Next Article in Journal
The Therapeutic Potential of Chemo/Thermotherapy with Magnetoliposomes for Cancer Treatment
Next Article in Special Issue
Association Studies in Clinical Pharmacogenetics
Previous Article in Journal
Population Pharmacokinetics of Doxycycline, Administered Alone or with N-Acetylcysteine, in Chickens with Experimental Mycoplasma gallisepticum Infection
Previous Article in Special Issue
Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceutics
Volume 14
Issue 11
10.3390/pharmaceutics14112441
pharmaceutics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Pharmacogenetic Study of the Impact of ABCB1 Single Nucleotide Polymorphisms on the Response to Cyclosporine in Psoriasis Patients

by
Alexandr Chernov
1,2,
Daria Kilina
3,
Tatiana Smirnova
4 and
Elvira Galimova
5,*
1
Department of Life Sciences, Ben-Gurion University, Beer Sheva 84105, Israel
2
Department of General Pathology and Pathological Physiology, Institute of Experimental Medicine, St. Petersburg 197376, Russia
3
HLA Laboratory, V.A. Almazov National Medical Research Center of the Ministry of Health of Russia, St. Petersburg 197341, Russia
4
City Dispensary of Dermatology and Venereology, St. Petersburg 192102, Russia
5
Interdisciplinary Laboratory for Neurobiology, Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia
*
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(11), 2441; https://doi.org/10.3390/pharmaceutics14112441
Submission received: 20 September 2022 / Revised: 30 October 2022 / Accepted: 2 November 2022 / Published: 11 November 2022
(This article belongs to the Special Issue Association Studies in Clinical Pharmacogenetics)
Browse Figure
Versions Notes

Abstract

:
Psoriasis is a chronic, T cell-mediated skin disease affecting 2–3% of the Caucasian population. Cyclosporine A is a calcineurin inhibitor that acts selectively on T cells. The cyclosporine A treatment response has been suggested to be modulated by single-nucleotide polymorphisms (SNPs) in the ABCB1 gene. The aim of this research was to evaluate the effect of ABCB1 genetic variants that could affect the response to a cyclosporine treatment in Russian psoriasis patients with the ABCB1 genotype status. The ABCB1 T-129C, G1199A, C1236T, G2677T/A and C3435T SNPs in the 168 patients with psoriasis were genotyped by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and TaqMan SNP genotyping assays. The ABCB1 C1236T, G2677T/A and C3435T SNPs were significantly associated with a negative response to cyclosporine therapy. A very strong association was evident for the C3435T SNP in the ABCB1 gene in the allele, dominant and recessive models (OR = 2.58, OR = 4.01, OR = 2.50, respectively). ABCB1 C1236T and G2677T/A polymorphisms were significantly associated with a negative response to the cyclosporine therapy in the codominant, dominant and recessive models (p ˂ 0.05). Additionally, the haplotype analysis identified that the TGC haplotype is significantly associated with a negative response to cyclosporine therapy in psoriasis patients (p ˂ 0.05). The current study to the best of our knowledge is the first of its kind to be performed in the Russian population. In conclusion, the present results suggest an association between the ABCB1 genetic variants and unresponsiveness to cyclosporine in the Russian population. Further, larger studies are necessary to confirm our findings and replicate them in various ethnic populations before its implementation in the clinical practice.

1. Introduction

Psoriasis is a chronic T cell-mediated skin disease affecting 2–3% of the Caucasian population. Cyclosporine A (CsA) is a calcineurin inhibitor that acts selectively on T cells, thereby affecting the production of multiple inflammatory cytokines. CsA is used for the treatment of severe psoriasis, showing significant variability in its efficacy, which is associated with varying degrees of toxicity [1]. In particular, CsA is associated with several side effects including neurotoxicity, hypertension, hyperlipidemia and chronic nephrotoxicity. The absorption of CsA is highly variable in psoriasis patients which can be explained by the function and expression of the multidrug efflux transporter P-gp P-glycoprotein (MDR1 Multidrug Resistance Protein 1, ABCB1 ATP Binding Cassette Subfamily B Member 1) (Figure 1).
P-gp performs the function of the ATP-dependent efflux transporter pump for the substrates from the cytoplasm to the extracellular space [2]. ABCB1 plays a key role in the occurrence of adverse events and the efficacy of the treatment with CsA, methotrexate, etanercept, topical steroids, biologic agents and other [3]. At the tissue level, ABCB1 is expressed in the brain, skin, liver, pancreas, kidney, intestine, testis, ovary, endometrium, placenta and adrenal glands as well as in the blood–brain and blood–placenta barriers (Figure 1) [4]. At the cellular level, the expression of ABCB1 was established in the plasma membrane, Golgi apparatus, endoplasmic reticulum, lysosomes and endosomes [5,6]. The expression of ABCB1 in psoriasis lesional skin was detected to be significantly decreased [7]. ABCB1 expression was inhibited by CsA in the peripheral blood monocytes of rheumatoid arthritis patients [8]. Lown K.S. et al. revealed the significant role of intestinal P-glycoprotein in the first-pass elimination of CsA [9]. In mdr1a (murine MDR1 homologue) knockout mice, which were compared with wild-type mice, the CsA levels in the brain were significantly higher after the intravenous cyclosporine administration [10].
The multidrug resistance 1 (MDR1 or ABCB1) gene, which encodes a 170-kDa P-glycoprotein, is found on chromosome 7 and contains 29 exons. ABCB1 is a highly polymorphic gene. More than 990 ABCB1 SNPs have been identified, the allelic frequencies of which varies widely among different populations [11]. In general, it has been demonstrated that ABCB1 SNPs are detected in all of the studied populations [11,12]. Among the ABCB1 SNPs, three polymorphic variants, C3435T in exon 26, C1236T in exon 12 and G2677T/A in exon 21, were extensively investigated and were identified functionally important. African American people (10%) have the lowest frequencies of polymorphic alleles when they were compared with Caucasian people (42–46%) and Asian people (45%). Tang K. et al. examined the haplotypes and linkage disequilibrium architecture of the ABCB1 gene in Caucasian, African American, Chinese, Malaysian and Indian populations [13]. This study reported that the major haplotype 1236T-2677T-3435T is highly represented in the non-African populations, while the haplotype 1236C-2677G-3435C in the African American population indicating a varied haplotype diversity between the different populations. Kimchi-Sarfaty et al. performed C1236T, G2677T/A and C3435T SNPs analyses, and they determined their haplotypes in the Ashkenazi Jewish population [12]. The Ashkenazi Jewish population is similar to the Caucasian population in the allele and genotype frequencies, and the frequency of the common 1236T-2677T-3435T haplotype is 23.6% [12]. In another study, the frequency of the 3435C allele was lower in near Eastern Jewish population (0.445) and the Mediterranean group (0.58), while the frequencies of the C allele were quite comparable among the Ashkenazi (0.65), Yemenite (0.645), and North-African (0.615) Jewish populations [14].
Pharmacogenetic and pharmacogenomics studies have demonstrated the influence of the polymorphisms of drug-metabolizing enzymes, transporters and receptors in variable drug responses. Nevertheless, pharmacogenetic investigations of CsA are scarce. Single nucleotide polymorphisms (SNPs)/mutations and epigenetics modifications affect the expression and function of [15,16,17,18] P-gp, contributing to inter-individual and inter-ethical variabilities in the drug response and susceptibility to diseases. The SNPs have also been associated with several toxic effects [15]. Wang R. investigated the effect of common ABCB1 C1236T, G2677T/A and C3435T genetics variants on the sensitivity, intracellular accumulation, and efflux of tacrolimus, cyclosporine A, sirolimus and everolimus in transfected LLC-PK1 cells [19]. ABCB1 overexpression resulted in increased resistance of the LLC-PK1 cells to tacrolimus, cyclosporine A, sirolimus and everolimus [19]. Polymorphisms in the ABCB1 gene have been found to be associated with a susceptibility to ulcerative colitis [20,21,22,23,24,25], Parkinson’s disease [26,27,28], Alzheimer’s disease [29,30], cancer [31,32,33,34,35], bullous pemphigoid [36,37], the osteonecrosis of the femoral head [38,39], major depressive disorder [40,41,42] and ischemic strokes [43]. A meta-analysis demonstrated an association between the ABCB1 C3435T polymorphic variant and the dose-adjusted concentration of cyclosporine after a kidney transplantation [44]. In a study involving 84 Greek psoriasis patients, ABCB1 C3435T polymorphism contributed to a lower ABCB1 activity [45].
Though the genetic polymorphism of ABCB1 may affect the disposition to the drug, produce variable drug effects, and may contribute to the disease risk susceptibility, there has been no pharmacogenetic study which analyzed the relationship between ABCB1 and the effectiveness of a cyclosporine treatment in the Russian population. The present study aimed to analyze the effect of ABCB1 polymorphisms on the response to cyclosporine therapies in Russian psoriasis patients who have an ABCB1 genotype status.

