Development of nanozyme based sensors as diagnostic tools in clinic applications: a review.

Since 1970, many artificial enzymes that imitate the activity and structure of natural enzymes have been discovered. Nanozymes are a group of nanomaterials with enzyme-mimetic properties capable of catalyzing natural enzyme processes. Nanozymes have attracted great interest in biomedicine due to their excellent stability, rapid reactivity, and affordable cost. The enzyme-mimetic activities of nanozymes may be modulated by numerous parameters, including the oxidative state of metal ions, pH, hydrogen peroxide (H2O2) level, and glutathione (GSH) concentration, indicating the tremendous potential for biological applications. This article delivers a comprehensive overview of the advances in the knowledge of nanozymes and the creation of unique and multifunctional nanozymes, and their biological applications. In addition, a future perspective of employing the as-designed nanozymes in biomedical and diagnostic applications is provided, and we also discuss the barriers and constraints for their further therapeutic use.

The Association Between Mean Glycated Haemoglobin or Glycaemic Variability and the Development of Retinopathy in People with Diabetes: A Retrospective Observational Cohort Study.

INTRODUCTION: To determine the association between mean glycated haemoglobin (HbA1c) or glycaemic variability and the development of diabetic retinopathy (DR) in people with diabetes. METHODS: An observational cohort study with people registered with a DR eye screening service between October 2012 and October 2017. Those who had no DR at the start of the study were followed for a maximum of 5 years. HbA1c measures were used to calculate HbA1c variability and mean HbA1c to assess any relationship between these and the risk of developing new onset DR. RESULTS: A total of 2511 individuals were followed up for up to 5 years. Of these, 542 (21.6%) developed DR. After adjustment, HbA1c variability was not significantly associated with the development of DR (p = 0.3435). However, the mean HbA1c was (p < 0.0001). Those with type 1 diabetes had an odds of 1.63 (95% CI 1.11-2.40) of a retinopathy diagnosis compared to those with type 2 diabetes. CONCLUSIONS: We have shown that mean HbA1c is associated with an increased risk of developing diabetic retinopathy. However, after adjustment for sex, age, diabetes type and the mean, the HbA1c variability no longer remained significant. Our data suggest that optimizing long-term glycaemic control remains paramount.

It has been known for a long time that if an individual's diabetes is not as well controlled as it could be, then they are at increased risk of developing complications over many years. These complications include diabetes-related eye disease (retinopathy). For many years, the way of measuring how well someone's diabetes was controlled was by measuring glycated haemoglobin (HbA_1c) which looked at how much glucose was attached to a red cell. This study looked at whether variation in HbA_1c over 5 years of follow-up was associated with greater risk of developing retinopathy, and if this relationship was stronger than just measuring HbA_1c alone. Previous work has shown that people with greater variation in HbA_1c are at increased risk of poor wound healing in those with diabetes-related foot ulcers. The present study looked at 2511 people who had no diabetes-related eye disease at the start of the study and who had been followed for 5 years. We found that variability in HbA_1c was not associated with an increased risk of developing diabetes-related eye disease, but confirmed that the average HbA_1c had the strongest relationship. Our data confirm that the focus of preventing diabetes-related eye disease should be on lowering HbA_1c.

Prevalence of CYP2C19 and ITGB3 polymorphisms among Bangladeshi patients who underwent percutaneous coronary intervention.

