ABCB1基因多态性和P-糖蛋白表达的相关性

p-糖蛋白作为一种广泛分布于全身各组织和器官的重要转运体,影响多种药物的体内的吸收、分布、代谢和排泄过程,还能防止外源性有害物质的侵入.p-糖蛋白由ABCB1基因编码,ABCB1基因多态性决定p-糖蛋白的蛋白表达量,进而影响p-糖蛋白的体内的功能作用.单核苷酸多态性(SNP)是P-糖蛋白产生变异的重要影响因素,可决定不同个体对药物治疗的不同应答,人体中存在的非同义和同义SNP均可对P-糖蛋白的转运功能产生重要影响.本文将对各组织器官中,ABCB1基因多态性与p-糖蛋白表达量的相关性进行综述.     

The Influence of C3435T Polymorphism of the ABCB1 Gene on Genetic Susceptibility to Depression and Treatment Response in Polish Population - Preliminary Report

Background: Despite the high prevalence of depression, the mechanism of the origin of this disease as well as the causes of resistance to therapy in some patients are still not fully understood. Increasingly, the possible role of genetic factors is considered. One of them is polymorphisms in the ABCB1 (MDR1) gene which encodes P-glycoprotein, responsible for the transport of xenobiotics, including antidepressant drugs, through the blood-brain barrier.Methods: C3435T was evaluated in 90 patients with recurrent depressive disorders (rDD). Genotyping was performed using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).Results: The obtained results indicate that the TT genotype occurred more frequently among patients with rDD than in healthy volunteers (p=0.0441). Also, at least one C allele was present significantly less frequent in the study group than in healthy individuals (p=0.0300). The severity of depressive symptoms was higher among patient with the CC genotype in comparison with the other genotypes (p=0.0106) but treatment response to antidepressants was better in this group than among patients with CT or TT genotypes (p=0.0301). Likewise, patients with the T allele have a significantly lower severity of symptoms (p=0.0026) and decreased therapy effectiveness (p=0.0142) than C allele carriers.Conclusions: This study suggests that C3435T polymorphisms in the ABCB1 gene are strongly associated with a predisposition to depression development, the severity of depressive symptoms and the effectiveness of therapy with using different groups of antidepressant agents.     

Possible Prediction of the Efficiency of Chemotherapy in Patients with Lymphoproliferative Diseases Based on MDR1 Gene G2677T and C3435T Polymorphisms

Study of polymorphism in MDR1 gene exons 21 and 26 revealed that T2677T and T3435T alleles are not a factor predisposing to lymphoproliferative diseases, but they determine the efficiency chemotherapy. Individuals with T2677T and T3435T haplotypes are at highest risk of drug resistance. Association between genotypes G2677T and C3435T was detected in normal subjects and in patients with lymphoproliferative diseases.     

Effects of the programmed cell death 1 (PDCD1) polymorphisms in susceptibility to systemic lupus erythematosus

The failure of immunological tolerance to self‐antigens plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). PD‐1 is an inhibitory receptor for regulating the immune system and preventing development of autoimmune disorders. This study aimed to determine the role of four single‐nucleotide polymorphisms (SNPs) within programmed cell death 1 (PDCD1 or PD‐1) gene and haplotypes defined by these SNPs in susceptibility to SLE in the Iranian population. Blood samples were obtained from 253 SLE and 564 healthy subjects. Red blood cells were lysed and genomic DNAs were extracted using salting‐out method. Genotype determinations of PD1.1, PD1.3, PD1.5 and PD1.9 SNPs were performed by polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP), and 12 haplotypes were constructed by PDCD1 SNPs. Our results showed significant differences in PD1.5 genotype frequencies between patient and control groups (p < .001). The frequencies of PD1.5 C/C, C/T and T/T genotypes versus other genotypes in SLE patients significantly differed from healthy subjects (p < .001, p = .001 and p = .002, respectively). Allelic analysis indicated a significant association between the frequency of PD1.5C allele and development of SLE in our population (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.51–2.42, p < .001). At the haplotype level, GGCC, GACT and GGCT haplotypes were significantly different between SLE and control groups (OR = 2.14, 95% CI = 1.73–2.66, p < .001; OR = 9.76, 95% CI = 4.47–21.3, p < .001; and OR = 0.32, 95% CI = 0.24–0.42, p < .001, respectively). Based on these findings, PD1.5 SNP and some haplotypes of PDCD1 contribute to SLE risk in the Iranian population.     