2. Methods

2.1. Patients

A total of 168 Russian psoriasis patients of European descent were recruited for genotyping (Table 1). The age of the psoriasis patients ranged from 28 to 93 (mean ± standard deviation (SD), 66.3 ± 15.0; 65 females and 103 males). The patients were treated in the City dispensary of Dermatology and Venereology of Saint Petersburg, Russia. Each patient was evaluated according to the standard protocol, including a complete history and physical examination. Descriptive characteristics on psoriasis patient’s demographics, comorbidities, and treatment history were collected. All of the patients had the classical pattern of skin lesions (chronic plaque lesions and psoriasis vulgaris) which were confirmed by a dermatologist. The Psoriasis Area and Severity Index (PASI) was applied to assess the disease activity and the effectiveness of the treatment [45]. All of the patients were treated with cyclosporine Neoral® (NEO, Novartis, Basel, Switzerland) oral solution containing 100 mg of cyclosporine/mL twice daily in a dose of 3 mg/kg/day. The patients had not been administered any other drugs during the period of three months. The patients were classified as responders (PASI score > 75%) and non-responders (PASI ≤ 50%) after three months of treatment with cyclosporine. This study was conducted in accordance with the Declaration of Helsinki. Each individual provided written informed consent before being entered into study. The study was approved by the local hospital ethics committee.

2.2. DNA Isolation and Genotyping

Peripheral blood samples of all of the subjects were collected in ethylenediamine tetraacetic acid (EDTA) tube and stored at −70 °C. The genomic DNA was extracted from peripheral blood samples using a standard phenol-chloroform extraction method [46]. The DNA samples were quantified twice using the NanoDrop Spectrophotometer (Thermo Scientific, Waltham, MA, USA). The samples of the genomic DNA were stored at −80 °C until they were used. One hundred and sixty-eight patients treated with cyclosporine were genotyped for ABCB1 polymorphisms using polymerase chain reaction-restriction fragment length polymorphism analysis PCR-RFLP and verified by TaqMan SNP genotyping assays. The ABCB1 T-129C, G1199A, C1236T, G2677T/A and C3435T SNPs were selected from a previous study [29] and the National Center for Biotechnology Information (NCBI) website (http://www.ensembl.org; www.ncbi.nlm.nih.gov/SNP (accessed on 1 January 2021)). We followed the genotyping protocol described by Vasilopoulos et al. in 2014 [29]. Primer sequences and annealing temperatures used for the analysis of each polymorphism are summarized in Table 2. We analyzed the T-129C, G1199A, C1236T, G2677T/A and C3435T SNPs in the ABCB1 gene (Table 2).
We followed the genotyping protocol described by Vasilopoulos et al. in 2014 [45]. The primer sequences and annealing temperatures used for the analysis of each polymorphism are summarized in Table 3. Moreover, the SNPs of the ABCB1 gene were re-analyzed by a Real-Time PCR using TaqMan® probes—C_27487486_10 was used for T-129C, C_15951365_20 was used for G1199A, C_7586662_10 was used for C1236T, C_11711720C_30 and C_11711720D_40 were used for G2677T/A, and C_7586657_20 for C3435T (Applied Biosystems Inc., Waltham, MA, USA) with TaqMan® Genotyping Master Mix, respectively.

2.3. Statistical Analysis

The allele, genotype, and genetic models frequencies and Hardy–Weinberg equilibriums were analyzed using the PLINK version 1.90. The differences in the Hardy–Weinberg equilibrium among all of the individuals in the allele and genetic model frequencies between the studied groups were assessed by Chi square (χ2) test. The statistical significance threshold was set to 0.05 for all of the tests. The odds ratios (ORs) and 95% confidence intervals (CI) were calculated where a statistically significant difference in the allele and genetic model frequencies was found. The linkage disequilibrium (LD) block between the SNP pairs in the genomic region of the ABCB1 locus and haplotypes were estimated using Haploview version 4.1 (Daly Lab, Cambridge, MA, USA) [47,48].

3. Results

3.1. Allele and Genetic Model Association Analysis with Response to Cyclosporine Treatment

Table 1 shows the clinical characteristics of the psoriasis patients who participated in the current study. The patients were classified as responders (PASI score > 75%) and non-responders (PASI ≤ 50%) after three months of treatment with cyclosporine.
All of the SNPs were in the Hardy–Weinberg equilibrium. The results of the ABCB1 T-129C, G1199A, C1236T, G2677T/A and C3435T SNP association analysis with response to the cyclosporine treatment are summarized in Table 3. The ABCB1 C1236T, G2677T/A and C3435T SNPs polymorphisms were significantly associated with a negative response to the cyclosporine therapy. The most significant results were found with C3435T SNP and were associated with an unresponsiveness to the cyclosporine therapy in the allele, dominant and recessive models (Table 4).
The allele 3435T in the ABCB1 gene demonstrated an association with a negative response to the cyclosporine therapy (OR = 2.58 95%, CI = 1.64–4.06) in the Russian population. Namely, the frequency of allele T of the C3435T SNP in the ABCB1 gene was significantly higher in the nonresponders compared to that in the responders (0.57% vs. 0.34%, respectively; Table 4). The risk of no response to the cyclosporine treatment was 1.6-fold higher in the carriers of the dominant model TT + CT vs. CC compared with the recessive TT vs. CC + CT model carriers (OR = 4.01, OR = 2.50, respectively). Concerning the G2677T/A SNP, because only one psoriasis patient had an A allele, the carriers of that allele were excluded from the analyses. Moreover, the ABCB1 C1236T and G2677T/A polymorphisms were significantly associated with a negative response to the cyclosporine therapy in the codominant, dominant and recessive models (p < 0.005). In addition, the association analysis revealed no statistically significant difference in the allele and genotype frequencies between the responders and nonresponders for the T-129C and G1199A SNPs.