INTRODUCTION: Antithrombotic agents are the basic therapeutic option for patients with arterial thrombosis who underwent percutaneous coronary intervention (PCI). In Bangladesh, aspirin and clopidogrel are frequently prescribed as antithrombotics or platelet inhibitors. Studies reported the genetic polymorphisms of CYP2C19*2, CYP2C19*17, and ITGB3 cause an alteration of the pharmacodynamic and pharmacokinetic profile of aspirin and clopidogrel. Therefore, we aimed to assess the prevalence of CYP2C19*2, CYP2C19*17, and ITGB3 polymorphisms among Bangladeshi patients with cardiovascular disease (CVD) who underwent PCI. METHODS: Here we assessed a total of 1,000 CVD patients (male 782 and female 218) who underwent PCI and were treated with clopidogrel and/or aspirin. We performed genotyping of patients treated with clopidogrel and aspirin by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) methods. The PCR products of clopidogrel-treated patients were screened with agarose gel electrophoresis and then digested with SmaI and NsiI-HF for CYP2C19*2 and CYP2C19*17, respectively. We genotyped aspirin-treated patients with T-ARMS-PCR for missense rs5918 (PlA1/A1) polymorphism of the ITGB3 gene. Then we ran the digested PCR products on 2% agarose gel electrophoresis to detect the mentioned polymorphisms. RESULTS: Among the clopidogrel-treated patients, we observed 64.1% polymorphism (hetero + mutant) of CYP2C19*2 (loss-of-function allele) and 22.7% (hetero + mutant) of CYP2C19*17 (gain-of-function allele). On the other hand, among the aspirin-treated patients, polymorphisms of ITGB3 were 84.1% homozygous (PlA1/A1), 15.6% heterozygous (PlA1/A2), and 0.3% mutant homozygous. CONCLUSION: In the present study, we observed a high prevalence of genetic polymorphisms of CYP2C19 and ITGB3 genes. Therefore, we recommend genotyping of CVD patients before prescribing clopidogrel or aspirin to prevent coagulation. Based on the genotyping study, the adjustment of doses or alternative generics might require to avoid therapeutic failure or toxicity in some cases.

Altered serum elements, antioxidants, MDA, and immunoglobulins are associated with an increased risk of seborrheic dermatitis.

BACKGROUND: The exact mechanism for the pathophysiology of seborrheic dermatitis (SD) remains unknown. According to past knowledge, neuropsychiatric disorders, weak immune responses, fungal infections, antioxidants deficiencies, and inadequate nutrition might involve in SD. Here we evaluated serum trace elements, micronutrients, antioxidants, malondialdehyde (MDA), and immunoglobulins in SD patients. METHODS: This case-control study recruited 75 SD patients and 76 age-and sex-matched healthy controls (HCs). We measured serum micronutrients using atomic absorption spectroscopic methods. Similarly, we assessed serum antioxidants applying the RP-HPLC techniques. Also, serum MDA and immunoglobulins levels were evaluated by UV-spectrophotometric and turbidimetric methods, respectively. RESULTS: We observed higher serum levels of copper, manganese, iron, calcium, magnesium, and MDA in SD patients than HCs. Together with vitamin E, we noticed lower serum concentrations of immunoglobulin A, G, and M in SD patients than HCs. The present study detected a positive correlation between serum zinc and calcium levels (r = 0.365, p = 0.009) in SD patients. However, we identified a negative correlation between serum copper and calcium levels (r = -0.298, p = 0.035). CONCLUSION: The present study suggests that the altered levels of micronutrients, antioxidants, MDA, and immunoglobulins are associated with the pathophysiology of SD. These changes may not be the cause but the consequences of the disease. These findings might help to understand the etiopathology and management of SD.

Genetic polymorphisms of GSTP1, XRCC1, XPC and ERCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer patients of Bangladesh.

Inter-individual genetic makeup can trigger variability in platinum-based chemotherapeutic responses and corresponding adverse drug reactions and toxicities. Exploring the genetic causes behind these inter-individual variabilities in platinum-based chemotherapeutic responses by investigating the effects of GSTP1 (rs1695), XRCC1 (rs25487), XPC (rs2228001) and ERCC1 (rs11615) genetic polymorphisms on toxicity and therapeutic response of this treatment among Bangladeshi advanced non-small cell lung cancer (NSCLC) patients was the aim of this study. 285 Clinically proven either stage IIIB or IV (advanced) NSCLC patients aging not less than 18 years old and receiving platinum-based chemotherapy were recruited to assess the influence of these four single nucleotide polymorphisms (SNPs) on peripheral leukocytes. Toxicity and response were evaluated by multivariate regression analyses using SPSS statistical software (version 17.0). XRCC1 (rs25487) polymorphism was found to act as a predictive factor for not only grade 3 and 4 anemia (p = 0.008), neutropenia (p = 0.010), thrombocytopenia (p = 0.025) and gastrointestinal toxicity (p = 0.002) but also for therapeutic response (p = 0.012) in platinum-based chemotherapy. Although GSTP1 (rs1695) polymorphism might serve as prognostic factor regarding grade 3 or 4 neutropenia, a significant (p = 0.044) improvement in response to platinum-based chemotherapy was observed. However, XPC (rs2228001) and ERCC1 (rs11615) polymorphisms could not establish any significant relation with toxicity or therapeutic response. XRCC1 (rs2228001) and GSTP1 (rs1695) polymorphisms might explain platinum-induced clinical outcomes in terms of both toxicity and therapeutic response variations among Bangladeshi advanced NSCLC patients.

