Multi-drug resistance-1 gene polymorphisms in nephrotic syndrome: Impact on susceptibility and response to steroids

Background

Role of multidrug resistance-1 (MDR-1) gene polymorphisms has not been clarified in nephrotic syndrome (NS). Additionally, researchers studied several genetic polymorphisms to explain their influence on different patients' responses to steroid; however the data were inconsistent. Therefore, we aimed to investigate the association of MDR-1 gene polymorphisms [C1236T, G2677T/A, C3435T] and haplotypes with susceptibility to childhood nephrotic syndrome, and whether they influence steroid response.

Methods

We detected MDR-1 gene polymorphisms using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 138 NS patients and 140 age and sex matched healthy children.

Results

The frequencies of MDR1 G2677T/A GT, GA, TT + AA genotypes or T allele, MDR1 C3435T TT genotype, and T allele genotype frequencies were significantly increased in NS group. While no significant differences were observed in distributions of C1236T genotypes or allele between NS patients and healthy children. Moreover, steroid non-responder NS patients had significantly higher frequencies of MDR1 G2677T/A GT, GA, and TT + AA genotypes than steroid responsive NS patients. We observed also that NS patients with age less than 6 years old had increased frequencies of MDR1 G2677T/A GT, GA, TT + AA genotypes or T allele MDR1 C3435T CT, TT genotypes and T allele. Interestingly the frequency of the TGC haplotype of MDR1 was lower in the initial steroid responders than in non-responders NS patients. On the contrary, there were no any association between the MDR1 haplotypes with NS susceptibility and they did not influence renal pathological findings.

Conclusion

Our data suggested that MDR1 C3435T or G2677T/A gene polymorphisms are risk factors of increased susceptibility, earlier onset of NS, and steroid resistance.     

The drug-transporter gene MDR1 C3435T and G2677T/A polymorphisms and the risk of multidrug-resistant epilepsy in Turkish children

One-third of all individuals with epilepsy are resistant to antiepileptic drug (AED) treatment. Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters. Several polymorphic variants within the multidrug resistance 1 (MDR1) gene, which encodes the major transmembrane efflux transporter P-glycoprotein, have been proposed to be associated with AED resistance in epilepsy patients. The aim of this study was to evaluate the effect of C3435T and G2677T/A polymorphisms of MDR1 on AED resistance in Turkish children with epilepsy. MDR1 C3435T and G2677T/A were genotyped in 152 patients with epilepsy, classified as drug-resistant in 69 and drug-responsive in 83. Genotypes of the C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction followed by restriction fragment length polymorphism. Genotype and allele frequencies of C3435T and G2677T/A polymorphisms of the MDR1 gene did not differ between drug-resistant and drug-responsive epilepsy patients. Our results suggest that MDR1 C3435T and G2677T/A polymorphisms are not associated with AED resistance in Turkish epileptic patients. To clarify the exact clinical implication of the MDR1 polymorphisms on the multidrug resistance in epilepsy, further investigations in various ethnic populations would be necessary.     

Simultaneous screening for three mutations in the ABCB1 gene

A noncoding C3435T mutation in exon 26 of the ABCB1 gene was found to be often associated with a G2677T(A) mutation in exon 21 encoding an Ala893Ser P-glycoprotein and with a noncoding C1236T mutation in exon 12. We developed a Pyrosequencing screening method that simultaneously detects all three mutations. After separate PCRs for each exon, the sequences around the potentially mutated nucleotide positions were simultaneously analyzed in a multiplex assay. The method was tested with DNA from 100 volunteers. Allele frequencies of the T1236, T2677, and T3435 alleles were 44, 42, and 50%, respectively. A mutation at position 3435 occurred together with a mutation at position 2677 or 1236 in 64 and 65% of the subjects, respectively. The most frequent haplotype, with 44.4%, was not mutated at all three positions, i.e., C1236, G2677, C3435. The second most frequent haplotype, with 37.1%, was mutated at all three positions, i.e., T1236, T2677, T3435. The most frequent genotype, with 36%, was heterozygously mutated at all three positions, i.e., C/T1236, G/T2677, C/T3435. The next most frequent genotypes were a homozygous nonmutated genotype, with 20%, and a homozygous mutated genotype, with 13%.     

MDR1 gene polymorphisms may be associated with Behçet's disease and its colchicum treatment response

Behçet's disease (BD) is a chronic multisystem disorder. Infectious agents, immune system mechanisms, and genetic factors are implicated in the etiopathogenesis of BD, which remains to be explained. The human MDR1 (ABCB1) gene encoder P-glycoprotein (P-gp) plays a key role in drug disposition, serves as a protective mechanism against xenobiotics, and provides additional protection for the brain, testis, and fetus. We investigated the genotype and haplotype distributions of three MDR1 gene polymorphisms (C1236T, G2677T/A, and C3435T) in 104 BD patients and 130 control subjects. The genotyping analysis was performed by using PCR–RFLP methods.     

The role of ABC-transporter gene polymorphisms in chemotherapy induced immunosuppression, a retrospective study in childhood acute lymphoblastic leukaemia

We examined the association of functional ABCB1 (MDR1) and ABCG2 (BCRP) polymorphisms with acute side effects of chemotherapy. Analyses were performed on clinical data from 138 patients treated with the ALL-BFM-95 protocol implying several substrates of these transporters. ABCB1 3435T>C, 2677G>T/A 1236C>T and ABCG2 421C>A genotypes were determined. A higher proportion of ABCB1 3435TT patients suffered excessive infectious complications than those harbouring at least one C allele (OR=2.5, p=0.03) during the whole half-year-long intensive phase of chemotherapy. Weaker associations were calculated when ABCB1 1236T-2677T-3435T haplotype homozygotes were tested against the remaining part of the population (OR=2.3, p=0.09). During the reinduction phase of therapy, the occurrence of severe leukocytopenia was similar among ABCB1 genotype groups. The frequency of any toxicities were not shown to differ according to the ABCG2 421C>A genotype. Our data suggest that the ABCB1 3435T>C genotype is associated with the infectious complications of the applied chemotherapy regimen.     

Genetic variability and haplotype profile of MDR1 in Saudi Arabian males

Polymorphisms in multidrug resistance (MDR1) gene play an important role in influencing the pharmacological action and toxicity profile of a large number of therapeutic agents, and in human susceptibility to various diseases. Because of genotypic variability, several studies were directed toward determination of the frequencies of MDR1 polymorphisms and/or haplotypes in different ethnic populations. In this study, we determined the frequencies of the most common three polymorphisms in the MDR1 gene (i.e., C1236T, G2677T, and C3435T) in Saudi Arabians and their haplotypes. Our results showed that the frequencies of 1236T, 2677T, and 3435T were 43.7?%, 40.2?%, and 42.2?%, respectively. In addition, the frequencies of the most common MDR1 haplotypes, C-G-C and T-T-T, were correspondent to 48.8 and 35.5?%. Furthermore, we identified moderate to strong linkage disequilibrium between the loci of these single nucleotide polymorphisms in the studied subjects. These identified frequencies in Saudi Arabians are different from that reported in the other ethnic groups.     

The association of MDR1 C3435T and G2677T/A polymorphisms with plasma platelet-activating factor levels and coronary artery disease risk in Turkish population

Increased levels of peripheral proinflammatory mediators can contribute to the development of coronary artery disease (CAD). Platelet activating factor (PAF) is an important proinflammatory mediator and plasma levels of PAF correlate with transmembrane transporter multidrug resistant 1 P-glycoprotein (MDR1 Pgp) expression and activity. MDR1 polymorphisms can affect the expression and activity of Pgp and plasma PAF levels. Therefore, we investigated the possible relationship between MDR1 C3435T and G2677T/A polymorphisms and plasma PAF levels and the risk of CAD. The study population consisted of 198 patients angiographically documented CAD, including 113 cases with at least 1 coronary artery with ≥ 50% luminal diameter stenosis and 85 control subjects with strictly normal coronary angiograms. Genotypes of the MDR1 C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Plasma PAF levels were detected by enzyme-linked immunosorbent assay (ELISA). There were no significant differences among plasma PAF levels in regard to MDR1 C3435T and G2677T polymorphisms in CAD patients and controls. No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in the MDR1 gene between the patients and the control subjects. Furthermore, analysis of MDR1 haplotypes did not show any associations with increased plasma PAF levels and risk of CAD. Our results suggest that plasma PAF levels are not associated with MDR1 gene polymorphisms. There is no association between MDR1 C3435T and G2677T/A polymorphisms and the risk of CAD in Turkish patients.     