OAS1 gene haplotype confers susceptibility to multiple sclerosis

Multiple sclerosis (MS) is associated with genetic susceptibility and unknown environmental triggers, possible viral infections, but the specific etiological mechanism that subsequently develops into an inflammatory/autoimmune cascade of events is poorly understood. Recently, genetic variants of 2',5'- oligoadenylate synthetase 1 (OAS1) gene, a critical enzyme involved in innate antivirus response, have been associated with differential enzyme activity and type 1 diabetes in both case-control and family studies. We hypothesized that polymorphisms in the OAS1 gene could influence the susceptibility to MS. To test this hypothesis, we conducted a case-control study of 333 patients with MS and 424 healthy controls and genotyped two OAS1 single nucleotide polymorphisms (SNPs) by restriction fragment length polymorphism method: rs 10774671, A/G SNP altering the splicing site at the seventh exon, and rs 3741981, a nonsynonymous (Ser162Gly) A/G SNP in the third exon. Haplotype but not single-marker analysis revealed an association of the haplotype created by the G allele at rs 10774671 and the A allele at rs 3741981 with the susceptibility to MS (P value = 8.8 x 10(-5)). Subjects carrying this haplotype had an increased risk of MS comparing with those not carrying it (odds ratio = 4.7, 95% confidence interval 2.1-10.9). Our findings indicate that the OAS1 gene polymorphisms may confer susceptibility to MS or serve as markers of functional variants and suggest that OAS1 activity is involved in the etiology of the disease. Future studies in a larger sample and association analysis with functional variants will clarify the role of the OAS1 gene in the susceptibility to MS.     

<Emphasis Type="Italic">MDR1</Emphasis> gene C<Superscript>1236</Superscript>T and C<Superscript>6+139</Superscript>T polymorphisms in the Russian population: Associations with predisposition to lymphoproliferative diseases and drug resistance

Study of MDR1 polymorphism in intron 6 and exon 12 of healthy individuals and patients with chronic lymphoproliferative diseases showed that the presence of mutant 6+139T allele is a factor determining resistance to lymphoproliferative diseases. Comparison of genotyping results in 53 patients and the data on the efficiency of drug therapy showed no significant associations of C¹²³⁶T and C⁶⁺¹³⁹T genotypes with drug resistance.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 10, pp. 454–457, October, 2004     

<Emphasis Type="Italic">MDR1</Emphasis> gene C<Superscript>1236</Superscript>T and C<Superscript>6+139</Superscript>T polymorphisms in the Russian population: associations with predisposition to lymphoproliferative diseases and drug resistance

Study of MDR1 polymorphism in intron 6 and exon 12 of healthy individuals and patients with chronic lymphoproliferative diseases showed that the presence of mutant 6+139T allele is a factor determining resistance to lymphoproliferative diseases. Comparison of genotyping results in 53 patients and the data on the efficiency of drug therapy showed no significant associations of C¹²³⁶T and C⁶⁺¹³⁹T genotypes with drug resistance.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 10, pp. 454–457, October, 2004     

ABCB1和ABCC2基因多态性与中国汉族儿童抗结核药物致肝毒性易感性的相关性研究

目的 探讨ABCB1和ABCC2基因多态性与中国汉族儿童抗结核药物致肝毒性(anti-tuberculosis drug-induced hepatotoxicity,ATDH)易感性的相关性.方法 在中国汉族结核病患儿中,采用病例对照研究,利用高通量的MassARRAY平台,对于ABCB1和ABCC2基因的16个标签单核苷酸多态性(single nucleotide polymorphisms,SNPs)位点展开基因分型,并采用logistic回归分析以上SNP位点等位基因和基因型频率在ATDH病例组和ATDH对照组中的分布差异.结果 本研究共纳入41例ATDH病例以及189例对照.ABCB1和ABCC2基因SNP位点的等位基因以及基因型在两组间频率分布差异均无统计学意义(P＞0.05).SNP位点分别按照显性遗传模型和隐性遗传模型分析,各位点基因型在两组间频率分布差异均无统计学意义(P＞0.05).结论 ABCB1和ABCC2基因多态性可能与中国汉族儿童ATDH的发生并无相关性.     

Genetic Variations and Haplotype Structures of the ABCB1 Gene in a Japanese Population: An Expanded Haplotype Block Covering the Distal Promoter Region, and Associated Ethnic Differences

As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks ?1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms ?1789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re‐assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally‐important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease‐association studies carried out using Asian subjects.     

Candidate gene analysis of SPARCL1 gene in patients with multiple sclerosis

Recently, proteomic analysis in cerebrospinal fluid (CSF) from patients with MS identified four proteins which are present in MS but not in normal human CSF, including SPARCL1, an extracellular matrix-associated protein member of the SPARC family. One hundred eighty-six patients with MS and 185 age-matched controls were genotyped for A/G single nucleotide polymorphism (SNP) in exon 1 (rs1049539), C/G SNP in exon 4 (rs1049544), resulting in a substitution of an aspartate with an histidine, and A/G substitution in the exon 5 (rs1130643), leading to the substitution of alanine with threonine. No significant differences in either allelic or genotypic frequency of the three SNPs were found (P>0.05), even in stratifying MS patients according to the course of the disease. Stratifying according to gender, a trend towards a decreased frequency of the C/C genotype of the rs1049544 was observed in male patients as compared with male controls (30.2% versus 44.0%; P=0.217). Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. However, the frequency of the C/C genotype of rs1049544 was decreased in male patients, possibly conferring a lower risk of developing MS in male population. Further studies are needed to clarify this issue.     

Association of HLA-DRB1*1502-DQB1*0501 haplotype with susceptibility to systemic lupus erythematosus in Thais

In this study, we investigated the association of HLA-DRB1 and DQB1 with Thai patients with SLE. A highly significant increase in the frequency of DRB1*1502 and DQB1*0501 was found in SLE patients compared with normal controls. DRB1*1501 and DRB1*1602 were also slightly increased. In contrast, DRB1*1202 and DQB1*0301 were decreased, and DRB1*0406 and DRB1*1401 were not found in the patients' group. The haplotype analysis revealed that DRB1*1502 - DQB1*0501 was most strongly associated with SLE, and also suggested a primary role for DRB1 rather than DQB1. Taken together with the previous report which demonstrated the association of the same haplotype in Taiwan, our present observations strongly suggested that DRB1*1502 - DQB1*0501 is the major HLA haplotype that confers susceptibility to SLE in the South-east Asian populations.     

ABCB1 polymorphisms associated with osteonecrosis of the femeral head

Aims: This case-control study was conducted to investigate the relation of ATP-binding cassette subfamily B member 1 (ABCB1) C1236T and C3435T polymorphisms and non-traumatic osteonecrosis of the femeral head (ONFH). Methods: We gathered 113 ONFH patients and 116 controls in the study. The polymorphisms of ABCB1 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Odds ratio (OR) with 95% confidence interval (CI) were adopted to analyze the correlation between ABCB1 polymorphisms and ONFH. Results: In the study, we found that the frequency of C3435T TT genotype was much lower in case group, compared with that of controls (17.7% vs. 23.3%). Moreover, OR and 95% CI values indicated that C3435T TT genotype served as a protective factor for ONFH (OR=0.34, 95% CI=0.15-0.75). Meanwhile, the risk for the T allele carriers was much lower than C allele (OR=0.60, 95% CI=0.42-0.87). However, C1236T polymorphism showed no significant effects on the pathogenesis of ONFH. In the haplotype analysis, T-T haplotype appeared to be an inhibitor for ONFH (OR=0.45, 95% CI=0.23-0.87). Conclusions: Based on the results, ABCB1 polymorphisms were associated with the risk for ONFH.     

Systemic sclerosis at the crossroad of polyautoimmunity

Objectives

Several epidemiological studies have revealed the co-occurrence of other autoimmune diseases (AIDs) within patients with systemic sclerosis (SSc). However, some of these studies were based on small cohorts and wide ranges of prevalence have been reported. Therefore to overcome these limitations of individual studies, we sought to perform a meta-analysis to determine the accurate prevalence of polyautoimmunity in SSc.

Methods

We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to March 2013. All cohort studies reporting on prevalence of other AIDs known to be associated with SSc were analyzed. Prevalence of polyautoimmunity and of each AID were then calculated.

Results

Ten studies reporting polyautoimmunity were identified corresponding to a total of 6102 SSc patients. Overall 1432 patients with at least one AID were identified corresponding to a weighted prevalence of polyautoimmunity equal to 25.7% CI 95% [20.1%–31.6%]. Overall 208/5139 SSc-patients had at least two additional AIDs resulting in a weighted prevalence of 3.9% [3.3%–4.4%]. The most prevalent associated AIDs were autoimmune thyroid disease (10.4%) followed by Sjögren's syndrome (7.7%) and dermatopolymyositis/polymyositis (5.6%).

Conclusion

Our results confirm that SSc polyautoimmunity is a frequent condition in SSc affecting a quarter of SSc-patients. The impact on the phenotype and also on the management and therapy will need to be addressed now in further works.     

ABCB1 (P-glycoprotein) but not ABCC1 (MRP1) is downregulated in peripheral blood mononuclear cells of spontaneously hypertensive rats

Although the kidney is a major target in hypertension, several studies have correlated important immune alterations with the development of hypertension in spontaneously hypertensive rats (SHR), like increased secretion of pro-inflammatory cytokines, inflammatory infiltration in kidneys and thymic atrophy. Because adenosine-triphosphate-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) and adenosine-triphosphate-binding cassette sub-family C member 1 (ABCC1; multidrug resistance protein 1), two proteins first described in multidrug resistant tumors, physiologically transport several immune mediators and are required for the adequate functioning of the immune system, we aimed to measure the expression and activity of these proteins in peripheral blood mononuclear cells (PBMC), thymocytes, and also kidneys of normotensive Wistar Kyoto rats and SHR. Our results showed that ABCB1, but not ABCC1, activity was diminished (nearly 50%) in PBMC. Moreover, Abcb1b gene was downregulated in PBMC and kidney of SHR and this was not counterbalanced by an upregulation of its homolog Abcb1a, suggesting that the diminished activity is due to downregulation of the gene. No alteration was detected in ABCB1 activity in SHR thymocytes, indicating that this downregulation occurs after lymphocytes leave the primary lymphoid organs. Even though it is not known at present which parameter(s) is(are) responsible for this downregulation, it may contribute for the altered immune response observed in hypertension and to possible altered drug disposition in hypertensive individuals, resulting in greater drug interaction and increased drug toxicity. Raphael C. Valente and Márcia A. M. Capella contributed equally to this work.     

HLA DPA1/DPB1 genotype and haplotype frequencies, and linkage disequilibria in Nigeria, Liberia, and Gabon

Abstract: The frequencies of DPA1 and DPB1 alleles and their occurrence in haplotypic linkage were assessed and compared in Nigerian, Liberian, and Gabonese individuals. Differences were seen in the distribution patterns; these differences were more pronounced between the Gabonese and the other two populations than between Liberians and Nigerians. Several haplotypic DPA1-DPB1 combinations could be verified by homozygosity. Linkage disequilibria of DPA1-DPB1 combinations, indicating further probable haplo-types, were estimated. Although different allele and haplotype frequencies were recognized in the three subgroups, the linkage disequilibria were mostly either positive or negative in all populations.     

Interactions between antiparkinsonian drugs and ABCB1/P-glycoprotein at the blood-brain barrier in a rat brain endothelial cell model

Parkinson's disease is a neurodegenerative disorder that requires treatment by dopaminergic agonists, which may be responsible for central side effects. We hypothesized that the efflux transporter ABCB1/P-glycoprotein played a role in brain disposition of antiparkinsonian drugs and could control central toxicity. We aimed to evaluate antiparkinsonian drugs as ABCB1 substrates and/or inhibitors in rat brain endothelial cells GPNT, in order to predict potential clinical drug-drug interactions. Among the antiparkinsonian drugs tested, levodopa, bromocriptine, pergolide and pramipexole were ABCB1 substrates. However, only bromocriptine could inhibit ABCB1 functionality with an IC(50) of 6.71 microM on Rhodamine 123 uptake and an IC(50) of 1.71 microM on digoxine uptake. Thus, bromocriptine at 100 microM is responsible for an increase of levodopa intracellular transport of about 2.05-fold versus control. Therefore, we can conclude that bromocriptine is a potent drug for medicinal interactions in vitro. Hence, in patients with Parkinson's disease, these results may be considered to optimise treatments individually.     

Pathophysiology of systemic sclerosis: current understanding and new insights

ABSTRACT

Introduction: Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by chronic and progressive tissue and organ fibrosis with broad patient-to-patient variability.

Some risk factors are known and include combination of persistent Raynaud’s phenomenon, steroid hormone imbalance, selected chemicals, thermal, or other injuries. Endogenous and/or exogenous environmental trigger/risk factors promote epigenetic mechanisms in genetically primed subjects.

Disease pathogenesis presents early microvascular changes with endothelial cell dysfunction, followed by the activation of mechanisms promoting their transition into myofibroblasts. A complex autoimmune response, involving innate and adaptive immunity with specific/functional autoantibody production, characterizes the disease. Progressive fibrosis and ischemia involve skin and visceral organs resulting in their irreversible damage/failure. Progenitor circulating cells (monocytes, fibrocytes), together with growth factors and cytokines participate in disease diffusion and evolution. Epigenetic, vascular and immunologic mechanisms implicated in systemic fibrosis, represent major targets for incoming disease modifying therapeutic approaches.

Areas covered: This review discusses current understanding and new insights of SSc pathogenesis, through an overview of the most relevant advancements to present aspects and mechanisms involved in disease pathogenesis.

Expert opinion: Considering SSc intricacy/heterogeneity, early combination therapy with vasodilators, immunosuppressive and antifibrotic drugs should successfully downregulate the disease progression, especially if started from the beginning.     

Transforming growth factor-beta1 polymorphisms in Korean patients with systemic sclerosis

Transforming growth factor-beta1 (TGF-beta1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate the role of TGF-beta1 gene polymorphisms in SSc, we genotyped six biallelic polymorphic positions (position -988, -800, and -509; and codons 10, 25, and 263) in 61 Korean SSc patients and in 148 healthy controls, using polymerase chain reaction-sequence-specific primers. Genetic polymorphisms were found at position -509 and codon 10 in Koreans. The allele frequencies of C/T at position -509 were 0.59/0.41 in patients and 0.56/0.44 in controls. The allele frequencies of C/T at codon 10 were 0.40/0.60 in patients and 0.50/0.50 in controls. In conclusion, no skewed distribution of TGF-beta1 gene polymorphisms was found in Korean patients with SSc.     

Cellular polarity modulates drug resistance in primary colorectal cancers via orientation of the multidrug resistance protein ABCB1

Colonic epithelial cells are highly polarised with a lumen-facing apical membrane, termed the brush border, and a basal membrane in contact with the underlying extracellular matrix (ECM). This polarity is often maintained in cancer tissue in the form of neoplastic glands and has prognostic value. We compared the cellular polarity of several ex vivo spheroid colonic cancer cultures with their parental tumours and found that those grown as non-attached colonies exhibited apical brush border proteins on their outer cellular membranes. Transfer of these cultures to an ECM, such as collagen, re-established the centralised apical polarity observed in vivo. The multidrug resistance protein ABCB1 also became aberrantly polarised to outer colony membranes in suspension cultures, unlike cultures grown in collagen, where it was polarised to central lumens. This polarity switch was dependent on the presence of serum or selected serum components, including epidermal growth factor (EGF), transforming growth factor-β1 (TGF-β1) and insulin-like growth factor-1 (IGF-1). The apical/basal orientation of primary cancer colon cultures cultured in collagen/serum was modulated by α2β1 integrin signalling. The polarisation of ABCB1 in colonies significantly altered drug uptake and sensitivity, as the outward polarisation of ABCB1 in suspension colonies effluxed substrates more effectively than ECM-grown colonies with ABCB1 polarised to central lumens. Thus, serum-free suspension colonies were more resistant to a variety of anti-cancer drugs than ECM-grown colonies. In conclusion, the local stroma, or absence thereof, can have profound effects on the sensitivity of colorectal cultures to drugs that are ABCB1 substrates. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.