SMAD2 rs4940086 heterozygosity increases the risk of cervical cancer development among the women in Bangladesh.

SMAD2 is a critical signal transducer molecule in the TGFß- SMAD pathway which is also known for its tumor suppressor role. Genetic variations in SMAD2 render cells insensitive to its anti-proliferative signals leading to tumor formation. In this study, we demonstrate the impact of single nucleotide polymorphisms (SNPs) of SMAD2 (rs4940086 and rs8085335) on cervical cancer risk development in Bangladeshi population. 132 cervical cancer patients and 98 control volunteers were enrolled in the study and genotyped utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between cervical cancer susceptibility and the chosen SNPs were evaluated through multiple logistic regression. SMAD2 rs4940086 heterozygous genotype (T/C) was associated with a 3.89 times higher risk of cervical cancer development (P = 0.001, AOR 3.89, 95% CI 1.777-8.513). The T/C and C/C genotypes in combination also significantly elevated cervical cancer risk (P = 0.035, AOR 1.876, 95% CI 1.047-3.364). Urban cancer patients had a significantly higher chance of carrying the rs4940086 polymorphism as compared to rural cancer patients (P = 0.045, OR 2.59 95% CI 1.02-6.59). SMAD2 rs8085335 heterozygous variant (A/G) demonstrated modest effects in increasing cervical cancer susceptibility (P = 0.594, AOR 1.247, 95% CI 0.554-2.809). Our results suggest that polymorphic variations in SMAD2, particularly rs4940086, can potentially elevate cervical cancer susceptibility in Bangladeshi women.

Evaluation of serum amino acids and non-enzymatic antioxidants in drug-naïve first-episode major depressive disorder.

BACKGROUND: The alterations of biological markers are thought to be effective tools to understand the pathophysiology and management of major depressive disorder (MDD). A lot of researches has implied many markers for depression, but any of them fully discovered the association between the markers and depression. The present study investigated the serum levels of amino acids and non-enzymatic antioxidants in major depression, and also explained their association with depression. METHODS: This study examined 247 MDD patients and 248 healthy controls (HCs) matched by age and sex. The Hamilton Depression Rating Scale (Ham-D) was used to all the participants to measure the severity of depression. Quantification of serum amino acids, vitamin A and E were carried out using the HPLC system whereas vitamin C levels were measured by UV-spectrophotometer. All the statistical analysis was performed by SPSS statistical software (version 23.0). The independent sample t-test, the Mann-Whitney U test, and the Fisher's exact test were applied to detect the group differences where a Bonferroni correction applied to the p value. RESULTS: It was observed that serum levels of four amino acids (methionine, phenylalanine, tryptophan, and tyrosine) along with three non-enzymatic antioxidants (vitamin A, E, and C) were significantly dropped in MDD patients compared to HCs (Cohen's d (d): - 0.45, - 0.50, - 0.68, - 0.21, - 0.27, - 0.65, and - 0.24, respectively). Furthermore, Ham-D scores of cases were negatively correlated with serum levels of methionine (r = - 0.155, p = 0.015) and tyrosine (r = - 0.172, p = 0.007). CONCLUSION: The present study suggests that lowered serum methionine, phenylalanine, tryptophan, tyrosine, and non-enzymatic antioxidants are associated with depression. The reduction of these parameters in MDD patients may be the consequence, and not the cause, of major depression.

Pharmacogenetic Variants in MTHFR Gene are Significant Predictors of Methotrexate Toxicities in Bangladeshi Patients With Acute Lymphoblastic Leukemia.

BACKGROUND: The objective of this pharmacogenetic study was to investigate the relationship of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with methotrexate (MTX)-induced toxicities and plasma homocysteine level in patients with acute lymphoblastic leukemia (ALL) from Bangladesh. Several polymorphisms result in reduced MTHFR activity that causes impaired remethylation of homocysteine to methionine and abnormal MTX metabolism, especially in tissues with high turnover. Therefore, the risk of elevated plasma homocysteine as well as MTX-induced toxicities become higher with MTHFR polymorphisms. PATIENTS AND METHODS: We recruited 160 patients with ALL receiving MTX containing chemotherapeutic protocol, and they were genotyped for MTHFR C677T and A1298C polymorphisms with polymerase chain reaction-restriction fragment length polymorphism. We also measured the plasma homocysteine level of 51 patients by the AxSYM homocysteine assay method. RESULTS: We found 68.1% CC, 26.3% CT, and 5.6% TT genotype for MTHFR C677T polymorphism and 39.3% AA, 46.9% AC, and 13.8% CC genotype for MTHFR A1298C polymorphism in patients with ALL. Our study suggested that MTX-induced mucositis and diarrhea are significantly associated with MTHFR C677T as well as MTHFR A1298C polymorphisms (P < .05). CONCLUSION: The risk of elevated plasma homocysteine level was 5 to 6 times higher for both polymorphisms. This study may help to identify the patients who are at higher risk for MTX-related toxicities.

Pharmacokinetics and Bioavailability Study of a Prednisolone Tablet as a Single Oral Dose in Bangladeshi Healthy Volunteers.

The aim of the study was to assess the pharmacokinetic and bioavailability of 2 formulations of 5-mg prednisolone tablets, reference product (Teva UK Limited) and Pred (Eskayef Bangladesh Ltd) as test product. The open-label, randomized, 2-way crossover studies were conducted on 14 healthy subjects. Participants were assigned to receive both products as a single dose (20 mg formulations, 4 × 5 mg tablets) followed by a 2 weeks' washout period. Following oral administration, samples were obtained at various time intervals and analyzed for prednisolone concentrations using a validated high-performance liquid chromatography assay method with ultraviolet detection. The obtained values for test and reference products were 683.00 ± 94.54 ng/mL and 635.16 ± 125.57 ng/mL for Cmax; 2716.54 ± 196.28 ng·h/mL and 2780.5 ± 119.73 ng·h/mL for AUC0-12; 3284.36 ± 138.12 ng·h/mL and 3317.96 ± 133.95 ng·h/mL for AUC0-∞, respectively. From the paired Student t test, no significant differences between 2 formulations were observed (P > .05). The 90% confidence intervals of Cmax, AUC0-12, and AUC0-∞ were found to be 99.0% to 100.9%, 99.4% to 100.5%, and 99.9% to 101.3%, respectively. Finally, it can be concluded that Pred (Test) of Eskayef Bangladesh Ltd and prednisolone (Reference) of Teva UK Limited are bioequivalent and interchangeable.

Elevated serum levels of malondialdehyde and cortisol are associated with major depressive disorder: A case-control study.

OBJECTIVES: Major depressive disorder is diagnosed on the basis of patient's self-reported experiences, behavior reported by relatives, and a mental status examination, and yet we do not have any reliable biomarker for this. Mood-regulating pathways are affected by oxidative injury to lipids and cortisol is released into the blood due to stimulation of corticotrophin receptors in the adrenal cortex. Here, we aimed to determine serum levels of malondialdehyde and cortisol in major depressive disorder patients and controls. METHODS: We collected blood samples from 247 major depressive disorder patients and 248 controls. Serum levels of malondialdehyde and cortisol were measured by ultraviolet spectrophotometry and enzyme-linked immunosorbent assay kit, respectively. RESULTS: We found malondialdehyde levels were significantly higher in patients than controls, with mean ± standard deviation at 4.49 ± 1.37 and 2.87 ± 0.82 µmol/L, respectively, p < 0.001. Cortisol levels were also found significantly higher in patients than controls, with mean ± SD at 19.22 ± 1.64 and 17.37 ± 1.34 µg/dL, respectively, p < 0.001. Significant negative correlation was observed between serum levels of malondialdehyde and cortisol in patients (r =-0.170, p = 0.021). Receiver operating characteristic analysis showed good diagnostic value for malondialdehyde and cortisol, with the area under the curve at 0.853 and 0.819, respectively. CONCLUSION: The present study suggests that increased serum levels of malondialdehyde and cortisol are strongly associated with major depressive disorder. We believe elevations of malondialdehyde and cortisol in serum level arise independently and they could serve as biomarkers for major depressive disorder.

Alterations of serum macro-minerals and trace elements are associated with major depressive disorder: a case-control study.

BACKGROUND: Major depressive disorder (MDD) is a mixed disorder with the highly irregular course, inconsistent response to treatment and has no well-known mechanism for the pathophysiology. Major causes of depression are genetic, neurobiological, and environmental. However, over the past few years, altered serum levels of macro-minerals (MM) and trace elements (TE) have been recognized as major causative factors to the pathogenesis of many mental disorders. The purpose of this study was to determine the serum levels of MM (calcium and magnesium) and TE (copper, iron, manganese, selenium, and zinc) in MDD patients and find out their associations with depression risk. METHODS: This prospective case-control study recruited 247 patients and 248 healthy volunteers matched by age and sex. The serum levels of MM and TE were analyzed by atomic absorption spectroscopy (AAS). Statistical analysis was performed with independent sample t-tests and Pearson's correlation test. RESULTS: We found significantly decreased concentrations of calcium and magnesium, iron, manganese, selenium, and zinc in MDD patients compared with control subjects (p < 0.05). But the concentration of copper was significantly increased in the patients than control subjects (p < 0.05). Data obtained from different inter-element relations in MDD patients and control subjects strongly suggest that there is a disturbance in the element homeostasis. CONCLUSION: Our study suggests that altered serum concentrations of MM and TE are major contributing factors for the pathogenesis of MDD. Alterations of these elements in serum levels of MDD patients arise independently and they may provide a prognostic tool for the assessment of depression risk.

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

BACKGROUND: Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. METHODS: Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. RESULTS: Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. CONCLUSION: DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients.

Genetic variants of SULT1A1 and XRCC1 genes and risk of lung cancer in Bangladeshi population.

Lung cancer is one of the most frequently occurring cancers throughout the world as well as in Bangladesh. This study aimed to correlate the prognostic and/or predictive value of functional polymorphisms in SULT1A1 (rs9282861) and XRCC1 (rs25487) genes and lung cancer risk in Bangladeshi population. A case-control study was conducted which comprises 202 lung cancer patients and 242 healthy volunteers taking into account the age, sex, and smoking status. After isolation of genomic DNA, genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method and the lung cancer risk was evaluated as odds ratio that was adjusted for age, sex, and smoking status. A significant association was found between SULT1A1 rs9282861 and XRCC1 rs25487 polymorphisms and lung cancer risk. In case of rs9282861 polymorphism, Arg/His (adjusted odds ratio = 5.06, 95% confidence interval = 3.05-8.41, p < 0.05) and His/His (adjusted odds ratio = 3.88, 95% confidence interval = 2.20-6.82, p < 0.05) genotypes were strongly associated with increased risk of lung cancer in comparison to the Arg/Arg genotype. In case of rs25487 polymorphism, Arg/Gln heterozygote (adjusted odds ratio = 4.57, 95% confidence interval = 2.79-7.46, p < 0.05) and Gln/Gln mutant homozygote (adjusted odds ratio = 4.99, 95% confidence interval = 2.66-9.36, p < 0.05) were also found to be significantly associated with increased risk of lung cancer. This study demonstrates that the presence of His allele and Gln allele in case of SULT1A1 rs9282861 and XRCC1 rs25487, respectively, involve in lung cancer prognosis in Bangladeshi population.

Effect of VKORC1 and CYP2C9 polymorphisms on warfarin dose requirement in Bangladeshi population.

Warfarin, an oral anticoagulant is one of the most widely prescribed drugs in modern medicine. Large inter-individuals variability due to age, gender, diet, concurrent drug interactions and variations in CYP2C9 and VKORC1 genes make the management of warfarin therapy challenging and yet no study has been conducted on the Bangladeshi population. The aim of the study was to identify the role of VKORC1 and CYP2C9 polymorphisms in Bangladeshi population in dose requirement of warfarin. We studied 87 heart valve replacement patients who were prescribed warfarin for minimum of 6 months with a target International normalized ratio of 2.0-3.5. Genotyping of VKORC1rs9923231 (-1639 G>A), CYP2C9*2 and CYP2C9*3 was performed by Polymerase Chain Reaction- Restriction Fragment Length Polymorphism. The frequencies of GG, AG and AA genotypes of VKORC1rs9923231 in the studied population were 87.4%, 8%, and 4.6% respectively whereas the frequencies of the CYP2C9*1/3 and CYP2C9*3/3 were 4.6% and 3.4% respectively. The CYP2C9*2 was not found in the studied population. The results of this study indicate that comparatively higher daily maintenance doses of warfarin were required to achieve the target INR for patients carrying both GG genotype of VKORC1rs9923231 and wild type variant of CYP2C9*3 whereas minimum dose were required for patient having AA genotype of VKORC1rs9923231 and *3/*3 variant of CYP2C9.

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population.

Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C

Elevated serum MDA and depleted non-enzymatic antioxidants, macro-minerals and trace elements are associated with bipolar disorder.

Genetic and neurobiological factors are considered to be the major causes of mood and mental disorders. However, over the past few years, increased levels of serum malondialdehyde and altered levels of various non-enzymatic antioxidants and essential minerals involved in abnormal functional activity have been identified as major contributing factors to the pathogenesis of several neurological disorders. The aim of this study was to determine the levels of the serum lipid peroxidation product malondialdehyde (MDA), antioxidants (vitamin A, E and C), macro-minerals (calcium, potassium and sodium) and trace elements (zinc, iron and selenium) in patients with bipolar disorder and to explore their role in disease progression. This is a prospective case-control study that evaluated 55 patients with bipolar disorder and 55 healthy volunteers matched by age and sex. Serum MDA levels were determined by UV spectrophotometry as a marker of lipid peroxidation. RP-HPLC was employed to investigate the serum vitamin A and E concentrations, whereas UV spectrophotometry was used to quantify levels of vitamin C. Serum macro-minerals and trace elements were analyzed by atomic absorption spectroscopy (AAS). Statistical analysis was performed with independent sample t-tests and Pearson's correlation test. We found significantly higher concentrations of MDA (p<0.05) and significantly lower concentrations of antioxidants (vitamin A, E and C) (p<0.05) in the patient group compared with control group. Regarding trace elements and macro-minerals, lower concentrations of zinc, calcium, iron, selenium, sodium and potassium were found in the patient group compared with control subjects (p<0.05). Our study suggests that high serum MDA concentrations and low serum concentrations of antioxidants, macro-minerals and trace elements are strongly associated with bipolar disorder.

Association of BRCA1, BRCA2, RAD51, and HER2 gene polymorphisms with the breast cancer risk in the Bangladeshi population.

PURPOSE: Breast cancer is considered as the most frequent female malignancy. Altered gene expressions due to genetic polymorphisms in the BRCA1, BRCA2, RAD51, and HER2 contribute toward the development of breast cancer, and yet, no such type of study has been conducted in the Bangladeshi population. This study was designed to evaluate the role of BRCA1rs80357713, BRCA1rs80357906, BRCA2rs11571653, RAD51rs1801320, and HER2rs1136201 polymorphisms as risk factors in the development of breast cancer in the Bangladeshi population. METHODS: A total 310 patients with invasive breast cancers were recruited as cases from different public and private hospitals of Bangladesh, and 250 Bangladeshi healthy women matching age with the patients were recruited as controls. Polymerase chain reaction-restriction fragment length polymorphism method was used to analyze the genetic polymorphisms. RESULTS: Patients carrying BRCA1/2 mutations, GC and GC plus CC genotypes of RAD51rs1801320, and AG plus GG genotype of HER2rs1136201 polymorphisms were found to be associated with breast cancer. In subgroup analysis, AG plus GG genotype of HER2rs1136201 was found to be associated with the breast cancer risk in the patients younger than 45 years of age compared with the older patients having more than 45 years of age, and RAD51rs1801320 was related to the tumor size and tumor aggressiveness (higher graded tumor). CONCLUSION: Our results indicate that BRCA1/BRCA2, RAD51rs1801320 and HER2rs1136201 polymorphisms were associated with breast cancer in the studied population.

Breast cancer risk in relation to TP53 codon 72 and CDH1 gene polymorphisms in the Bangladeshi women.

Pharmacogenomic studies play a significant role in understanding the risk of breast cancer where genetic abnormalities are implicated as the etiology of cancer. Various polymorphisms of tumor suppressor gene TP53 and E-cadherin (CDH1) have been found to be associated with increased breast cancer risk worldwide. This study aimed to analyze the contribution of TP53 and CDH1 gene anomalies in breast cancer risk in the Bangladeshi breast cancer patients. For risk determination, 310 patients with breast cancer and 250 controls from Bangladeshi women were recruited who are matched up with age and use of contraceptives with patients. Genetic polymorphisms were detected by using polymerase chain reaction restriction fragment length polymorphism. A significant association was found between TP53Arg72Pro (rs1042522) and CDH1 -160 C/A (rs16260) polymorphisms and breast cancer risk. In case of P53rs1042522 polymorphism, Arg/Pro (P = 0.0053, odds ratio (OR) = 1.69) and Pro/Pro (P = 0.018, OR = 1.83) genotypes were associated with increased risk of breast cancer in comparison to the Arg/Arg genotype. Arg/Pro + Pro/Pro genotype and Pro allele also increased the risk of breast cancer (P = 0.002, OR = 1.73; P = 0.004, OR = 1.43, respectively). In case of CDH1rs16260 polymorphism, C/A heterozygote and combined C/A + A/A genotypes were found to be strongly associated (P = 0.005, OR = 1.67; P = 0.0037, OR = 1.68) with increased risk of breast cancer. The variant A allele also increased the breast cancer risk (P = 0.0058, OR = 1.52). The present study demonstrates that P53Arg72Pro and CDH1rs16260 polymorphisms are associated with elevated breast cancer risk in the Bangladeshi population.

Prevalence of CYP2C19 alleles, pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population.

The extent to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity between studies. We used the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method for genotyping loss of function (LOF) allele, CYP2C19*2 and gain of function (GOF) allele, CYP2C19*17 in 163 patients undergoing PCI and 165 healthy volunteers from an ethnically distinctive Bangladeshi population. Thirty-eight patients took prasugrel and 125 patients took clopidogrel among whom 30 patients had their clopidogrel active metabolites (CAM) determined by LC-MS/MS 1-1.5 h after clopidogrel intake. All patients who underwent PCI had their P2Y12 per cent inhibition (PRI) measured by VerifyNow System. The impact of different genotypes on CAM and PRI were also determined. We did not find significant variation of CYP2C19*2 (P > 0.05) and CYP2C9*17 (P > 0.05) alleles among healthy volunteers and patients. CAM concentration as well as PRI by clopidogrel varied significantly (P < 0.05) based on genotypic variation of CYP2C19*2 and CYP2C19*17 individually. Such influence was not observed in case of prasugrel. Genotypic variation did not impact PRI but as a whole PRI by prasugrel was better than that of clopidogrel (P < 0.05). Due to presence of both of alleles the effect on PRI by clopidogrel could not be predicted, effectively indicating possible involvement of other factors. Genotype guided clopidogrel dose adjustment would be beneficial and therefore we propose mandatory genotyping before clopidogrel dosing. Prasugrel proved to be less affected by genotypic variability, but due to lack of sufficient long-term toxicity data, caution would be adopted before substituting clopidogrel.

Effect of GSTP1 and ABCC4 gene polymorphisms on response and toxicity of cyclophosphamide-epirubicin-5-fluorouracil-based chemotherapy in Bangladeshi breast cancer patients.

The most important cytotoxic drug namely, cyclophosphamide used in breast cancer along with epirubicin and 5-fluorouracil, is transported by ABCC transporters and detoxified by glutathione S-transferases (GSTs). The activities of these enzymes and transporters may vary in different population due to the presence of genetic polymorphisms. This study was aimed to evaluate the effects of GSTP1rs1695 and ABCC4rs9561778 polymorphisms on the response and toxicities produced by chemotherapy used in the treatment of Bangladeshi breast cancer patients. A total of 200 and 56 patients with invasive breast cancers were recruited from different public and private hospitals of Bangladesh of which 117 patients received neoadjuvant chemotherapy to examine the response as well as the toxicity, and another 139 patients received adjuvant chemotherapy to evaluate only the toxicity. Genetic polymorphisms of the mentioned genes were detected by using Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR RFLP). Patients carrying AG and AG plus GG genotype of GSTP1rs1695 were more likely to have a good response, whereas no association of ABCC4rs9561778 was found with the chemotherapy response. Patients carrying GT and GT plus TT genotypes of ABCC4rs9561778 were found to be associated with anemia, neutropenia, leukopenia, and gastrointestinal toxicities when compared with GG genotype whereas no association was found with thrombocytopenia. GSTP1rs1695 was not associated with any type of toxicities investigated. Our result indicates that GSTP1rs1695 polymorphism was strongly associated with the response of chemotherapy, whereas ABCC4rs9561778 polymorphism was significantly related with chemotherapy-induced toxicities.