Association of MDR1 gene SNPs and haplotypes with the tacrolimus dose requirements in Han Chinese liver transplant recipients

Background

This work seeks to evaluate the association between the C/D ratios (plasma concentration of tacrolimus divided by daily dose of tacrolimus per body weight) of tacrolimus and the haplotypes of MDR1 gene combined by C1236T (rs1128503), G2677A/T (rs2032582) and C3435T (rs1045642), and to further determine the functional significance of haplotypes in the clinical pharmacokinetics of oral tacrolimus in Han Chinese liver transplant recipients.

Methodology/Principal Findings

The tacrolimus blood concentrations were continuously recorded for one month after initial administration, and the peripheral blood DNA from a total of 62 liver transplant recipients was extracted. Genotyping of C1236T, G2677A/T and C3435T was performed, and SNP frequency, Hardy-Weinberg equilibrium, linkage disequilibrium, haplotypes analysis and multiple testing were achieved by software PLINK. C/D ratios of different SNP groups or haplotype groups were compared, with a p value<0.05 considered statistically significant. Linkage studies revealed that C1236T, G2677A/T and C3435T are genetically associated with each other. Patients carrying T-T haplotype combined by C1236T and G2677A/T, and an additional T/T homozygote at either position would require higher dose of tacrolimus. Tacrolimus C/D ratios of liver transplant recipients varied significantly among different haplotype groups of MDR1 gene.

Conclusions

Our studies suggest that the genetic polymorphism could be used as a valuable molecular marker for the prediction of tacrolimus C/D ratios of liver transplant recipients.     

MDR1 mRNA expression and MDR1 gene variants as predictors of response to chemotherapy in patients with acute myeloid leukaemia: a meta-analysis

Abstract

Data from 30 pharmacogenomic studies that investigated MDR1 mRNA expression or gene variants (C3435T, G2677TA, C1236T) and response to therapy in acute myeloid leukaemia (AML) were synthesized. Anthracycline-based regimens were mainly used. MDR1 mRNA overexpression was associated with poor response to therapy [odds ratio (OR)?=?2.49 95% confidence interval (CI) 1.38–4.50]. The gene variants were not associated with response to treatment; the generalized ORs, a genetic model-free approach, for the variants C3435T, G2677TA and C1236T were OR_G?=?0.86 (95% CI 0.55–1.37), OR_G?=?0.97 (95% CI 0.58–1.64) and OR_G?=?1.17 (95% CI 0.75--1.83), respectively. There is indication that MDR1 mRNA expression may be considered as a potential marker for response to chemotherapy in AML patients.     

Common ABCB1 polymorphisms associated with susceptibility to infantile spasms in the Chinese Han population

Infantile spasms are a severe epileptic encephalopathy with a variety of etiologies that occur in infancy and early childhood. Subjects with infantile spasms are at a higher risk for evolving into intractable epileptic spasms, tending to be refractory to conventional antiepileptic drugs. Genetic polymorphisms of the P-glycoprotein-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients. Conflicting findings have been reported in different populations; few studies have explored whether this apparent association is affected by other host factors, such as specific epilepsy syndrome. We performed a case-control study to determine whether the risk of infantile spasms is influenced by common ABCB1 polymorphisms in a Han Chinese children's population consisting of 91 patients and 368 healthy individuals. DNA was isolated from whole blood, and three genetic polymorphisms (C1236T, G2677T/A, and C3435T) were assayed by PCR-RFLP. There were significant differences in the distributions of 3435TT [P = 0.001; odds ratio = 2.47; 95% confidence interval (CI) = 1.44-4.27] and 3435CT [P < 0.001; odds ratio = 0.28; 95% CI = 0.15-0.54] genotypes between infantile spasm cases and controls. No significant differences were observed in allelic and haplotypic frequencies of ABCB1 polymorphisms between the two groups. This study demonstrated that variations in the C3435T gene play an important role in the pathogenesis of infantile spasms in the Han Chinese population; 3435TT is associated with increased risk of having this epilepsy syndrome.     

Polymorphism of human MDR1 gene in the Siberian and central Asian populations

The multidrug resistance gene (MDR1, ABCB1) encodes transmembrane P-glycoprotein an ATP-dependent transporter, which is involved in elimination of drugs, xenobiotics, peptides from a cell. It is expressed in such organs as a brain, kidneys, a liver, a gastroenteric tract. It is supposed, that this protein may take part in formation of individual resistance to action of adverse factors of an environment, such as toxic substances, xenobiotics and infectious diseases. A number of polymorphisms in MDR1 gene is associated with a expression level and functioning of the gene, as well as with the ability to eliminate drugs and with the resistance to various neurodegeneration and gastroenteric tract diseases. In this study the frequencies of five single nucleotide polymorphisms (SNPs) (3435C/T, 2677G/T/A, 1236C/T, +139C/T and -1G/A), located in MDR1 gene, frequencies of haplotypes, the genetic differentiation and linkage disequilibrium pattern in populations of Russians, Tuvinians, northern and southern Kirghizes are described. Significant genetic differences were found between populations of Russians and northern Kirghizes, and also between Tuvinians and northern Kirghizes. The linkage disequilibrium pattern is characterized by high population specificity.     

MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case–control studies

Multidrug resistance 1 (MDR1) gene encodes the ATP-dependent cellular efflux pump P-glycoprotein (P-gp) which efflux of a variety of substances across the membrane. P-gp could serve a role in cancer etiology based on its physiological role of protecting cells from xenobiotics or metabolites. The C3435T (rs1045642) polymorphism of the MDR1 gene which could influence the P-gp expression and function have been implicated in the cancer risk. However, the results from the published studies on the association between this polymorphism and cancer risk are conflicting. To drive a more precise estimation of this association, we performed a meta-analysis of 39 case-control studies, including a total of 9,265 cancer cases and 13,502 controls. We used odds ratios (ORs) with their 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the MDR1 3435TT genotype were associated with an increased cancer risk than those with the CC (OR = 1.29, 95% CI: 1.10-1.51) or CT/CC (OR = 1.18, 95% CI: 1.04-1.34) genotypes, similar to the CT or CT/TT compared with the CC genotype. In the stratified analyses, the increased risks were more pounced among hematologic malignances (OR = 1.27, 95% CI: 1.10-1.46, P (heterogeneity) = 0.415), breast cancer (1.42, 1.04-1.94, 0.018), renal cancer (1.77, 1.28-2.46, 0.307), Caucasians (1.21, 1.07-1.38, 0.000) and population-based studies (1.20, 1.05-1.36, 0.000) in a dominant model. The results suggested that the MDR1 C3435T polymorphism may contribute to cancer risk.     

Association of the colorectal cancer and <Emphasis Type="Italic">MDR1</Emphasis> gene polymorphism in an Iranian population

The human multidrug resistance (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics, bacterial toxins, drugs and other biologically active compounds, possibly carcinogens. In this study, an association of MDR1 gene polymorphism and the occurrence of colorectal cancer were evaluated. In this case-control-designed 118 unrelated colorectal cancer and 137 sex-and-ages matched healthy controls were enrolled. The C3435T MDR1 gene polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism method. Significantly increased frequencies of the 3435T allele and the 3435TT were observed in patients with colorectal cancer compared with controls (P = 0.03; OR, 95% CI; 1.46 for 3435T allele and P = 0.003; OR, 95% CI; 2.2 for 3435TT genotype). In contrast, frequency of genotype TT was significantly higher in controls compared to colorectal cancer (P = 0.006; OR, 95% CI; 0.49 for TC genotype). In this study suggest that C3435T MDR1 polymorphism has an association with colorectal cancer. The results support that the presence of allele C results in decreased susceptibility to colorectal cancer.     

Polymorphism of the human <Emphasis Type="Italic">MDR1</Emphasis> gene in Siberian and Central Asian populations

The multidrug resistance gene MDR1 (ABCB1) codes for a P-glycoprotein that acts as an ATP-dependent transporter and is involved in removing drugs, xenobiotics, and peptides from the cell. MDR1 is expressed in the brain, kidneys, liver, and gastrointestinal tract. The P-glycoprotein is thought to play a role in individual resistance to xenobiotics and infections. Several polymorphisms of MDR1 are associated with the level of its expression and resistance to various neurodegenerative and gastrointestinal diseases. The allele and haplotype frequencies, genetic differentiation, and linkage disequilibrium for five MDR1 single nucleotide polymorphisms (3435C/T, 2677G/T/A, 1236C/T, +139C/T, and ?1G/A) were studied in the Russian, Tuvinian, and northern and southern Kyrgyz populations. Significant genetic differences were observed between Russians and northern Kyrgyz and between Tuvinians and northern Kyrgyz. The linkage disequilibrium pattern was characterized by high population specificity.     

Association of MDR1 C3435T polymorphism with bipolar disorder in patients treated with valproic acid

P-glycoprotein (P-gp), an efflux transporter protein, is an ABC transporter encoded by the multidrug resistance 1 gene (MDR1, ABCB1). The common synonymous C3435T polymorphism in exon 26 is reported to associate with lower P-gp functional expression and drug uptake. Many extended pharmacogenomics, functional, and complex disease association studies focused mainly on this polymorphism. We investigated the association of exon 26 C3435T genetic variants of MDR1 gene with susceptibility to bipolar disorder and serum valproic acid concentration. Totally, 104 patients meeting DSM-IV criteria for bipolar disorder and 169 controls were admitted to the study. There was statistically significant difference between the genotypes of bipolar patients (CT 91.2%, TT 6.8%, and CC 2%) and controls (CT 52.7%, TT 26%, CC 21.3%) although their allelic distribution was similar. The serum valproic acid concentrations of the patients with CT, TT and CC genotypes were 72.92 ± 20.55, 80.47 ± 14.01 and 68.29 ± 12.17 μg/ml, respectively, and there was no significant difference between the C3435T genotypes.     

Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients

The objective of this study was to evaluate whether genetic polymorphisms of CYP3A5 (A6986G, CYP3A5*3), ABCB1 (C1236T, G2677T/A, C3435T) and NR1I2 (A7635G) significantly impact the pharmacokinetics of prednisolone in renal transplant recipients. Ninety-five recipients were given repeated doses of triple therapy immunosuppression consisting of prednisolone, tacrolimus and mycophenolate mofetil. Twenty-eight days after renal transplantation, plasma prednisolone concentrations were measured by high-performance liquid chromatography. Comparisons of the CYP3A5 and ABCB1 genotypes revealed no significant differences in the prednisolone pharmacokinetics. The mean prednisolone C(max) for recipients (n=14) having both the ABCB1 3435CC genotype and the CYP3A5*3/*3 genotype was significantly higher than those (n=11) having both ABCB1 3435TT and CYP3A5*3/*3 genotypes (180ng/mL versus 129ng/mL, P=0.0392). The plasma concentrations of prednisolone in recipients having both ABCB1 3435CC and CYP3A5*3/*3 genotypes tended to be higher than those having both ABCB1 3435TT and CYP3A5*3/*3 genotypes. The mean AUC(0-24) and C(max) values for prednisolone in recipients having the NR1I2 7635G allele (AG: n=45, GG: n=32) were significantly lower than in patients having the 7635AA allele (n=18) (7635GG versus 7635AA, P=0.0308 for AUC(0-24), P=0.0382 for C(max) of prednisolone). In conclusion, NR1I2 (A7635G) rather than CYP3A5 or ABCB1 allelic variants affected patient variability of plasma prednisolone concentration. Recipients carrying the NR1I2 7635G allele seemed to possess higher metabolic activity for prednisolone in the intestine, greatly reducing its maximal plasma concentration.     

Association between MDR1 C3435T polymorphism and risk of breast cancer

The C3435T (rs1045642) polymorphism, located in multi-drug resistance gene 1 (MDR1), has demonstrated its role in decreasing the P-gp activity level which is related to the carcinogenesis. Many published studies have evaluated the association between the MDR1 C3435T polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of the association between MDR1 C3435T polymorphism and risk of breast cancer, we performed a meta-analysis comprised of 10 case–control studies, including 5282 breast cancer cases and 7703 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. The overall results indicated that the variant genotypes were associated with a significantly increased risk of breast cancer (TT versus CC: OR = 1.45, 95% CI = 1.14–1.30, TT versus CT/CC: OR = 1.13, 95% CI = 1.04–1.23, TT/CT versus CC: OR = 1.22, 95% CI = 1.02–1.46). Our results suggest that the MDR1 C3435T polymorphism may contribute to individual susceptibility to breast cancer.     

Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population

Molecular variants of polymorphic drug metabolizing enzymes and drug transporters are attributed to differences in individual's therapeutic response and drug toxicity in different populations. We sought to determine the genotype and allele frequencies of polymorphisms for major phase II drug-metabolizing enzymes (TPMT, UGT1A1) and drug transporter (MDR1) in South Indians. Allelic variants of TPMT (*2,*3A,*3B,*3C & *8), UGT1A1 (TA)6>7 and MDR1 (2677G>T/A & 3435C>T) were evaluated in 450-608 healthy South Indian subjects. Genomic DNA was extracted by phenol-chloroform method and genotype was determined by PCR-RFLP, qRT-PCR, allele specific PCR, direct sequencing and SNaPshot techniques. The frequency distributions of TPMT, UGT1A1 and MDR1 gene polymorphisms were compared between the individual 4 South Indian populations viz., Tamilian, Kannadiga, Andhrite and Keralite. The combined frequency distribution of the South Indian populations together, was also compared with that of other major populations. The allele frequencies of TPMT*3C, UGT1A1 (TA)7, MDR1 2677T, 2677A and 3435T were 1.2, 39.8, 60.3, 3.7, and 61.6% respectively. The other variant alleles such as TPMT*2, *3A, *3B and *8 were not identified in the South Indian population. Sub-population analysis showed that the distribution of UGT1A1 (TA)6>7 and MDR1 allelic variants differed between the four ethnic groups. However, the frequencies of TPMT*3C allele were similar in the four South Indian populations. The distribution of TPMT, UGT1A1 and MDR1 gene polymorphisms of the South Indian population was significantly different from other populations.     

MDR1基因多态性及其临床相关性研究进展

体内外研究证明,人体中P—gP在药物的吸收、分布、代谢和排泄（ADME）过程中发挥了非常重要的作用。多药耐药基因MDR1（ABCB1）是P-gP的编码基因。药物基因组学和遗传药理学研究发现在不同个体中MDR1基因多态性与P—gP表达和功能的改变密切相关,而且这些多态位点存在基因型分布和等位基因频率的种族差异性。近几年,已陆续发现在MDR1基因中有50处单核苷酸多态性（SNPs）和3处插入与缺失多态性。随后,大量文献报道某些位点的SNPs如C3435T会使个体患病的易感性增加。因此人们相信,深入研究MDR1基因多态性与P—gP的生理和生化方面的相关性将对个体医疗有着非常深远的意义。文章总结了国外最新的研究进展并结合本实验室的工作着重讨论了4个方面：1）P—gP对药代动力学性质的影响：2）MDR1基因多态性及其对遗传药理学性质的影响;3）MDR1^C3435T的单核苷酸多态性与P-gP表达和功能之间的相关性：4）MDR1基因多态性与人类某些疾病之间的相关性。     

Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach

Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene–gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (P_corr = 0.0465, P_corr = 0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (P_corr = 0.0465). Haplotype analysis further revealed A_CYP3A4–A_CYP3A5 haplotype to be significantly associated with responders (P_corr = 0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with ‘grade 1 or no leucopenia’ (P_corr = 0.0465, P_corr = 0.048). On evaluating higher order gene–gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2–4 anemia and dose delay/reduction due to neutropenia (P = 0.024, P = 0.004, P = 0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes.