Xiao-Jing Xu

ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients.

Aims: Some study found that ATP‐binding cassette (ABC) efflux transporters play an important role in antiepileptic drug resistance, especially ABCB1 and ABCC2. The aims of this study were to evaluate the relationship between the genetic polymorphisms of ABCC2 and ABCB1 and the therapeutic efficacy of antiepileptic drugs (AEDs) in Chinese epileptic patients. Methods:ABCB1 rs1045642 (3435C>T) and ABCC2 rs717620 (−24C>T), rs3740066 (3972C>T), and rs2273697 (1249G>A) polymorphisms loci in 537 Chinese epilepsy patients (217 drug resistant patients and 320 drug responders) were genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Results:ABCC2 rs717620 −24TT genotype was significantly associated with drug resistant epilepsy (odds ratio [OR]= 4.06 [1.79–9.20], P= 0.001). The OR values of ABCC2 rs717620 −24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes were markedly higher in drug resistant patients (OR = 1.57 [1.08–2.29], P= 0.018; OR = 1.49 [1.02–2.18], P= 0.038, respectively) compared with responsive patients. ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not associated with drug resistant epilepsy. Linkage disequilibrium (LD) test showed that the ABCC2 rs717620 were in strong LD with rs2273697 (D’= 0.694) and rs3740066 (D’= 0.699). The frequencies of haplotypes TGT (ABCC2 −24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients was significantly higher than those in responsive patients (21.0% vs. 14.2%, P < 0.05). Conclusion:ABCC2−24C>T, 3972C>T polymorphisms and one ABCC2 haplotype is associated with AED resistance; ABCC2 1249G>A and ABCB1 3435C>T polymorphisms are not associated with AED resistance in our study. These data suggest that ABCC2 polymorphisms and haplotype may affect the response of antiepileptic drugs.

KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) Polymorphisms Affect Therapeutic Efficacy of Repaglinide in Chinese Patients With Type 2 Diabetes

This study showed that the polymorphisms KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) are associated with a heightened risk of developing type 2 diabetes mellitus (T2DM). We also explored the effects of these polymorphisms on the efficacy of repaglinide therapy in Chinese patients with T2DM. A total of 259 patients with T2DM and 188 healthy controls were genotyped. Forty patients with various genotypes were randomly selected to undergo an 8‐week repaglinide treatment regimen. Patients with the G allele of the KCNJ11 Lys23Glu polymorphism showed higher levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (P < 0.05). After repaglinide treatment, patients with the GA or AA genotype showed higher levels of FPG, PPG, and glycated hemoglobin (HbA1c) compared with patients with the GG genotype (P < 0.05). Patients with the C allele of TCF7L2 rs290487(C/T) had higher total cholesterol levels and lower body mass index (BMI) (P < 0.05). In patients with the TT genotype, the drug showed better efficacy with respect to levels of fasting insulin, triglycerides, and low‐density lipoprotein cholesterol (LDL‐c) than in patients with the CC or CT genotype (P < 0.05). The KCNJ11 and TCF7L2 polymorphisms were associated with repaglinide efficacy.

Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients

BACKGROUND Cisplatin toxicity severely obstacles successful chemotherapy in lung cancer patients. Cisplatin uptake is considered as one of the major factors contributing to the side effects of cisplatin. Genetic variances of core genes also affect cisplatin toxicity. It has been identified that CTR1, copper transporter protein 1, plays an essential role in cisplatin uptake. The purpose of this study is to investigate whether CTR1 polymorphism is associated with platinum toxicity in non-small cell lung cancer (NSCLC) patients. METHOD 204 incident NSCLC patients from three different institutions were enrolled and followed up. These patients were histologically confirmed with non-small cell lung cancer. All patients have accepted cisplatin-based chemotherapy for at least two cycles. Twenty SNPs of CTR1 were detected in these patients. RESULT CTR1 rs10981694 A>C polymorphism is associated with cisplatin induced severe toxicity in NSCLC patients. C-carrier subjects presented poorer tolerance to ototoxicity (p<0.05). The survival times of patients with different rs10981694 genetic polymorphism were not significantly different. CONCLUSION NSCLC patients carrying C allele of CTR1 rs10981694 presented more sensitivity to ototoxicity after cisplatin treatment. CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients.

Genetic polymorphism of copper transporter protein 1 is related to platinum resistance in Chinese non-small cell lung carcinoma patients†

Chemotherapeutic resistance to platinum‐based anticancer drugs is a major obstacle in the successful treatment of lung cancer. Cellular uptake and platinum accumulation are considered the most important factors contributing to platinum resistance. The copper transporter family is the major plasma membrane transporter for platinum uptake. Copper transporter protein 1 (CTR1) plays an essential role in cisplatin influx and is closely related to platinum resistance by influencing platinum uptake and accumulation. The aim of the present study was to determine whether CTR1 polymorphisms are associated with platinum resistance in non‐small cell lung carcinoma (NSCLC) patients. A total of 282 incident Chinese Han NSCLC patients were enrolled in the study and followed up at three different institutions. All patients underwent at least two cycles of platinum‐based chemotherapy. Twenty single‐nucleotide polymorphisms of CTR1 were detected from genomic DNA samples. Genetic polymorphisms of CTR1 at rs7851395 and rs12686377 were associated with platinum resistance in NSCLC patients. Patients with a GT haplotype presented with increased susceptibility to platinum resistance (P < 0.05), whereas an AG haplotype contributed to longer survival (P < 0.05). In conclusion, a significant relationship was found between rs7851395 and rs12686377 polymorphisms and platinum resistance, as well as clinical outcomes, in Chinese NSCLC patients. Thus, CTR1 plays an essential role in platinum resistance and could be considered a predictive marker for the pretreatment evaluation of NSCLC patients.

Effects of SCN1A and GABA receptor genetic polymorphisms on carbamazepine tolerability and efficacy in Chinese patients with partial seizures: 2-year longitudinal clinical follow-up.

Aims: To investigate the tolerability and efficacy of carbamazepine treatment in patients with partial‐onset seizures and the association with polymorphisms in the sodium channel α‐subunit type 1 (SCN1A), and gamma‐aminobutyric acid (GABA) receptor genes among the Chinese Han population. Methods: 448 patients were genotyped for single nucleotide polymorphisms selected of the SCN1A and GABA‐receptor genes. Monotherapy with carbamazepine (CBZ) was administered to the patients. The effectiveness of CBZ treatment was evaluated with regard to efficacy by the decrease in seizures and tolerability by retention rates. Results:SCN1A rs3812718 A/G with CBZ tolerability (P= 0.038) throughout 24 months of clinical follow‐up and the GABRA1 rs2290732 A/G were significantly associated with CBZ tolerability (P= 0.001). The maintenance dose and serum level of CBZ in AA genotype carriers of rs3812718 A/G were significantly higher than those of GG genotype carriers between 3 and 12 months of follow‐up. The proportion of AA genotype carriers of rs2298771 A/G with seizure free was significantly higher than that of AG+GG genotype carriers from 3 months to 15 months of follow‐up (P < 0.05). Conclusion: rs3812718 A/G and rs2290732 A/G polymorphisms affected the tolerability of CBZ. rs2298771 A/G was associated with efficacy of CBZ treatment.

The prognostic value of altered eIF3a and its association with p27 in non-small cell lung cancers.

Background Over-expressed eukaryotic initiation factor 3a (eIF3a) in non-small cell lung cancer (NSCLC) contributed to cisplatin sensitivity. However, the role of eIF3a in oncogenesis was still controversial. This study was designed to investigate the prognostic impact of eIF3a and p27 in radically resected NSCLC patients. Methods The expression levels of subcellular eIF3a and p27 were evaluated immunohistochemically in 537 radically resected NSCLC samples, and another cohort of 210 stage II NSCLC patients. Disease specific survival (DSS) and disease free survival (DFS) were analyzed by Kaplan-Meier method and Cox regression model. Results The subcellular expression of eIF3a was strongly correlated with status of p27 (Spearman rank coefficient correlation for cytoplasmic eIF3a and p27 = 0.653, for nuclear staining = 0.716). Moreover, survival analysis revealed favorable prognostic impact of nuclear eIF3a, p27, and the combination high nuclear staining on NSCLC (Hazards Ratio = 0.360, 95%CI = 0.109–0.782, P = 0.028). In addition, interaction research between biomarkers and chemotherapy status disclosed cisplatin-based regimen trend to prolong DSS of stage II NSCLC patients with high eIF3a-C (P = 0.036)and low p27-N (P = 0.031). Conclusions Our findings suggested altered eIF3a expression closely correlated with p27 status, and the association was of prognostic value for resected NSCLC. Altered expression of eIF3a and p27 predicted prognosis of NSCLC independently.

Association between eIF3α polymorphism and severe toxicity caused by platinum-based chemotherapy in non-small cell lung cancer patients.

Platinum‐induced toxicity severely impedes successful chemotherapy in lung cancer patients. The nucleotide excision repair (NER) pathway is considered as one of the major factors contributing to platinum effects. Furthermore, genetic variances of the NER pathway influence platinum toxicity. eIF3α, over expressed in many malignancies, is an up‐stream gene of NER and could regulate its activity. The purpose of this study was to investigate whether eIF3α polymorphism is associated with severe platinum toxicity in patients with non‐small cell lung cancer (NSCLC).

NeuroD1 A45T and PAX4 R121W polymorphisms are associated with plasma glucose level of repaglinide monotherapy in Chinese patients with type 2 diabetes

AIMS We aimed to determine whether NeuroD1/BETA2 and PAX4 polymorphisms were associated with the therapeutic efficacy of repaglinide in Chinese type 2 diabetes mellitus (T2DM) patients. METHODS Three hundred and sixty-eight T2DM patients and 132 healthy control subjects were genotyped by restriction fragment length polymorphism. Forty-three patients with various genotypes were randomly selected to undergo 8 weeks of repaglinide treatment (3 mg day(-1)). Fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin, fasting and postprandial serum insulin (FINS, PINS), homeostasis model assessment for insulin resistance, serum triglyceride, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol were determined before and after repaglinide treatment. RESULTS The allelic frequency of NeuroD1/BETA2 T45 was higher in T2DM patients than in the control subjects [13.45 vs. 6.82%, P < 0.01, odds ratios = 2.342 (1.365, 4.019), P= 0.002]. Type 2 diabetes mellitus patients with the mutated allele of NeuroD1/BETA2 A45T polymorphism showed higher FINS (13.46 ± 12.57 vs. 10.04 ± 7.09 mU l(-1) , P < 0.05) (11.67, 14.83 vs. 8.38, 11.37) and PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l(-1), P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than individuals with the T allele. The PAX4 R121W R allele carriers had higher PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l(-1), P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than subjects with the W allele. After repaglinide treatment, patients with the T allele of NeuroD1/BETA2 A45T polymorphisms had attenuated efficacy on fasting plasma glucose (-2.79 ± 2.14 vs.-0.99 ± 1.80 mmol l(-1), P < 0.01) (-3.53, -1.84 vs.-1.99, -0.13) and postprandial plasma glucose (-6.71 ± 5.90 vs.-2.54 ± 3.39 mmol l(-1), P < 0.01) (-9.28, -4.62 vs.-4.34, -0.84). Patients with the RR genotype of PAX4 R121W showed better efficacy with respect to the level of postprandial plasma glucose than R/W genotypes (-6.53 ± 6.52 vs.-2.95 ± 1.17 mmol l(-1), P < 0.05) (-8.20, -4.89 vs.-3.92, -1.20). CONCLUSIONS The NeuroD1/BETA2 and PAX4 polymorphisms were substantially associated with plasma glucose level after repaglinide monotherapy.

The A/G allele of eIF3a rs3740556 predicts platinum-based chemotherapy resistance in lung cancer patients

eIF3a is the largest subunit of eukaryotic translation initiation factor 3, which has been suggested to affect tumor progression and activity of nucleotide excision repair pathway contributing to platinum resistance. The purpose of this study was to investigate possible mutations in promoter and exon regions of eIF3a gene and to assess whether eIF3a mutation status have prognostic and predictive significance in platinum-based chemotherapeutic lung cancer patients. 771 lung cancer patients were enrolled and followed up. These patients were newly diagnosed with incident lung cancer, which was confirmed histologically or cytologically, and accepted platinum-based chemotherapy for at least two cycles. Three novel mutations of eIF3a were found, including 11279G>A in intron 6, Arg438Lys in exon 9, 29671G>A in intron 15, with minor allele frequency of 0.16, 0.18, 0.16, respectively. A-carrier patients of rs3740556 conferred a significantly better platinum-based chemotherapy response (p < 0.05) and seemed to live longer. eIF3a genetic polymorphisms can be considered as predictive tools for pretreatment evaluation of platinum-based chemotherapy. Lung cancer patients carrying rs3740556 A allele tended to have a favorable prognosis after treatment with platinum-based chemotherapy.

NAMPT -3186C/T polymorphism affects repaglinide response in Chinese patients with Type 2 diabetes mellitus

1. In the present study, we investigated the associations of nicotinamide phosphoribosyltransferase (NAMPT)‐3186 C/T and ‐948G/T polymorphisms with the risk of Type 2 diabetes mellitus (T2DM) and their impact on the efficacy of repaglinide in Chinese Han T2DM patients.