3.2. Haplotype Association Analysis with Response to Cyclosporine Treatment

The haplotype specific analyses of the ABCB1 polymorphisms are presented in Table 5. The haplotypes with a frequency below 1% were excluded from the analyses, thereby improving the statistical power. The linkage disequilibrium (LD) analysis indicated the existence of one haplotype block (formed by the C3435T, G2677T/A and C1236T SNPs) in the chromosome 7 region among the Russian group. Additionally, the haplotype analysis provided one haplotype that was significantly associated with a negative response to the cyclosporine therapy in the Russian population. Namely, the block 1 haplotype TGC frequency was significantly higher in the nonresponders compared to the responders (0.27% vs. 0.11%, respectively; Table 4). In addition, the association analysis revealed no statistically significant difference in the haplotype frequencies between the responders and nonresponders for the haplotypes CTC, CGC, CTT and TTC.

4. Discussion

The development of drug resistance decreases the effectiveness of drug treatment and increases the cost of drug development. In addition, the treatment of psoriasis is associated with a considerable economic burden, with the average annual costs per patient being EUR 11928 in Sweden, EUR 8372 in Italy, and EUR 2866–6707 in Germany based on the treatment type [49]. In searching for the discovery in the multidrug resistance phenotype, many studies have been focused on the MDR1 gene. Taking into account that cyclosporine is frequently used in the treatment of various autoimmune diseases, such as psoriasis, rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus and diabetes mellitus, the identification of MDR1 polymorphisms may help us to find the cause of the ineffectiveness of their therapy.
In this study, we identified the SNPs in the ABCB1 gene as genetic variants with clinically relevant effects on the psoriasis response of cyclosporine. The ABCB1 C3435T, G2677T/A, and C1236T polymorphisms were significantly associated with a negative response to the cyclosporine therapy in the allele, codominant, dominant and recessive models. The most significant result was obtained with ABCB1 C3435T SNP that was associated with a negative response to the cyclosporine therapy. Additionally, the haplotype analysis presented that the TGC haplotype was significantly associated with a negative response to the cyclosporine therapy in the Russian population. Our study had some limitations. Firstly, we did not have a replication cohort in the present study, which would have validated our results, and secondly, our study had a limited sample size. Further studies of different populations are required in order to explore the influence of these variants of the ABCB1 gene on the effectiveness of the cyclosporine treatment in psoriasis patients.
The 3435T allele frequency is known to vary amongst populations with a high prevalence in the Caucasian population [50]. The synonymous C3435T SNP seems to be of the highest biological importance in protein functioning by changing the mRNA stability, performing alternative splicing or by the modification of the translation efficiency [35]. The homozygous TT genotype is associated with more than two-fold lower duodenal ABCB1 protein expression when it was compared with the CC samples [15].
Numerous pharmacogenetic studies have revealed and confirmed the C3435T locus as a potential genetic marker of the effectiveness of the drug treatment of psoriasis, epilepsy, organ transplantation and cancer [44,45,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]. Vasilopoulos et al. found that there were associations of the C3435T SNP with a negative response to cyclosporine in the Greek population [45]. A meta-analysis demonstrated an association between the ABCB1 C3435T polymorphic variant and the dose-adjusted concentration of cyclosporine after a kidney transplantation [44]. The effect of C3435T polymorphism on the pharmacokinetics of tacrolimus in liver transplantation was confirmed in Caucasian populations [51]. The studies of organ transplant Caucasian patients have reported on the associations of the C3435T polymorphisms with higher calcineurin inhibitors (CNIs: cyclosporine and tacrolimus) concentrations [52,53,54,55], whereas the association investigations in Asian patients indicated that the C3435T genetic variant did not influence the CNI concentrations [56,57,58,59,60]. Adult cardiac transplant studies have demonstrated inconsistent results [61,62]. In study of 170 heart transplant recipients, the ABCB1 3435CC genotype was associated with an increased risk of rejection [61]. Taegtmeyer et al. did not find the ABCB1 3435CC genotype to be risk factors for the development of acute rejection [62].
Kwan et al. investigated impact of the ABCB1 C3435T SNP in drug resistance in 746 Han Chinese people, and they showed a significantly higher the TT genotype frequency in the patients with drug-resistant epilepsy [63]. However, the effect the C3435T SNP was not confirmed in some studies that were conducted on Caucasian populations [64,65]. Nevertheless, a meta-analysis in 3,912 drug-resistant epileptic patients and 4,419 epileptic patients established the association C3435T polymorphism with drug resistance in epilepsy in a Caucasian population [66]. A subsequent meta-analysis detected the association of the ABCB1 3435TT genotype with the risk of antiepileptic drugs resistance [67].
Numerous associations’ studies and meta-analyses have established the impact of the ABCB1 rs1045642 genetic variant in cancer treatment outcomes concerning chemotoxicity, overall survival, and therapeutic responses. The impact of the C3435T SNP on the imatinib response in chronic myeloid leukemia (CML) patients have been widely estimated, however, the results of the studies were contradictory. A meta-analysis by combining data from a total of 12 studies including 1826 patients indicated that the 3435T allele predicted a worse response to imatinib in CML patients. Loscocco et al. found that the ABCB1 3435TT genotype correlated with a higher probability to achieve an MR3 molecular response in a shorter time in 90 CML patients that were treated with nilotinib [68]. Gregers et al. observed higher liver toxicity values after high-dose methotrexate was administered to acute lymphoblastic leukemia patients with the 3435CC variant versus the 3435CT/TT one [69]. In a meta-analysis involving nine (770 patients), five (566 patients) and three studies (367 patients), no significant association of C3435T in a dominant genetic model with a response to chemotherapy in patients with breast cancer was seen [70]. However, the results did not change after the stratification by ethnicity, cancer type and response criteria [70]. Schaich et al. examined the association of the genetic variants of the ABCB1 gene with the survival of glioblastoma patients who were treated with temozolomide in [71]. The ABCB1 3435CC genotype is associated with a 37% survival rate in glioblastoma patients after a temozolomide treatment [71]. The carriers of the homozygous 3435CC genotype had a higher survival rate when they were compared with the heterozygous genotype carriers in an Indian population [72]. Malmström et al. found a significant correlation with survival for the ABCB1 G1199A SNP in a Swedish population, with the median OS for the homozygous GG patients being 18.2 months versus 11.5 months for the heterozygous AG (p = 0.012) [73].
In total, there are inconsistent results in the studies regarding the effects of ABCB1 polymorphisms on the treatment response in patients with different diseases, and these can be due to them having small sample sizes, inter-ethical variability, differences in concomitant medication and using single time-point sampling [74].

5. Conclusions

In conclusion, we demonstrated a strong association between the cyclosporine therapy in psoriasis and the ABCB1 C1236T, G2677T/A and C3435T SNPs. Further studies with a larger sample size are needed to verify this issue. The detection of pharmacogenetic markers of a treatment response may be useful in predicting the clinical response to psoriasis therapies, and these would help in the improvement of personalized therapy. In future, combination OMICs technologies with known clinical and immunological data will allow us to identify the potential pharmacogenetic markers and therapeutic targets [3].

Author Contributions

A.C. and E.G. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: E.G. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: E.G. and T.S. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: D.K. and E.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Higher Education of the Russian Federation, grant number No 075-15-2022-302 (20 April 2022) and the Federal State Budgetary Scientific Institution «Institute of Experimental Medicine» (FSBSI«IEM») and the Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences (state assignment, 2021–2022).

Institutional Review Board Statement

This study was conducted in accordance with the Declaration of Helsinki. The study was approved by the local hospital ethics committee (No 37818).

Informed Consent Statement

Each individual provided written informed consent before being entered into study.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Prieto-Pérez, R.; Cabaleiro, T.; Daude´n, E.; Ochoa, D.; Román, M.; Abad-Santos, F. Pharmacogenetics of topical and systemic treatment of psoriasis. Pharmacogenomics 2013, 14, 1623–1634. [Google Scholar] [CrossRef] [PubMed]
  2. Schinkel, A.H. The physiological function of drug-transporting P-glycoproteins. Semin. Cancer Biol. 1997, 8, 161–170. [Google Scholar] [CrossRef] [PubMed]
  3. Sutherland, A.; Power, R.; Rahman, P.; O’Rielly, D.D. Pharmacogenetics and pharmacogenomics in psoriasis treatment: Current challenges and future prospects. Expert Opin. Drug Metab. Toxicol. 2016, 12, 923–935. [Google Scholar] [CrossRef] [PubMed]
  4. Silva, R.; Vilas-Boas, V.; Carmo, H.; Dinis-Oliveira, R.J.; Carvalho, F.; Bastos, M.D.L.; Remião, F. Modulation of P-glycoprotein efflux pump: Induction and activation as a therapeutic strategy. Pharmacol. Ther. 2015, 149, 1–123. [Google Scholar] [CrossRef]
  5. Schinkel, A.; Smit, J.; van Tellingen, O.; Beijnen, J.; Wagenaar, E.; van Deemter, L.; Mol, C.; van der Valk, M.; Robanus-Maandag, E.; Riele, H.T.; et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994, 77, 491–502. [Google Scholar] [CrossRef]
  6. Fu, D.; Arias, I.M. Intracellular trafficking of P-glycoprotein. Int. J. Biochem. Cell Biol. 2012, 44, 461–464. [Google Scholar] [CrossRef] [Green Version]
  7. Diamanti, A.P.; Rosado, M.; Germano, V.; Scarsella, M.; Giorda, E.; Podestà, E.; D’Amelio, R.; Carsetti, R.; Laganà, B. Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthritis by cyclosporine A: Modulation of P-glycoprotein function. Clin. Immunol. 2011, 138, 9–13. [Google Scholar] [CrossRef]
  8. Hashimoto, N.; Nakamichi, N.; Nanmo, H.; Kimura, K.-I.; Masuo, Y.; Sakai, Y.; Schinkel, A.H.; Sato, S.; Soga, T.; Kato, Y. Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein. Pharm. Res. 2019, 36, 158. [Google Scholar] [CrossRef]
  9. Lown, K.S.; Mayo, R.R.; Leichtman, A.B.; Hsiao, H.-L.; Turgeon, D.K.; Schmiedlin-Ren, P.; Brown, M.B.; Guo, W.; Rossi, S.J.; Benet, L.Z.; et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine*. Clin. Pharmacol. Ther. 1997, 62, 248–260. [Google Scholar] [CrossRef] [Green Version]
  10. Schinkel, A.H.; Wagenaar, E.; van Deemter, L.; Mol, C.; Borst, P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Investig. 1995, 96, 1698–1705. [Google Scholar] [CrossRef]
  11. Kroetz, D.L.; Pauli-Magnus, C.; Hodges, L.M.; Huang, C.C.; Kawamoto, M.; Johns, S.J.; Stryke, D.; E Ferrin, T.; DeYoung, J.; Taylor, T.; et al. Pharmacogenetics of membrane transporters investigators. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003, 13, 481–494. [Google Scholar] [CrossRef] [PubMed]
  12. Kimchi-Sarfaty, C.; Marple, A.H.; Shinar, S.; Kimchi, A.M.; Scavo, D.; Roma, M.I.; Kim, I.-W.; Jones, A.; Arora, M.; Gribar, J.; et al. Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics 2007, 8, 29–39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Tang, K.; Wong, L.P.; Lee, E.J.; Chong, S.S.; Lee, C.G. Genomic evidence for recent positive selection at the human MDR1 gene locus. Hum. Mol. Genet. 2004, 13, 783–797. [Google Scholar] [CrossRef] [PubMed]
  14. Ostrovsky, O.; Nagler, A.; Korostishevsky, M.; Gazit, E.; Galski, H. Genotype and Allele Frequencies of C3435T Polymorphism of the MDR1 Gene in Various Jewish Populations of Israel. Ther. Drug Monit. 2004, 26, 679–684. [Google Scholar] [CrossRef] [PubMed]
  15. Hoffmeyer, S.; Burk, O.; von Richter, O.; Arnold, H.P.; Brockmöller, J.; Johne, A.; Cascorbi, I.; Gerloff, T.; Roots, I.; Eichelbaum, M.; et al. Functional polymorphism of the human multidrug-resistance gene: Multiple sequence variations and correlations of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. USA 2000, 97, 3473–3478. [Google Scholar] [CrossRef] [PubMed]
  16. Nakamura, T.; Sakaeda, T.; Horinouchi, M.; Tamura, T.; Aoyama, N.; Shirakawa, T.; Matsuo, M.; Kasuga, M.; Okumura, K. Effect of the mutation (C3435T) et exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin. Pharmacol. Ther. 2002, 71, 297–303. [Google Scholar] [CrossRef]
  17. Nikisch, G.; Eap, C.B.; Baumann, P. Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: A pilot study. Pharmacol. Res. 2008, 58, 344–347. [Google Scholar] [CrossRef]
  18. Uhr, M.; Grauer, M.T.; Yassouridis, A.; Ebinger, M. Blood–brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J. Psychiatr. Res. 2007, 41, 179–188. [Google Scholar] [CrossRef]
  19. Wang, R.; Sun, X.; Deng, Y.-S.; Qiu, X.-W. Effects of MDR1 1236C > T-2677G > T-3435C > T polymorphisms on the intracellular accumulation of tacrolimus, cyclosporine A, sirolimus and everolimus. Xenobiotica 2019, 49, 1373–1378. [Google Scholar] [CrossRef]
  20. Schwab, M.; Schaeffeler, E.; Marx, C.; Fromm, M.F.; Kaskas, B.; Metzler, J.; Stange, E.; Herfarth, H.; Schoelmerich, J.; Gregor, M.; et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003, 124, 26–33. [Google Scholar] [CrossRef]
  21. Ho, G.-T.; Soranzo, N.; Nimmo, E.; Tenesa, A.; Goldstein, D.; Satsangi, J. ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: Discrimination of critical variants using a gene-wide haplotype tagging approach. Hum. Mol. Genet. 2006, 15, 797–805. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Huebner, C.; Browning, B.L.; Petermann, I.; Han, D.Y.; Philpott, M.; Barclay, M.; Gearry, R.; McCulloch, A.; Demmers, P.; Ferguson, L.R. Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis. Inflamm. Bowel Dis. 2009, 15, 1784–1793. [Google Scholar] [CrossRef] [PubMed]
  23. Juyal, G.; Midha, V.; Amre, D.; Sood, A.; Seidman, E.; Thelma, B. Associations between common variants in the MDR1 (ABCB1) gene and ulcerative colitis among North Indians. Pharm. Genom. 2009, 19, 77–85. [Google Scholar] [CrossRef]
  24. Mijac, D.; Vukovic-Petrovic, I.; Mijac, V.; Perovic, V.; Milić, N.; Djuranovic, S.; Bojic, D.; Popovic, D.; Culafić, D.; Krstic, M.; et al. MDR1 gene polymorphisms are associated with ulcerative colitis in a cohort of Serbian patients with inflammatory bowel disease. PLoS ONE 2018, 13, e0194536. [Google Scholar] [CrossRef] [Green Version]
  25. Petryszyn, P.; Dudkowiak, R.; Gruca, A.; Jaźwińska-Tarnawska, E.; Ekk-Cierniakowski, P.; Poniewierka, E.; Wiela-Hojeńska, A.; Głowacka, K. C3435T Polymorphism of the ABCB1 Gene in Polish Patients with Inflammatory Bowel Disease: A Case–Control and Meta-Analysis Study. Genes 2021, 12, 1419. [Google Scholar] [CrossRef]
  26. Westerlund, M.; Belin, A.C.; Anvret, A.; Håkansson, A.; Nissbrandt, H.; Lind, C.; Sydow, O.; Olson, L.; Galter, D. Association of a polymorphism in the ABCB1 gene with Parkinson’s disease. Park. Relat. Disord. 2009, 15, 422–424. [Google Scholar] [CrossRef]
  27. Ahmed, S.S.; Husain, R.A.; Kumar, S.; Ramakrishnan, V. Association between MDR1 gene polymorphisms and Parkinson’s disease in Asian and Caucasian populations: A meta-analysis. J. Neurol. Sci. 2016, 368, 255–262. [Google Scholar] [CrossRef]
  28. Huang, H.; Peng, C.; Liu, Y.; Liu, X.; Chen, Q.; Huang, Z. Genetic association of NOS1 exon18, NOS1 exon29, ABCB1 1236C/T, and ABCB1 3435C/T polymorphisms with the risk of Parkinson’s disease: A meta-analysis. Medicine 2016, 95, e4982. [Google Scholar] [CrossRef]
  29. Cascorbi, I.; Flüh, C.; Remmler, C.; Haenisch, S.; Faltraco, F.; Grumbt, M.; Peters, M.; Brenn, A.; Thal, D.R.; Warzok, R.W.; et al. Association of ATP-binding cassette transporter variants with the risk of Alzheimer’s disease. Pharmacogenomics 2013, 14, 485–494. [Google Scholar] [CrossRef]
  30. Zhong, X.; Liu, M.Y.; Sun, X.H.; Wei, M.J. Association between ABCB1 polymorphisms and haplotypes and Alzheimer’s disease: A meta-analysis. Sci. Rep. 2016, 6, 32708. [Google Scholar] [CrossRef]
  31. Siegsmund, M.; Brinkmann, U.; Scháffeler, E.; Weirich, G.; Schwab, M.; Eichelbaum, M.; Fritz, P.; Burk, O.; Decker, J.; Alken, P.; et al. Association of the P-glycoprotein Transporter MDR1(C3435T) Polymorphism with the Susceptibility to Renal Epithelial Tumors. J. Am. Soc. Nephrol. 2002, 13, 1847–1854. [Google Scholar] [CrossRef] [Green Version]
  32. Wang, L.-H.; Song, Y.-B.; Zheng, W.-L.; Jiang, L.; Ma, W.-L. The association between polymorphisms in the MDR1 gene and risk of cancer: A systematic review and pooled analysis of 52 case–control studies. Cancer Cell Int. 2013, 13, 46. [Google Scholar] [CrossRef] [Green Version]
  33. Yan, Y.; Liang, H.; Xie, L.; He, Y.; Li, M.; Li, R.; Li, S.; Qin, X. Association of MDR1 G2677T polymorphism and leukemia risk: Evidence from a meta-analysis. Tumor Biol. 2014, 35, 2191–2197. [Google Scholar] [CrossRef] [Green Version]
  34. Ma, C.-X.; Sun, Y.-H.; Wang, H.-Y. ABCB1 polymorphisms correlate with susceptibility to adult acute leukemia and response to high-dose methotrexate. Tumor Biol. 2015, 36, 7599–7606. [Google Scholar] [CrossRef]
  35. Ruan, L.; Ma, L.; Liu, H.; Yang, H.; Feng, Y. ABCB1 C3435T polymorphism is associated with leukemia susceptibility: Evidence from a meta-analysis. OncoTargets Ther. 2015, 8, 1009–1015. [Google Scholar] [CrossRef] [Green Version]
  36. Rychlik-Sych, M.; Barańska, M.; Dudarewicz, M.; Skrętkowicz, J.; Żebrowska, A.; Owczarek, J.; Waszczykowska, E. Polymorphism in the ABCB1 gene is associated with the risk of bullous pemphigoid in a polish population. JDDG J. Dtsch. Dermatol. Ges. 2017, 15, 499–505. [Google Scholar] [CrossRef]
  37. Rychlik-Sych, M.; Barańska, M.; Dudarewicz, M.; Skrętkowicz, J.; Żebrowska, A.; Woźniacka, A.; Owczarek, J.; Orszulak-Michalak, D.; Waszczykowska, E. Haplotypes of ABCB1 1236C> T (rs1128503), 2677G> T/A (rs2032582), and 3435C> T (rs1045642) in patients with bullous pemphigoid. Arch. Dermatol. Res. 2018, 310, 515–522. [Google Scholar] [CrossRef] [Green Version]
  38. Zhang, Y.; Xie, H.; Zhao, D.; Wang, B.; Yang, L.; Meng, Q. Association of ABCB1 C3435T polymorphism with the susceptibility to osteonecrosis of the femoral head: A meta-analysis. Medicine 2017, 96, e6049. [Google Scholar] [CrossRef]
  39. Huang, R.; Zhan, Q.; Hu, W.; Yang, R.; Cheng, N.; Han, Y.; Yue, X. Association of ABCB1 and CYP450 Gene Polymorphisms and their DNA Methylation Status with Steroid-Induced Osteonecrosis of the Femoral Head in the Chinese Population. Genet. Test. Mol. Biomark. 2020, 24, 789–797. [Google Scholar] [CrossRef]
  40. Fujii, T.; Ota, M.; Hori, H.; Sasayama, D.; Hattori, K.; Teraishi, T.; Yamamoto, N.; Hashikura, M.; Tatsumi, M.; Higuchi, T.; et al. Association between the functional polymorphism (C3435T) of the gene encoding P-glycoprotein (ABCB1) and major depressive disorder in the Japanese population. J. Psychiatr. Res. 2012, 46, 555–559. [Google Scholar] [CrossRef]
  41. Zhang, L.; Xie, W.-W.; Wu, R.-R.; Yu, Y.; Zhao, J.-P.; Li, L.-H. Case-control association study of ABCB1 gene and major depressive disorder in a local Chinese Han population. Neuropsychiatr. Dis. Treat. 2015, 11, 1967–1971. [Google Scholar] [CrossRef] [Green Version]
  42. Jeleń, A.M.; Sałagacka, A.; Żebrowska-Nawrocka, M.; Mirowski, M.; Talarowska, M.; Gałecki, P.; Balcerczak, E. The Influence of C3435T Polymorphism of the ABCB1 Gene on Genetic Susceptibility to Depression and Treatment Response in Polish Population—Preliminary Report. Int. J. Med. Sci. 2015, 12, 974–979. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Kim, Y.-O.; Kim, S.-Y.; Yun, D.H.; Lee, S.-W. Association between ABCB1 Polymorphisms and Ischemic Stroke in Korean Population. Exp. Neurobiol. 2012, 21, 164–171. [Google Scholar] [CrossRef] [Green Version]
  44. Lee, J.; Wang, R.; Yang, Y.; Lu, X.; Zhang, X.; Wang, L.; Lou, Y. The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta-Analysis. Basic Clin. Pharmacol. Toxicol. 2015, 117, 117–125. [Google Scholar] [CrossRef]
  45. Vasilopoulos, Y.; Sarri, C.; Zafiriou, E.; Patsatsi, A.; Stamatis, C.; Ntoumou, E.; Fassos, I.; Tsalta, A.; Karra, A.; Roussaki-Schulze, A.; et al. A pharmacogenetic study of ABCB1 polymorphisms and cyclosporine treatment response in patients with psoriasis in the Greek population. Pharm. J. 2014, 14, 523–525. [Google Scholar] [CrossRef]
  46. Mathew, C.G.P. The isolation of high molecular weight eukaryotic DNA. Nucleic Acids 1985, 2, 31–34. [Google Scholar]
  47. Barrett, J.C.; Fry, B.; Maller, J.; Daly, M.J. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics 2004, 21, 263–265. [Google Scholar] [CrossRef] [Green Version]
  48. Gabriel, S.B.; Schaffner, S.F.; Nguyen, H.; Moore, J.M.; Roy, J.; Blumenstiel, B.; Higgins, J.; DeFelice, M.; Lochner, A.; Faggart, M.; et al. The Structure of Haplotype Blocks in the Human Genome. Science 2002, 296, 2225–2229. [Google Scholar] [CrossRef] [Green Version]
  49. Feldman, S.R.; Burudpakdee, C.; Gala, S.; Nanavaty, M.; Mallya, U.G. The economic burden of psoriasis: A systematic literature review. Expert Rev. Pharmacoecon. Outcomes Res. 2014, 14, 685–705. [Google Scholar] [CrossRef]
  50. Ameyaw, M.M.; Regateiro, F.; Li, T.; Liu, X.; Tariq, M.; Mobarek, A.; Thornton, N.; Folayan, G.O.; Githang’a, J.; Indalo, A.; et al. MDR1 pharmacogenetics: Frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 2001, 11, 217–221. [Google Scholar] [CrossRef]
  51. Liu, Y.Y.; Li, C.; Cui, Z.; Fu, X.; Zhang, S.; Fan, L.L.; Ma, J.; Li, G. The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: A meta-analysis. Gene 2013, 531, 476–488. [Google Scholar] [CrossRef]
  52. Foote, C.J.; Greer, W.; Kiberd, B.; Fraser, A.; Lawen, J.; Nashan, B.; Belitsky, P. Polymorphisms of Multidrug Resistance Gene (MDR1) and Cyclosporine Absorption in De Novo Renal Transplant Patients. Transplantation 2007, 83, 1380–1384. [Google Scholar] [CrossRef]
  53. Tejera, B.I.; Rubio, M.A.; Martínez-Moreno, J.; Malia, M.R.; Arizón, J.M.; García, A.S. Pharmacogenetic analysis of the absorption kinetics of cyclosporine in a population of Spanish cardiac transplant patients. Farm. Hosp. 2009, 33, 324–329. [Google Scholar]
  54. Yates, C.R.; Zhang, W.; Song, P.; Li, S.; Gaber, A.O.; Kotb, M.; Honaker, M.R.; Alloway, R.R.; Meibohm, B. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J. Clin. Pharmacol. 2003, 43, 555–564. [Google Scholar] [CrossRef]
  55. Soria, M.L.M.; Berga, J.K.; Catalán, S.B.; Payá, J.M.; Mateu, L.P.; Torres, N.J. Genetic polymorphisms and individualized tacrolimus dosing. Transpl. Proc. 2010, 42, 3031–3033. [Google Scholar] [CrossRef]
  56. Chowbay, B.; Cumaraswamy, S.; Cheung, Y.B.; Zhou, Q.; Lee, E.J.D. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 2003, 13, 89–95. [Google Scholar] [CrossRef]
  57. Sun, J.-Y.; Wang, X.-G.; Zou, Y.-G.; Wang, Y.-P.; Liang, D.-R.; Liang, M.-Z.; Miao, J. Association of CYP3A5 and MDR1 genetic polymorphisms with the blood concentration of tacrolimus in Chinese liver and renal transplant recipients. Sichuan da Xue Xue Bao 2013, 44, 573–577. [Google Scholar]
  58. Kuzuya, T.; Kobayashi, T.; Moriyama, N.; Nagasaka, T.; Yokoyama, I.; Uchida, K.; Nakao, A.; Nabeshima, T. Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients1. Transplantation 2003, 76, 865–868. [Google Scholar] [CrossRef]
  59. Hu, Y.-F.; Qiu, W.; Liu, Z.-Q.; Zhu, L.-J.; Liu, Z.-Q.; Tu, J.-H.; Wang, D.; Li, Z.; He, J.; Zhong, G.-P.; et al. Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation. Clin. Exp. Pharmacol. Physiol. 2006, 33, 1093–1098. [Google Scholar] [CrossRef]
  60. Goto, M.; Masuda, S.; Saito, H.; Uemoto, S.; Kiuchi, T.; Tanaka, K.; Inui, K.I. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 2002, 12, 451–457. [Google Scholar] [CrossRef]
  61. Barnard, J.B.; Richardson, S.; Sheldon, S.; Fildes, J.; Pravica, V.; Hutchinson, I.V.; Leonard, C.T.; Yonan, N. The MDR1/ABCB1 Gene, a High-Impact Risk Factor for Cardiac Transplant Rejection. Transplantation 2006, 82, 1677–1682. [Google Scholar] [CrossRef] [Green Version]
  62. Taegtmeyer, A.B.; Breen, J.B.; Smith, J.; Burke, M.; Leaver, N.; Pantelidis, P.; Lyster, H.; Yacoub, M.H.; Barton, P.J.R.; Banner, N.R. ATP-Binding Cassette Subfamily B Member 1 Polymorphisms Do Not Determine Cyclosporin Exposure, Acute Rejection or Nephrotoxicity After Heart Transplantation. Transplantation 2010, 89, 75–82. [Google Scholar] [CrossRef]
  63. Kwan, P.; Baum, L.; Wong, V.; Ng, P.W.; Lui, C.H.; Sin, N.C.; Hui, A.C.; Yu, E.; Wong, L.K. Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. Epilepsy Behav. 2007, 11, 112–117. [Google Scholar] [CrossRef]
  64. Tan, N.C.K.; Heron, S.E.; Scheffer, I.E.; Pelekanos, J.T.; McMahon, J.M.; Vears, D.F.; Mulley, J.C.; Berkovic, S.F. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology 2004, 63, 1090–1092. [Google Scholar] [CrossRef]
  65. Sills, G.J.; Mohanraj, R.; Butler, E.; McCrindle, S.; Collier, L.; Wilson, E.A.; Brodie, M.J. Lack of Association between the C3435T Polymorphism in the Human Multidrug Resistance (MDR1) Gene and Response to Antiepileptic Drug Treatment. Epilepsia 2005, 46, 643–647. [Google Scholar] [CrossRef]
  66. Lv, W.-P.; Han, R.-F.; Shu, Z.-R. Associations between the C3435T polymorphism of the ABCB1 gene and drug resistance in epilepsy: A meta-analysis. Int. J. Clin. Exp. Med. 2014, 7, 3924–3932. [Google Scholar]
  67. Chouchi, M.; Kaabachi, W.; Klaa, H.; Tizaoui, K.; Turki, I.B.Y.; Hila, L. Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: Updated systematic review and meta-analysis. BMC Neurol. 2017, 17, 32. [Google Scholar] [CrossRef] [Green Version]
  68. Loscocco, F.; Visani, G.; Ruzzo, A.; Bagaloni, I.; Fuligni, F.; Galimberti, S.; Di Paolo, A.; Stagno, F.; Pregno, P.; Annunziata, M.; et al. Clinical Relevance of ABCB1, ABCG2, and ABCC2 Gene Polymorphisms in Chronic Myeloid Leukemia Patients Treated with Nilotinib. Front. Oncol. 2021, 11, 672287. [Google Scholar] [CrossRef]
  69. Gregers, J.; Gréen, H.; Christensen, I.J.; Dalhoff, K.; Schroeder, H.; Carlsen, N.; Rosthoej, S.; Lausen, B.; Schmiegelow, K.; Peterson, C. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharm. J. 2015, 15, 372–379. [Google Scholar] [CrossRef]
  70. Madrid-Paredes, A.; Cañadas-Garre, M.; Sánchez-Pozo, A.; Expósito-Ruiz, M.; Calleja-Hernández, M. ABCB1 gene polymorphisms and response to chemotherapy in breast cancer patients: A meta-analysis. Surg. Oncol. 2017, 26, 473–482. [Google Scholar] [CrossRef] [Green Version]
  71. Schaich, M.; Kestel, L.; Pfirrmann, M.; Robel, K.; Illmer, T.; Kramer, M.; Dill, C.; Ehninger, G.; Schackert, G.; Krex, D. A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann. Oncol. 2008, 20, 175–181. [Google Scholar] [CrossRef] [PubMed]
  72. Munisamy, M.; Munisamy, S.; Kumar, J.P.; Jose, A.; Thomas, L.; Baburaj, G.; Subbiah, V. Pharmacogenetics of ATP binding cassette transporter MDR1(1236C>T) gene polymorphism with glioma patients receiving Temozolomide-based chemoradiation therapy in Indian population. Pharm. J. 2021, 21, 262–272. [Google Scholar] [CrossRef] [PubMed]
  73. Malmström, A.; Łysiak, M.; Åkesson, L.; Jakobsen, I.; Mudaisi, M.; Milos, P.; Hallbeck, M.; Fomichov, V.; Broholm, H.; Grunnet, K.; et al. ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide. Pharm. J. 2020, 20, 213–219. [Google Scholar] [CrossRef] [PubMed]
  74. Xiao, Q.; Zhou, Y.; Lauschke, V.M. Ethnogeographic and inter-individual variability of human ABC transporters. Qual. Life Res. 2020, 139, 623–646. [Google Scholar] [CrossRef] [PubMed]
Pharmaceutics 14 02441 g001 550
Figure 1. PGP (P-gp P-glycoprotein, ABCB1 (ATP-binding cassette sub-family B member 1), MDR1 (multidrug resistance protein 1), and CD243 expression in organs with excretory roles (e.g., liver, kidney and small intestine) and at blood–tissue barriers (e.g., blood–brain, blood–testis and blood–placenta), plasma membrane, Golgi apparatus, endoplasmic reticulum, lysosomes and endosomes and cyclosporine transport.
Figure 1. PGP (P-gp P-glycoprotein, ABCB1 (ATP-binding cassette sub-family B member 1), MDR1 (multidrug resistance protein 1), and CD243 expression in organs with excretory roles (e.g., liver, kidney and small intestine) and at blood–tissue barriers (e.g., blood–brain, blood–testis and blood–placenta), plasma membrane, Golgi apparatus, endoplasmic reticulum, lysosomes and endosomes and cyclosporine transport.
Pharmaceutics 14 02441 g001
Table
Table 1. Demographic and clinical information.
Table 1. Demographic and clinical information.
SubphenotypeSample Set
Number of cases168
Male: female ratio of affected103:65
Age affected at entry to the study
Mean ± S.D.66.3 ± 15.0
Range28–93
Number of affected with age of onset
<40 years (type I psoriasis)135
>40 years (type II psoriasis)33
PASI at baseline, mean ± S.D.14.75 ± 3.77
PASI at 3 months, mean ± S.D.4.72 ± 3.10
Responders, percentage104 (63%)
Nonresponders, percentage64 (37%)
S.D.—mean ± standard deviation. PASI—The Psoriasis Area and Severity Index.
Table
Table 2. ABCB single nucleotide polymorphisms (SNPs) analyzed in this study.
Table 2. ABCB single nucleotide polymorphisms (SNPs) analyzed in this study.
NoSNPsPositionLocationVariantMutationAmino Acid
Change
1rs3213619chr7:87600877Exon 1T-129C5’-UTR
2rs2229109chr7:87550493Exon11G1199AmissenseSer400Asn
3rs1128503chr7:87550285Exon 12C1236TsynonymousGly412Gly
4rs2032582chr7:87531302Exon 21G2677T/AmissenseAla893Ser/Thr
5rs1045642chr7:87509329Exon 26C3435TsynonymousIle1145Ile
Table
Table 3. List of SNPs, primer sequences, type of enzymes used for PCR-RFLP analysis in this study.
Table 3. List of SNPs, primer sequences, type of enzymes used for PCR-RFLP analysis in this study.
SNPsPrimers SequenceAnnealing
Temperature (°C)		Restriction
Enzyme,
Incubation Conditions
T-129C (rs321361)F 5′-ATTGGCTGGGCAGGAACA-3′
R 5′-TTTGGAAGATACTCCGAC-3′		58 °CMsp II, 37 °C,16 h
G1199A (rs222910)F 5′-CAGCTATTCGAAGAGTGGGC-3′
R 5′-CCGTGAGAAAAAAACTTCAAGG-3′		57 °CEco57I, 65 °C, 20 min
C1236T (rs112850)F 5′-TCTTTGTCACTTTATCCAGC-3′
R 5′-TCTCACCATCCCCTCTGT-3′		58 °CHaeIII, 37 °C, 4 h
G2677T/A (rs203258)F 5′-TGCAGGCTATAGGTTCCAGG-3′
R 5′-GTTTGACTCACCTTCCCAG-3′		58 °CBsrI, 65 °C, 4 h
F 5′-TGCAGGCTATAGGTTCCAGG-3′
R 5′-TTTAGTTTGACTCACCTTCCCG-3′		58 °CBanI, 37 °C, 4 h
C3435T (rs104564)F 5′-TAGGCCAGAGAGGCTGCC-3′
R 5′-AGTGGCTCCGAGCACACC-3′		58 °CMboI, 37 °C, 4 h
F: Forward primer. R: reverse primer.
Table
Table 4. Association analysis of SNPs from ABCB1 gene with response to cyclosporine therapy at 3 months.
Table 4. Association analysis of SNPs from ABCB1 gene with response to cyclosporine therapy at 3 months.
SNPGenetic ModelNonresponders
PASI ˂ 50
a p No
n = 64		Responders
PASI ˃ 75
p No
n = 104		b χ2c p-Value
C3435T (rs1045642)Allele model
T vs. C		74/5472/13617.353.1 × 10−5
Codominant model
TT vs. CT vs. CC		22/30/1218/36/5015.60.0004
Dominant model
TT + CT vs. CC		52/1254/5014.60.00013
Recessive model
TT vs. CC + CT		22/4218/865.450.02
G2677T/A (rs2032582)Allele model
T(A) vs. G		50/7898/1102.080.148
Codominant model
T(A)/T(A) vs. GT(A) vs. GG		8/34/2230/38/367.20.027
Dominant model
T(A)/T(A) + GT(A) vs. GG		42/2268/360.0010.974
Recessive model
T(A)/T(A) vs. GG + GT(A)		8/5630/746.040.013
C1236T (rs1128503)Allele model
T vs. C		48/8880/1281.790.180
Codominant model
TT vs. CT vs. CC		8/24/3212/56/364.570.101
Dominant model
TT + CT vs. CC		32/3268/363.890.048
Recessive model
TT vs. CC + CT		8/5612/920.030.851
G1199A (rs2229109)Allele model
T vs. C		8/12024/1842.570.108
Codominant model
TT vs. CT vs. CC		0/8/560/24/802.570.885
Dominant model
TT + CT vs. CC		8/5624/800.040.871
Recessive model
TT vs. CC + CT		0/640/1043.030.552
T-129C (rs3213619)Allele model
T vs. C		4/12410/1980.560.453
Codominant model
TT vs. CT vs. CC		0/4/602/6/960.480.735
Dominant model
TT + CT vs. CC		4/608/960.370.599
Recessive model
TT vs. CC + CT		0/642/1040.780.532
Significant results are shown in bold face. a p No: genetic model frequency, b χ2: chi-square, c p: p-value.
Table
Table 5. Haplotype association analysis of SNPs from MDR1 gene with response to cyclosporine therapy at 3 months.
Table 5. Haplotype association analysis of SNPs from MDR1 gene with response to cyclosporine therapy at 3 months.
HaplotypeNonresponders
PASI < 50
a p No (%)
n = 64		Responders
PASI > 75
p No (%)
n = 104		b χ2 Statisticc p-Value
d Block1 (chromosome 7 region in a Russian population is formed by C3435T, G2677T/A, C1236T SNPs
TGC0.270.1113.342.0 × 10−4
CTC0.110.182.860.090
CGC0.150.222.230.135
CTT0.070.143.650.055
TTC0.140.091.980.158
Significant results are shown in bold face. a p No: genetic model frequency, b χ2: chi-square, c p: p-value, d haplotype combinations with less than 1% frequency are not displayed.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Chernov, A.; Kilina, D.; Smirnova, T.; Galimova, E. Pharmacogenetic Study of the Impact of ABCB1 Single Nucleotide Polymorphisms on the Response to Cyclosporine in Psoriasis Patients. Pharmaceutics 2022, 14, 2441. https://doi.org/10.3390/pharmaceutics14112441

AMA Style

Chernov A, Kilina D, Smirnova T, Galimova E. Pharmacogenetic Study of the Impact of ABCB1 Single Nucleotide Polymorphisms on the Response to Cyclosporine in Psoriasis Patients. Pharmaceutics. 2022; 14(11):2441. https://doi.org/10.3390/pharmaceutics14112441

Chicago/Turabian Style

Chernov, Alexandr, Daria Kilina, Tatiana Smirnova, and Elvira Galimova. 2022. "Pharmacogenetic Study of the Impact of ABCB1 Single Nucleotide Polymorphisms on the Response to Cyclosporine in Psoriasis Patients" Pharmaceutics 14, no. 11: 2441. https://doi.org/10.3390/pharmaceutics14112441

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop