Influence of GSTT1 and GSTP1 polymorphisms on type 2 diabetes mellitus and diabetic retinopathy risk in the Chinese population: a case control study

Background: Studies have revealed the association of glutathione S-transferases (GSTM1 and GSTT1) deletion (null) polymorphism with the risks of developing type 2 diabetes mellitus (T2DM) and its complications. The present study aimed to investigate the relationship between GSTT1/ GSTP1 gene polymorphisms and the risks of T2DM and diabetic retinopathy (DR) in a Chinese population.Methods: In this case-control study, a total of 336 subjects with T2DM and a defined ophthalmologic status were recruited from the Second People’s Hospital of Yunnan Province between June 2014 and October 2016. Seventy-two age-matched healthy controls were also enrolled. Physical examinations and laboratory tests were performed. The frequencies of GSTT1 genotypes in all participants were determined by polymerase chain reaction (PCR) followed by agarose gel electrophoresis. Genotyping of GSTP1 gene was identified by PCR amplification followed by sequencing.Results: Compared with healthy controls, the GSTT1-null genotype was significantly more common in diabetic patients with or without DR (all P < 0.05). However, there was no difference in the frequencies of the GSTP1 genotype (AA, GA, GG) between diabetic patients with or without DR and healthy controls. Furthermore, neither the GSTP1 nor GSTT1 genetic polymorphism was associated with the development of DR. In the present study, the risk of developing T2DM was significantly higher in subjects carrying the combined heterozygous GSTP1 (AG) and null GSTT1 genotypes (OR = 0.40, 95% CI = 0.21-0.74, P = 0.02).Conclusions: The deletion of the GSTT1 genotype was associated with a higher risk of developing T2DM, whether alone or in combination with GSTP1, indicating that the null genotype of GSTT1 may serve as a potential biomarker for T2DM in the Chinese population, which is helpful for clinicians to make more effective risk-based decisions.

Influence of GSTP1 Polymorphism on the Clinical Outcomes of Patients With Advanced NSCLC Receiving First-Line Bevacizumab-Based Regimen: A Real-World Retrospective Study

Background: This study was to investigate the influence of GSTP1 gene polymorphism on the clinical outcomes of patients with advanced non-small-cell lung cancer (NSCLC) receiving first-line bevacizumab plus chemotherapy regimen. Methods: A total of 128 patients with advanced NSCLC who were administered with bevacizumab-based first-line regimens were recruited in this study. Available blood specimen and peripheral blood mononuclear cells (PBMCs) of the patients were obtained for the analysis of polymorphism and GSTP1 gene mRNA expression, respectively. The association between genotype status and clinical outcomes and other variates was analyzed and presented. Results: The prevalence of rs1695 were in accordance with Hardy-Weinberg Equilibrium ( P = .978). Patients with GG and AG genotypes were merged in a pattern of dominant inheritance to seek for the potentially clinical significance. Analysis of efficacy exhibited that the objective response rate (ORR) of patients with AA genotype and AG/GG genotypes were 62.1% (54/87) and 51.2% (21/41) ( P = 0.245). Prognosis demonstrated that the median progression-free survival (PFS) of patients with AA genotype and AG/GG genotypes were 9.5 and 5.6 months, respectively ( P = .007). Furthermore, the median overall survival (OS) of the two genotypes were 22.0 and 16.6 months, respectively ( P = .003). In addition, adjusted in multivariate Cox analysis for OS, AG/GG genotype was an independent factor for OS. Interestingly, mRNA analysis suggested that the mRNA expression of GSTP1 in PBMC of the patients with AG/GG genotypes of rs1695 polymorphism was significantly higher than those of patients with AA genotype ( P < .001). Conclusion: GSTP1 polymorphism rs1695 could be used for the prognostic evaluation of patients with advanced NSCLC receiving bevacizumab combined chemotherapy regimen.

Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

The role of GSTP1 and MTHFR gene polymorphic markers in the decreased response to doxorubicin therapy of breast cancer patients

Рак молочной железы (РМЖ), является заболеванием, в патогенезе которого принимают участие множество различных факторов, в том числе и генетические, а именно однонуклеотидные замены в генах биотрансформации ксенобиотиков и одноуглеродного обмена. В частности, изменения в генах GSTP1 и MTHFR, влияют на риск развития РМЖ, и могу приводить к нечувствительности опухоли к препаратам антрациклинового ряда, например, к доксорубицину. Целью данной работы являлось изучение влияния полиморфных маркёров rs1695 гена GSTP1 и rs1801133 и rs1801131 гена MTHFR на риск развития РМЖ и чувствительность к терапии доксорубицином. Методы. В работу было включено 239 больных РМЖ из Москвы и Московской области, для которых был установлен диагноз и клинические патоморфологические особенности, включая иммуногистологический статус опухоли. В качестве популяционного контроля использовали сопоставимую по возрасту выборку онкологически здоровых женщин (n = 200). Определение генотипов полиморфных маркёров rs1695, rs1801133, rs1801131 проводилось методом анализа кривых плавления ДНК с помощью ПЦР «в реальном времени» на амплификаторе “Real-time CFX96 Touch” (Bio-Rad, США) с использованием готовой смеси для ПЦР qPCRmix-HS (Евроген, Россия). Результаты. Выявлены статистически значимые ассоциации полиморфного маркёра rs1695 гена GSTP1 и rs1801133 гена MTHFR с риском развития РМЖ (OR = 1,15, CI95% = 1,14-2,00, р = 0,0114 и OR = 1,57, CI95% = 1,19-2,08, р = 0,0023, соответственно). При анализе ассоциации изученных полиморфных маркёров с эффективностью ответа на химиотерапию доксорубицином было показано, что в группе больных с «плохим» ответом на химиотерапию выявлялось значимое увеличение частоты аллеля Val полиморфного маркёра rs1695 гена GSTP1 и аллеля С полиморфного маркёра rs1801133 гена MTHFR. Нами также выявлена статистически значимая ассоциация полиморфного маркёра rs1801133 гена MTHFR (р = 0,0397) с выживаемостью больных с РМЖ. Заключение. Полученные нами результаты дополняют информацию о причинах возникновения резистентности к доксорубицину, и дают возможность сформировать группы риска с негативным ответом на данную химиотерапию. Background. Breast cancer (BC) is a multifactorial disease. Different factors contribute to the BC pathogenesis, including genetic factors, such as single-nucleotide variations in genes of xenobiotic biotransformation and one-carbon metabolism. Specifically, changes in GSTP1 and MTHFR genes influence the risk of BC and may result in a decreased response of the tumor to anthracycline drugs, such as doxorubicin. Aim. The aim of this study was to evaluate the effect of polymorphic markers, rs1695 of the GSTP1 gene and rs1801133 and rs1801131 of the MTHFR gene, on the risk of BC and sensitivity to the doxorubicin therapy. Methods. The study included 239 BC patients from Moscow and the Moscow Region with established clinical pathomorphological features of the tumor, including the immune histological status. The population control group consisted of age-matched women without an oncological disease (n = 200). Genotypes of rs1695, rs1801133, and rs1801131 polymorphic markers were determined by analysis of DNA melting curves with real-time PCR performed on a Real-time CFX96 Touch amplifier (Bio-Rad, USA) with a qPCRmix-HS ready-to-use PCR kit (Eurogen, Russia). Results. The study showed statistically significant associations of the GSTP1 gene rs1695 polymorphic marker and the MTHFR gene rs1801133 polymorphic marker with the risk of BC (OR = 1.15, CI95% = 1.14-2.00; p = 0.0114 and OR = 1.57, CI95% = 1.19-2.08; p = 0.0023, respectively). The study of polymorphic marker association with response to the doxorubicin chemotherapy showed that in the group of patients with a poor response to chemotherapy, frequencies of the Val allele in the GSTP1 gene rs1695 polymorphic marker and the C allele in the MTHFR gene rs1801133 polymorphic marker were significantly increased. Also, the MTHFR gene rs1801133 polymorphic marker (p = 0.0397) was significantly associated with survival of BC patients. Conclusion. The results of this study supplemented information about causes for resistance to doxorubicin and will allow isolating groups at risk with a negative response to the doxorubicin chemotherapy.