires during hospitalization and 1 year after hospital discharge (Figure A1). Patients who were deemed to be clopidogrel-resistant and experienced clopidogrel-related safety issues were considered cases, as opposed to controls, who reacted well to clopidogrel and had no adverse reactions, respectively.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Helsinki Declaration and has been approved by the Ethics Committee at the Clinical Centre of Montenegro, Podgorica (approval No 03/01-14664/1).

2.2 ABCB1 genotyping

DNA was extracted from the whole-blood EDTA samples using the Purelink™ genomic DNA kit (Invitrogen, Carlsbad, CA, USA). Genotyping for three common ABCB1 SNPs, rs1128503 (1236C > T), rs2032582 (2677G > A/T), and rs1045642 (3435C > T), was performed on SaCycler-96 (Sacace Biotechnologies, Como, Italy) by the real-time PCR method, using TaqMan Genotyping Master Mix and the corresponding TaqMan DME genotyping assays (Thermo Fisher Scientific, Waltham, MA, USA).

2.3 Statistical analysis

ABCB1 haplotype analysis and haplotype frequency calculations were performed using Arlequin, version 3.11 (http://cmpg.unibe.ch/software/arlequin3). Testing for Hardy–Weinberg equilibrium was performed with the χ 2 test. IBM SPSS Statistics, version 22 (IBM Corporation, Armonk, NY, USA), was employed in statistical analysis, with p < 0.05 considered significant. The influence of ABCB1 genotype and concomitant drug therapy on efficacy and safety of clopidogrel treatment was assessed using the χ 2/Fisher exact test.

3 Results

The study subjects included 72 men and 34 women, 32 to 77 years old (mean ± SD: 59.5 ± 8.9), diagnosed with either myocardial infarction (n = 50), angina pectoris (n = 52), or atrial fibrillation (n = 4). Eighty-eight patients (83.0%) were co-treated with at least one drug known to either increase (tirofiban, warfarin, or acenocoumarol (n = 3), heparin or enoxaparin (n = 37)) or decrease its serum level and/or effect (six receiving felodipine, nifedipine, or diltiazem, and 81 omeprazole or pantoprazole). In addition, five patients were co-treated with other drugs that do not interact with clopidogrel, i.e., prednisone or methylprednisone. Clopidogrel was ineffective in 11 patients (10.4%), while in 8 cases (7.5%) it caused at least 1 bleeding episode as an adverse drug reaction.

The frequencies of the ABCB1 SNPs, genotypes, haplotypes, and diplotypes are presented in Table 1. None of the SNPs deviated from Hardy–Weinberg equilibrium (p > 0.07). Comparison among ABCB1 genotypes did not reveal any significant association of 1236C > T, 2677G > A/T, or 3435C > T with clopidogrel efficacy (p = 0.253). Similarly, no association was observed between any SNPs and bleeding episodes as the indicator of clopidogrel safety (p = 0.424). Concomitant therapy did not appear to affect clopidogrel efficacy (p = 0.244) or safety (p = 0.255).

Table 1

SNP, genotype, haplotype, and diplotype frequencies of ABCB1 in Montenegrin clopidogrel-treated patients

Observed frequency 95% Confidence interval
Allele rs1128503 (1236C < T) 0.429 (91/212) 0.365, 0.497
rs2032582 (2677G < T/A) 0.448 (95/212) 0.383, 0.515
rs1045642 (3435C < T) 0.528 (112/212) 0.461, 0.594
Genotype rs1128503 (1236C < T) CC 0.302 (32/106) 0.223, 0.395
CT 0.538 (57/106) 0.443, 0.630
TT 0.160 (17/106) 0.102, 0.243
rs2032582 (2677G < T/A) GG 0.321 (34/106) 0.102, 0.243
GT 0.462 (49/106) 0.370, 0.557
GA 0.000 (0/106) 0.000, 0.043
TT 0.208 (22/106) 0.141, 0.295
AT 0.009 (1/106) 0.000, 0.058
AA 0.000 (0/106) 0.000, 0.043
rs1045642 (3435C < T) CC 0.179 (19/106) 0.117, 0.264
CT 0.585 (62/106) 0.490, 0.674
TT 0.236 (25/106) 0.165, 0.326
Haplotypea C-G-C 0.415 (88/212) 0.351, 0.482
T-T-T 0.354 (75/212) 0.293, 0.420
C-G-T 0.075 (16/212) 0.046, 0.120
C-T-T 0.066 (14/212) 0.039, 0.109
T-G-C 0.033 (7/212) 0.015, 0.068
T-G-T 0.028 (6/212) 0.012, 0.062
T-T-C 0.014 (3/212) 0.003, 0.043
C-T-C 0.009 (2/212) 0.001, 0.036
C-A-T 0.005 (1/212) 0.000, 0.029
Diplotypea C-G-C/T-T-T 0.349 (37/106) 0.265, 0.444
T-T-T/T-T-T 0.123 (13/106) 0.072, 0.200
C-G-C/C-G-T 0.113 (12/106) 0.065, 0.190
C-G-C/C-G-C 0.104 (11/106) 0.058, 0.179
C-G-C/T-G-T 0.057 (6/106) 0.024, 0.121
C-G-C/C-T-T 0.038 (4/106) 0.012, 0.097
C-G-C/T-G-C 0.038 (4/106) 0.012, 0.097
C-G-T/T-T-T 0.038 (4/106) 0.012, 0.097
C-T-T/T-T-T 0.038 (4/106) 0.012, 0.097
C-T-T/C-T-T 0.028 (3/106) 0.007, 0.084
C-G-C/C-T-C 0.019 (2/106) 0.001, 0.071
T-T-C/T-T-T 0.019 (2/106) 0.001, 0.071
C-G-C/T-T-C 0.009 (1/106) 0.000, 0.058
T-T-T/C-A-T 0.009 (1/106) 0.000, 0.058
T-G-C/T-G-C 0.009 (1/106) 0.000, 0.058
T-G-C/T-T-T 0.009 (1/106) 0.000, 0.058
  1. a

    1236C/T-2677G/T/A-3435C/T.

4 Discussion

Clopidogrel has unfavorable pharmacokinetics. Its bioavailability, which varies considerably, has been deemed essential for developing both drug resistance and bleeding episodes as its adverse effects. This is particularly important considering that usually only 10–15% of clopidogrel dose becomes active after administration, mainly due to biotransformation by CYP2C19 [17]. We have previously shown the importance of CYP2C19 genetic polymorphism for variability in therapeutic response to clopidogrel in Montenegrin cardiology patients [4]. Our previous findings remain in line with the Cochrane database and the Clinical Pharmacogenetics Implementation Consortium Guideline, recommending clinical use and confirming the cost-effectiveness of CYP2C19 genotype testing in patients prescribed with clopidogrel [18,19].

However, clopidogrel is an orally administered drug whose bioavailability additionally depends on the rate of intestinal absorption, and this process seems to be significantly affected by intestinal expression and function of P-gp [6]. Thus, we have broadened our pharmacogenetic analysis of clopidogrel efficacy and safety as to include the potential role of most common and tenably functional SNPs of P-gp-coding gene ABCB1. As to our best knowledge, this is the first study related to ABCB1 genetic polymorphism in Montenegrins. Although we did determine and report frequency distributions of ABCB1 SNPs 1236C > T, 2677G > A/T, or 3435C > T in Montenegrin cardiology patients, we failed to detect any significant correlation between ABCB1 genetic polymorphism and clopidogrel efficacy and safety.

The overall frequency distributions of 1236C > T, 2677G > A/T, and 3435C > T ABCB1 variants display significant interethnic variability [8], with differences as high as 62 vs 13% of European Americans carrying variant alleles as compared to African Americans, respectively [10]. Similarly, comparison in terms of allele frequency between Africans, Caucasians, and Asians revealed marked variations for each of the alleles as well, e.g., 3435T frequency distribution spanning from 17% in Ghana and Kenya, up to 57% in Portugal and 66% in South-west Asia [20]. Yet, among Caucasians examined, ABCB1 SNPs are rather uniformly distributed, 1236T ranging from 41% in German [21], 42% in French [22] to 46% in Serbian [23], 2677A/T from 45% in French [22] and German [21], 47% in Serbian [23] to 49% in Hungarians [24], and 3435T from 46% in French [22], 52% in British [20], 53% in Serbian [23], 54% in German [21], to 57% in Hungarians [24]. It is easy to note that ABCB1 genetic polymorphism observed in Montenegrins conforms well to the previously published European data, including those from other clopidogrel-receiving patients [25,26,27].

It has been confirmed that the presence of ABCB1 3435C > T alters the pharmacokinetics of clopidogrel [6,28], as well as many other drugs [29]. As 3435C > T is a synonymous variant, which by definition is not expected to change primary structure of the coding protein [30], in an attempt to understand its role in drug transport other mechanisms should be considered. While its effect can be the result of altered messenger RNA splicing or P-gp protein stability, one of the most plausible explanations might actually be a strong linkage disequilibrium with other non-synonymous SNPs, including 1236C > T and 2677G > A/T. As the impact of ABCB1 genetic polymorphism on clopidogrel pharmacokinetics requires comprehensive analysis, in this study we have estimated both separate and combined effects of all three SNPs, i.e., assessed the impact of both individual ABCB1 SNPs and ABCB1 1236C/T-2677G/T/A-3435C/T genotypes on patients’ response to clopidogrel treatment.

Although no significant difference could be observed between carriers and noncarriers of specific alleles or genotypes in terms of clopidogrel efficacy and safety, it should be noted that the number of patients included in this study is relatively small, that the patients were not on monotherapy with clopidogrel but rather treated with other drugs with potential for both pharmacokinetics and pharmacodynamics interactions with clopidogrel, as well as that other already confirmed genetic factors [4] were not taken into account during the analysis. Thus, the absence of correlation between ABCB1 genotypes and indicators of efficacy and safety of clopidogrel in this study should be apprehended conditionally, although it conforms well to conclusions of several similar studies [31,32,33,34,35]. Namely, previously published larger and better-controlled studies, which have observed higher risk of clopidogrel resistance [36,37] and higher risk of major cardiovascular adverse events [38] in carriers of different variant ABCB1 alleles, warrant further investigation of the role of ABCB1 genetic polymorphisms not only in Montenegrins but also in other populations, where clopidogrel remains one of the most frequently prescribed antiplatelet drugs.

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Appendix

Figure A1 Questions included in patient interview 1 year after hospital discharge.
Figure A1

Questions included in patient interview 1 year after hospital discharge.

Figure A2 Patient questionnaire during hospitalization.
Figure A2

Patient questionnaire during hospitalization.

  1. Funding: This study was financially supported by the Ministry of Science, Montenegro (Grant No. 01-907) and the Ministry of Science and Technology of the Republic of Serbia (Grant No. 175007, 175046, and 175056).

  2. Author contributions: S.M. contributed to acquisition and interpretation of data, and drafting of the manuscript. Z.T. contributed to study concept and design, and data interpretation. J.C. contributed to genotyping analysis. M.S.Z. contributed to acquisition of data. N.D. contributed to study concept and design, data analysis and interpretation, and drafting of the manuscript. All authors contributed to critical manuscript revision. The authors applied the FLAE approach for the sequence of authors.

  3. Conflict of interest: The authors state no conflict of interest.

  4. Data availability statement: All data generated or analyzed during this study are included in this published article.

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Received: 2020-11-16
Revised: 2021-01-12
Accepted: 2021-01-12
Published Online: 2021-02-18

© 2021 Snezana Mugosa et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  6. LncRNA PVT1 promotes cervical cancer progression by sponging miR-503 to upregulate ARL2 expression
  7. Two new inflammatory markers related to the CURB-65 score for disease severity in patients with community-acquired pneumonia: The hypersensitive C-reactive protein to albumin ratio and fibrinogen to albumin ratio
  8. Circ_0091579 enhances the malignancy of hepatocellular carcinoma via miR-1287/PDK2 axis
  9. Silencing XIST mitigated lipopolysaccharide (LPS)-induced inflammatory injury in human lung fibroblast WI-38 cells through modulating miR-30b-5p/CCL16 axis and TLR4/NF-κB signaling pathway
  10. Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats
  11. ABCB1 polymorphism in clopidogrel-treated Montenegrin patients
  12. Metabolic profiling of fatty acids in Tripterygium wilfordii multiglucoside- and triptolide-induced liver-injured rats
  13. miR-338-3p inhibits cell growth, invasion, and EMT process in neuroblastoma through targeting MMP-2
  14. Verification of neuroprotective effects of alpha-lipoic acid on chronic neuropathic pain in a chronic constriction injury rat model
  15. Circ_WWC3 overexpression decelerates the progression of osteosarcoma by regulating miR-421/PDE7B axis
  16. Knockdown of TUG1 rescues cardiomyocyte hypertrophy through targeting the miR-497/MEF2C axis
  17. MiR-146b-3p protects against AR42J cell injury in cerulein-induced acute pancreatitis model through targeting Anxa2
  18. miR-299-3p suppresses cell progression and induces apoptosis by downregulating PAX3 in gastric cancer
  19. Diabetes and COVID-19
  20. Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
  21. TEAD4 is a novel independent predictor of prognosis in LGG patients with IDH mutation
  22. circTLK1 facilitates the proliferation and metastasis of renal cell carcinoma by regulating miR-495-3p/CBL axis
  23. microRNA-9-5p protects liver sinusoidal endothelial cell against oxygen glucose deprivation/reperfusion injury
  24. Long noncoding RNA TUG1 regulates degradation of chondrocyte extracellular matrix via miR-320c/MMP-13 axis in osteoarthritis
  25. Duodenal adenocarcinoma with skin metastasis as initial manifestation: A case report
  26. Effects of Loofah cylindrica extract on learning and memory ability, brain tissue morphology, and immune function of aging mice
  27. Recombinant Bacteroides fragilis enterotoxin-1 (rBFT-1) promotes proliferation of colorectal cancer via CCL3-related molecular pathways
  28. Blocking circ_UBR4 suppressed proliferation, migration, and cell cycle progression of human vascular smooth muscle cells in atherosclerosis
  29. Gene therapy in PIDs, hemoglobin, ocular, neurodegenerative, and hemophilia B disorders
  30. Downregulation of circ_0037655 impedes glioma formation and metastasis via the regulation of miR-1229-3p/ITGB8 axis
  31. Vitamin D deficiency and cardiovascular risk in type 2 diabetes population
  32. Circ_0013359 facilitates the tumorigenicity of melanoma by regulating miR-136-5p/RAB9A axis
  33. Mechanisms of circular RNA circ_0066147 on pancreatic cancer progression
  34. lncRNA myocardial infarction-associated transcript (MIAT) knockdown alleviates LPS-induced chondrocytes inflammatory injury via regulating miR-488-3p/sex determining region Y-related HMG-box 11 (SOX11) axis
  35. Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis
  36. Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis
  37. Potential prognostic markers and significant lncRNA–mRNA co-expression pairs in laryngeal squamous cell carcinoma
  38. Gamma irradiation-mediated inactivation of enveloped viruses with conservation of genome integrity: Potential application for SARS-CoV-2 inactivated vaccine development
  39. ADHFE1 is a correlative factor of patient survival in cancer
  40. The association of transcription factor Prox1 with the proliferation, migration, and invasion of lung cancer
  41. Is there a relationship between the prevalence of autoimmune thyroid disease and diabetic kidney disease?
  42. Immunoregulatory function of Dictyophora echinovolvata spore polysaccharides in immunocompromised mice induced by cyclophosphamide
  43. T cell epitopes of SARS-CoV-2 spike protein and conserved surface protein of Plasmodium malariae share sequence homology
  44. Anti-obesity effect and mechanism of mesenchymal stem cells influence on obese mice
  45. Long noncoding RNA HULC contributes to paclitaxel resistance in ovarian cancer via miR-137/ITGB8 axis
  46. Glucocorticoids protect HEI-OC1 cells from tunicamycin-induced cell damage via inhibiting endoplasmic reticulum stress
  47. Prognostic value of the neutrophil-to-lymphocyte ratio in acute organophosphorus pesticide poisoning
  48. Gastroprotective effects of diosgenin against HCl/ethanol-induced gastric mucosal injury through suppression of NF-κβ and myeloperoxidase activities
  49. Silencing of LINC00707 suppresses cell proliferation, migration, and invasion of osteosarcoma cells by modulating miR-338-3p/AHSA1 axis
  50. Successful extracorporeal membrane oxygenation resuscitation of patient with cardiogenic shock induced by phaeochromocytoma crisis mimicking hyperthyroidism: A case report
  51. Effects of miR-185-5p on replication of hepatitis C virus
  52. Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis
  53. Primary localized cutaneous nodular amyloidosis presenting as lymphatic malformation: A case report
  54. Multimodal magnetic resonance imaging analysis in the characteristics of Wilson’s disease: A case report and literature review
  55. Therapeutic potential of anticoagulant therapy in association with cytokine storm inhibition in severe cases of COVID-19: A case report
  56. Neoadjuvant immunotherapy combined with chemotherapy for locally advanced squamous cell lung carcinoma: A case report and literature review
  57. Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage
  58. Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage
  59. Invasive ductal carcinoma and small lymphocytic lymphoma/chronic lymphocytic leukemia manifesting as a collision breast tumor: A case report and literature review
  60. Clonal diversity of the B cell receptor repertoire in patients with coronary in-stent restenosis and type 2 diabetes
  61. CTLA-4 promotes lymphoma progression through tumor stem cell enrichment and immunosuppression
  62. WDR74 promotes proliferation and metastasis in colorectal cancer cells through regulating the Wnt/β-catenin signaling pathway
  63. Down-regulation of IGHG1 enhances Protoporphyrin IX accumulation and inhibits hemin biosynthesis in colorectal cancer by suppressing the MEK-FECH axis
  64. Curcumin suppresses the progression of gastric cancer by regulating circ_0056618/miR-194-5p axis
  65. Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway
  66. lncRNA NEAT1 regulates CYP1A2 and influences steroid-induced necrosis
  67. A two-microRNA signature predicts the progression of male thyroid cancer
  68. Isolation of microglia from retinas of chronic ocular hypertensive rats
  69. Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study
  70. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte
  71. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma
  72. Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer
  73. circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells
  74. Resveratrol pretreatment mitigates LPS-induced acute lung injury by regulating conventional dendritic cells’ maturation and function
  75. Ubiquitin-conjugating enzyme E2T promotes tumor stem cell characteristics and migration of cervical cancer cells by regulating the GRP78/FAK pathway
  76. Carriage of HLA-DRB1*11 and 1*12 alleles and risk factors in patients with breast cancer in Burkina Faso
  77. Protective effect of Lactobacillus-containing probiotics on intestinal mucosa of rats experiencing traumatic hemorrhagic shock
  78. Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway
  79. Endothelial cell-derived SSAO can increase MLC20 phosphorylation in VSMCs
  80. Downregulation of STOX1 is a novel prognostic biomarker for glioma patients
  81. miR-378a-3p regulates glioma cell chemosensitivity to cisplatin through IGF1R
  82. The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats
  83. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ
  84. The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
  85. Red blood cell distribution width-standard deviation but not red blood cell distribution width-coefficient of variation as a potential index for the diagnosis of iron-deficiency anemia in mid-pregnancy women
  86. Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium
  87. Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers
  88. Molecular characterization and phylogenetic studies of Echinococcus granulosus and Taenia multiceps coenurus cysts in slaughtered sheep in Saudi Arabia
  89. ITGB5 mutation discovered in a Chinese family with blepharophimosis-ptosis-epicanthus inversus syndrome
  90. ACTB and GAPDH appear at multiple SDS-PAGE positions, thus not suitable as reference genes for determining protein loading in techniques like Western blotting
  91. Facilitation of mouse skin-derived precursor growth and yield by optimizing plating density
  92. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model
  93. Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
  94. Expression of CDK9 in endometrial cancer tissues and its effect on the proliferation of HEC-1B
  95. Novel predictor of the occurrence of DKA in T1DM patients without infection: A combination of neutrophil/lymphocyte ratio and white blood cells
  96. Investigation of molecular regulation mechanism under the pathophysiology of subarachnoid hemorrhage
  97. miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3
  98. Bioengineering and Biotechnology
  99. Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review
  100. Agriculture
  101. Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis
  102. Crop-livestock integration practices, knowledge, and attitudes among smallholder farmers: Hedging against climate change-induced shocks in semi-arid Zimbabwe
  103. Food Science and Nutrition
  104. Effect of food processing on the antioxidant activity of flavones from Polygonatum odoratum (Mill.) Druce
  105. Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China
  106. Diversity of microbiota in Slovak summer ewes’ cheese “Bryndza”
  107. Comparison between voltammetric detection methods for abalone-flavoring liquid
  108. Composition of low-molecular-weight glutenin subunits in common wheat (Triticum aestivum L.) and their effects on the rheological properties of dough
  109. Application of culture, PCR, and PacBio sequencing for determination of microbial composition of milk from subclinical mastitis dairy cows of smallholder farms
  110. Investigating microplastics and potentially toxic elements contamination in canned Tuna, Salmon, and Sardine fishes from Taif markets, KSA
  111. From bench to bar side: Evaluating the red wine storage lesion
  112. Establishment of an iodine model for prevention of iodine-excess-induced thyroid dysfunction in pregnant women
  113. Plant Sciences
  114. Characterization of GMPP from Dendrobium huoshanense yielding GDP-D-mannose
  115. Comparative analysis of the SPL gene family in five Rosaceae species: Fragaria vesca, Malus domestica, Prunus persica, Rubus occidentalis, and Pyrus pyrifolia
  116. Identification of leaf rust resistance genes Lr34 and Lr46 in common wheat (Triticum aestivum L. ssp. aestivum) lines of different origin using multiplex PCR
  117. Investigation of bioactivities of Taxus chinensis, Taxus cuspidata, and Taxus × media by gas chromatography-mass spectrometry
  118. Morphological structures and histochemistry of roots and shoots in Myricaria laxiflora (Tamaricaceae)
  119. Transcriptome analysis of resistance mechanism to potato wart disease
  120. In silico analysis of glycosyltransferase 2 family genes in duckweed (Spirodela polyrhiza) and its role in salt stress tolerance
  121. Comparative study on growth traits and ions regulation of zoysiagrasses under varied salinity treatments
  122. Role of MS1 homolog Ntms1 gene of tobacco infertility
  123. Biological characteristics and fungicide sensitivity of Pyricularia variabilis
  124. In silico/computational analysis of mevalonate pyrophosphate decarboxylase gene families in Campanulids
  125. Identification of novel drought-responsive miRNA regulatory network of drought stress response in common vetch (Vicia sativa)
  126. How photoautotrophy, photomixotrophy, and ventilation affect the stomata and fluorescence emission of pistachios rootstock?
  127. Apoplastic histochemical features of plant root walls that may facilitate ion uptake and retention
  128. Ecology and Environmental Sciences
  129. The impact of sewage sludge on the fungal communities in the rhizosphere and roots of barley and on barley yield
  130. Domestication of wild animals may provide a springboard for rapid variation of coronavirus
  131. Response of benthic invertebrate assemblages to seasonal and habitat condition in the Wewe River, Ashanti region (Ghana)
  132. Molecular record for the first authentication of Isaria cicadae from Vietnam
  133. Twig biomass allocation of Betula platyphylla in different habitats in Wudalianchi Volcano, northeast China
  134. Animal Sciences
  135. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens
  136. Predators of the giant pine scale, Marchalina hellenica (Gennadius 1883; Hemiptera: Marchalinidae), out of its natural range in Turkey
  137. Honey in wound healing: An updated review
  138. NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block
  139. Radiotherapy for the treatment of pulmonary hydatidosis in sheep
  140. Retraction
  141. Retraction of “Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating microRNA-34a-5p/NOTCH1 signaling pathway”
  142. Special Issue on Reuse of Agro-Industrial By-Products
  143. An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli
  144. Special Issue on Computing and Artificial Techniques for Life Science Applications - Part II
  145. Relationship of Gensini score with retinal vessel diameter and arteriovenous ratio in senile CHD
  146. Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits
  147. Establishment of the New Zealand white rabbit animal model of fatty keratopathy associated with corneal neovascularization
  148. lncRNA MALAT1/miR-143 axis is a potential biomarker for in-stent restenosis and is involved in the multiplication of vascular smooth muscle cells
https://doi.org/10.1515/biol-2021-0017
Keywords for this article
ABCB1; P-glycoprotein; clopidogrel; single nucleotide polymorphism
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Research progress on the mechanism of orexin in pain regulation in different brain regions
  3. Adriamycin-resistant cells are significantly less fit than adriamycin-sensitive cells in cervical cancer
  4. Exogenous spermidine affects polyamine metabolism in the mouse hypothalamus
  5. Iris metastasis of diffuse large B-cell lymphoma misdiagnosed as primary angle-closure glaucoma: A case report and review of the literature
  6. LncRNA PVT1 promotes cervical cancer progression by sponging miR-503 to upregulate ARL2 expression
  7. Two new inflammatory markers related to the CURB-65 score for disease severity in patients with community-acquired pneumonia: The hypersensitive C-reactive protein to albumin ratio and fibrinogen to albumin ratio
  8. Circ_0091579 enhances the malignancy of hepatocellular carcinoma via miR-1287/PDK2 axis
  9. Silencing XIST mitigated lipopolysaccharide (LPS)-induced inflammatory injury in human lung fibroblast WI-38 cells through modulating miR-30b-5p/CCL16 axis and TLR4/NF-κB signaling pathway
  10. Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats
  11. ABCB1 polymorphism in clopidogrel-treated Montenegrin patients
  12. Metabolic profiling of fatty acids in Tripterygium wilfordii multiglucoside- and triptolide-induced liver-injured rats
  13. miR-338-3p inhibits cell growth, invasion, and EMT process in neuroblastoma through targeting MMP-2
  14. Verification of neuroprotective effects of alpha-lipoic acid on chronic neuropathic pain in a chronic constriction injury rat model
  15. Circ_WWC3 overexpression decelerates the progression of osteosarcoma by regulating miR-421/PDE7B axis
  16. Knockdown of TUG1 rescues cardiomyocyte hypertrophy through targeting the miR-497/MEF2C axis
  17. MiR-146b-3p protects against AR42J cell injury in cerulein-induced acute pancreatitis model through targeting Anxa2
  18. miR-299-3p suppresses cell progression and induces apoptosis by downregulating PAX3 in gastric cancer
  19. Diabetes and COVID-19
  20. Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor
  21. TEAD4 is a novel independent predictor of prognosis in LGG patients with IDH mutation
  22. circTLK1 facilitates the proliferation and metastasis of renal cell carcinoma by regulating miR-495-3p/CBL axis
  23. microRNA-9-5p protects liver sinusoidal endothelial cell against oxygen glucose deprivation/reperfusion injury
  24. Long noncoding RNA TUG1 regulates degradation of chondrocyte extracellular matrix via miR-320c/MMP-13 axis in osteoarthritis
  25. Duodenal adenocarcinoma with skin metastasis as initial manifestation: A case report
  26. Effects of Loofah cylindrica extract on learning and memory ability, brain tissue morphology, and immune function of aging mice
  27. Recombinant Bacteroides fragilis enterotoxin-1 (rBFT-1) promotes proliferation of colorectal cancer via CCL3-related molecular pathways
  28. Blocking circ_UBR4 suppressed proliferation, migration, and cell cycle progression of human vascular smooth muscle cells in atherosclerosis
  29. Gene therapy in PIDs, hemoglobin, ocular, neurodegenerative, and hemophilia B disorders
  30. Downregulation of circ_0037655 impedes glioma formation and metastasis via the regulation of miR-1229-3p/ITGB8 axis
  31. Vitamin D deficiency and cardiovascular risk in type 2 diabetes population
  32. Circ_0013359 facilitates the tumorigenicity of melanoma by regulating miR-136-5p/RAB9A axis
  33. Mechanisms of circular RNA circ_0066147 on pancreatic cancer progression
  34. lncRNA myocardial infarction-associated transcript (MIAT) knockdown alleviates LPS-induced chondrocytes inflammatory injury via regulating miR-488-3p/sex determining region Y-related HMG-box 11 (SOX11) axis
  35. Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis
  36. Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis
  37. Potential prognostic markers and significant lncRNA–mRNA co-expression pairs in laryngeal squamous cell carcinoma
  38. Gamma irradiation-mediated inactivation of enveloped viruses with conservation of genome integrity: Potential application for SARS-CoV-2 inactivated vaccine development
  39. ADHFE1 is a correlative factor of patient survival in cancer
  40. The association of transcription factor Prox1 with the proliferation, migration, and invasion of lung cancer
  41. Is there a relationship between the prevalence of autoimmune thyroid disease and diabetic kidney disease?
  42. Immunoregulatory function of Dictyophora echinovolvata spore polysaccharides in immunocompromised mice induced by cyclophosphamide
  43. T cell epitopes of SARS-CoV-2 spike protein and conserved surface protein of Plasmodium malariae share sequence homology
  44. Anti-obesity effect and mechanism of mesenchymal stem cells influence on obese mice
  45. Long noncoding RNA HULC contributes to paclitaxel resistance in ovarian cancer via miR-137/ITGB8 axis
  46. Glucocorticoids protect HEI-OC1 cells from tunicamycin-induced cell damage via inhibiting endoplasmic reticulum stress
  47. Prognostic value of the neutrophil-to-lymphocyte ratio in acute organophosphorus pesticide poisoning
  48. Gastroprotective effects of diosgenin against HCl/ethanol-induced gastric mucosal injury through suppression of NF-κβ and myeloperoxidase activities
  49. Silencing of LINC00707 suppresses cell proliferation, migration, and invasion of osteosarcoma cells by modulating miR-338-3p/AHSA1 axis
  50. Successful extracorporeal membrane oxygenation resuscitation of patient with cardiogenic shock induced by phaeochromocytoma crisis mimicking hyperthyroidism: A case report
  51. Effects of miR-185-5p on replication of hepatitis C virus
  52. Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis
  53. Primary localized cutaneous nodular amyloidosis presenting as lymphatic malformation: A case report
  54. Multimodal magnetic resonance imaging analysis in the characteristics of Wilson’s disease: A case report and literature review
  55. Therapeutic potential of anticoagulant therapy in association with cytokine storm inhibition in severe cases of COVID-19: A case report
  56. Neoadjuvant immunotherapy combined with chemotherapy for locally advanced squamous cell lung carcinoma: A case report and literature review
  57. Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage
  58. Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage
  59. Invasive ductal carcinoma and small lymphocytic lymphoma/chronic lymphocytic leukemia manifesting as a collision breast tumor: A case report and literature review
  60. Clonal diversity of the B cell receptor repertoire in patients with coronary in-stent restenosis and type 2 diabetes
  61. CTLA-4 promotes lymphoma progression through tumor stem cell enrichment and immunosuppression
  62. WDR74 promotes proliferation and metastasis in colorectal cancer cells through regulating the Wnt/β-catenin signaling pathway
  63. Down-regulation of IGHG1 enhances Protoporphyrin IX accumulation and inhibits hemin biosynthesis in colorectal cancer by suppressing the MEK-FECH axis
  64. Curcumin suppresses the progression of gastric cancer by regulating circ_0056618/miR-194-5p axis
  65. Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway
  66. lncRNA NEAT1 regulates CYP1A2 and influences steroid-induced necrosis
  67. A two-microRNA signature predicts the progression of male thyroid cancer
  68. Isolation of microglia from retinas of chronic ocular hypertensive rats
  69. Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study
  70. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte
  71. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma
  72. Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer
  73. circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells
  74. Resveratrol pretreatment mitigates LPS-induced acute lung injury by regulating conventional dendritic cells’ maturation and function
  75. Ubiquitin-conjugating enzyme E2T promotes tumor stem cell characteristics and migration of cervical cancer cells by regulating the GRP78/FAK pathway
  76. Carriage of HLA-DRB1*11 and 1*12 alleles and risk factors in patients with breast cancer in Burkina Faso
  77. Protective effect of Lactobacillus-containing probiotics on intestinal mucosa of rats experiencing traumatic hemorrhagic shock
  78. Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway
  79. Endothelial cell-derived SSAO can increase MLC20 phosphorylation in VSMCs
  80. Downregulation of STOX1 is a novel prognostic biomarker for glioma patients
  81. miR-378a-3p regulates glioma cell chemosensitivity to cisplatin through IGF1R
  82. The molecular mechanisms underlying arecoline-induced cardiac fibrosis in rats
  83. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ
  84. The influence of MTHFR genetic polymorphisms on methotrexate therapy in pediatric acute lymphoblastic leukemia
  85. Red blood cell distribution width-standard deviation but not red blood cell distribution width-coefficient of variation as a potential index for the diagnosis of iron-deficiency anemia in mid-pregnancy women
  86. Small cell neuroendocrine carcinoma expressing alpha fetoprotein in the endometrium
  87. Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers
  88. Molecular characterization and phylogenetic studies of Echinococcus granulosus and Taenia multiceps coenurus cysts in slaughtered sheep in Saudi Arabia
  89. ITGB5 mutation discovered in a Chinese family with blepharophimosis-ptosis-epicanthus inversus syndrome
  90. ACTB and GAPDH appear at multiple SDS-PAGE positions, thus not suitable as reference genes for determining protein loading in techniques like Western blotting
  91. Facilitation of mouse skin-derived precursor growth and yield by optimizing plating density
  92. 3,4-Dihydroxyphenylethanol ameliorates lipopolysaccharide-induced septic cardiac injury in a murine model
  93. Downregulation of PITX2 inhibits the proliferation and migration of liver cancer cells and induces cell apoptosis
  94. Expression of CDK9 in endometrial cancer tissues and its effect on the proliferation of HEC-1B
  95. Novel predictor of the occurrence of DKA in T1DM patients without infection: A combination of neutrophil/lymphocyte ratio and white blood cells
  96. Investigation of molecular regulation mechanism under the pathophysiology of subarachnoid hemorrhage
  97. miR-25-3p protects renal tubular epithelial cells from apoptosis induced by renal IRI by targeting DKK3
  98. Bioengineering and Biotechnology
  99. Green fabrication of Co and Co3O4 nanoparticles and their biomedical applications: A review
  100. Agriculture
  101. Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis
  102. Crop-livestock integration practices, knowledge, and attitudes among smallholder farmers: Hedging against climate change-induced shocks in semi-arid Zimbabwe
  103. Food Science and Nutrition
  104. Effect of food processing on the antioxidant activity of flavones from Polygonatum odoratum (Mill.) Druce
  105. Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China
  106. Diversity of microbiota in Slovak summer ewes’ cheese “Bryndza”
  107. Comparison between voltammetric detection methods for abalone-flavoring liquid
  108. Composition of low-molecular-weight glutenin subunits in common wheat (Triticum aestivum L.) and their effects on the rheological properties of dough
  109. Application of culture, PCR, and PacBio sequencing for determination of microbial composition of milk from subclinical mastitis dairy cows of smallholder farms
  110. Investigating microplastics and potentially toxic elements contamination in canned Tuna, Salmon, and Sardine fishes from Taif markets, KSA
  111. From bench to bar side: Evaluating the red wine storage lesion
  112. Establishment of an iodine model for prevention of iodine-excess-induced thyroid dysfunction in pregnant women
  113. Plant Sciences
  114. Characterization of GMPP from Dendrobium huoshanense yielding GDP-D-mannose
  115. Comparative analysis of the SPL gene family in five Rosaceae species: Fragaria vesca, Malus domestica, Prunus persica, Rubus occidentalis, and Pyrus pyrifolia
  116. Identification of leaf rust resistance genes Lr34 and Lr46 in common wheat (Triticum aestivum L. ssp. aestivum) lines of different origin using multiplex PCR
  117. Investigation of bioactivities of Taxus chinensis, Taxus cuspidata, and Taxus × media by gas chromatography-mass spectrometry
  118. Morphological structures and histochemistry of roots and shoots in Myricaria laxiflora (Tamaricaceae)
  119. Transcriptome analysis of resistance mechanism to potato wart disease
  120. In silico analysis of glycosyltransferase 2 family genes in duckweed (Spirodela polyrhiza) and its role in salt stress tolerance
  121. Comparative study on growth traits and ions regulation of zoysiagrasses under varied salinity treatments
  122. Role of MS1 homolog Ntms1 gene of tobacco infertility
  123. Biological characteristics and fungicide sensitivity of Pyricularia variabilis
  124. In silico/computational analysis of mevalonate pyrophosphate decarboxylase gene families in Campanulids
  125. Identification of novel drought-responsive miRNA regulatory network of drought stress response in common vetch (Vicia sativa)
  126. How photoautotrophy, photomixotrophy, and ventilation affect the stomata and fluorescence emission of pistachios rootstock?
  127. Apoplastic histochemical features of plant root walls that may facilitate ion uptake and retention
  128. Ecology and Environmental Sciences
  129. The impact of sewage sludge on the fungal communities in the rhizosphere and roots of barley and on barley yield
  130. Domestication of wild animals may provide a springboard for rapid variation of coronavirus
  131. Response of benthic invertebrate assemblages to seasonal and habitat condition in the Wewe River, Ashanti region (Ghana)
  132. Molecular record for the first authentication of Isaria cicadae from Vietnam
  133. Twig biomass allocation of Betula platyphylla in different habitats in Wudalianchi Volcano, northeast China
  134. Animal Sciences
  135. Supplementation of probiotics in water beneficial growth performance, carcass traits, immune function, and antioxidant capacity in broiler chickens
  136. Predators of the giant pine scale, Marchalina hellenica (Gennadius 1883; Hemiptera: Marchalinidae), out of its natural range in Turkey
  137. Honey in wound healing: An updated review
  138. NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block
  139. Radiotherapy for the treatment of pulmonary hydatidosis in sheep
  140. Retraction
  141. Retraction of “Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating microRNA-34a-5p/NOTCH1 signaling pathway”
  142. Special Issue on Reuse of Agro-Industrial By-Products
  143. An effect of positional isomerism of benzoic acid derivatives on antibacterial activity against Escherichia coli
  144. Special Issue on Computing and Artificial Techniques for Life Science Applications - Part II
  145. Relationship of Gensini score with retinal vessel diameter and arteriovenous ratio in senile CHD
  146. Effects of different enantiomers of amlodipine on lipid profiles and vasomotor factors in atherosclerotic rabbits
  147. Establishment of the New Zealand white rabbit animal model of fatty keratopathy associated with corneal neovascularization
  148. lncRNA MALAT1/miR-143 axis is a potential biomarker for in-stent restenosis and is involved in the multiplication of vascular smooth muscle cells
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