Null Polymorphism Research Articles

Null polymorphism of the GSTM1 and GSTT1 genes in susceptibility to colorectal tumorigenesis: systematic review with meta-analysis

Objective: To assess if GSTT1 and GSTM1 null polymorphisms increase susceptibility to colorectal cancer. Methods: A search was conducted in PubMed, SciELO, BVS, and Medline databases. Forty articles were selected, totaling 12,698 cases and 19,517 controls. Odds ratios with 95% confidence intervals were used, and p-values <0.05 were considered significant. The Dersimonian-Laird method was applied for p-values <0.05, and the Mantel-Haenszel method was used otherwise. All p-values were two-tailed with an alpha value of 0.05 determined a priori. STATA 16.0 software was utilized. Result: A higher risk of colorectal cancer was shown in the general population for the GSTM1 null genotype (OR=1.11; 95%CI [1.03, 1.19]; P<0.01). No significant risk was observed for GSTT1 or the GSTM1/GSTT1 null combination (OR=1.09; 95%CI [0.98, 1.22]; P<0.01 and OR=1.13; 95%CI [0.89, 1.43]; P<0.01, respectively). In subgroup analysis, increased colorectal cancer risk was found for Asians with the GSTM1 null genotype (OR=1.10; 95%CI [1.02, 1.20]; P=0.02) and GSTM1/GSTT1 null combination (OR=1.49; 95%CI [1.03, 2.15]; P<0.01). Conclusion: The findings suggest that the GSTM1 null polymorphism and the GSTM1/GSTT1 null combination are potential susceptibility factors for colorectal cancer, particularly in the Asian population.

The timing and severity of clozapine-associated neutropenia in the US: Is the risk overstated?

BackgroundConcern about clozapine-associated neutropenia contributes to clozapine's underutilization and racial disparities in access. People with African ancestry are more likely to have lower normative absolute neutrophil counts (ANC), associated with the Duffy null genetic polymorphism. Recent data on clozapine-associated neutropenia in the US are lacking. MethodsPatients prescribed clozapine in the Johns Hopkins Medicine electronic medical record (EMR) between 2013 and 2023 were identified. Duffy null Associated Neutrophil Count (DANC) was assigned if there were two ANC's < 2000 cells/μL, >30 days apart, before starting clozapine. Rates of neutropenia, timing of first neutropenia, and demographic differences were explored. Results974 received clozapine and had ANC's available, with 63.9 % male, 51.1 % White, and 39 % Black. 287 were presumed to start clozapine during the study period, and were 62.4 % male, 46 % White, and 44.9 % Black. No patients developed severe neutropenia. 59 (6.1 %) developed mild or moderate neutropenia. 19 (6.6 %) new starts had presumed DANC, and none developed neutropenia. 11 of 16 presumed new starts who developed neutropenia did so within eight months. No demographic differences were found between groups for presumed new starts. For non-new starts, where DANC assignment was not possible, Black patients were more likely than White patients to develop neutropenia (OR 3.48, 95 % CI [1.65, 7.73]). DiscussionTo our knowledge, this is the first observational study of clozapine-associated neutropenia in the US in the past decade, and it includes a substantial proportion of Black patients. ANC monitoring requirements may be too strict, contributing to clozapine underutilization.

The ACTN3 p.Arg577Ter Genetic Variants Biomarker of the Fitness Performance, in Oaxaca Amerindian Population

Backgrond. ACTN3 is primarily expressed in fast skeletal muscle fibres. A common nonsense polymorphism in this gene is ACTN3 R577X (rs1815739:C&gt;T) results in replacement of an arginine (R) with a premature stop codon (X) at amino acid 577 in the fast muscle protein α-actinin-3, which causes an absolute deficiency of α-actinin-3 protein and alterations in muscle metabolism. A common null polymorphism in the ACTN3 gene The ACTN3 p.Arg577Ter allele (p.R577* or R577X) has undergone positive selection, with an increase in the X allele frequency as modern humans migrated out of Africa into the colder, less species-rich Eurasian climates Aim. Analized the frequency of allele or genotypes from ACTN3 p.Arg577Ter genetic variants biomarker of the fitness performance, in Oaxaca Amerindian population. Methods. From people of different ethnic groups the State of Oaxaca, DNA was extracted from peripheral blood to extract DNA using the geneKatcher kit (invitrogene), to amplify the polymorphism p.Arg577Ter was realized by qRT_PCR, using tqman probes by determined by allelic discrimination. Results. The more frequency allele is wild type R in all populations, more tan 50%. The Genotype more prevalent is heterocygote RX. In afromexican population Genotype XX o ter-X/ter-X is a allelic variant. Distribution allelic and genotype is verry heterogenus in the populations. In conclusión the ACTN3 R577X gene variant can be used as a clinical marker for the selection of sports talents in the state of Oaxaca, considering that it has already been validated at the population level, with the R allele being more frequent in the state, which is the one associated with a greater selective advantage in sports that require muscular strength and greater physical performance.

Association of mRNA expression and polymorphism of antioxidant glutathione-S-transferase (GSTM1 and GSTT1) genes with the risk of Gestational Diabetes Mellitus (GDM)

Gestational Diabetes Mellitus (GDM) is a medical complication during the gestational period in which woman who had never been diagnosed with diabetes develops hyperglycemia. Prior studies have demonstrated that the advancement of GDM and its consequences arises from a disparity between oxidants and antioxidants in the cells. The observed outcomes can be attributed to an excessive formation of reactive oxygen species (ROS) within the cells, coupled with a reduced activity of anti-oxidative enzymes. Glutathione S-transferase (GSTs) is recognized as an antioxidant enzyme that is belong to as a phase II family member of detoxifying enzymes. These metabolic multigene catalysts are found into the cytoplasm of the cell. GSTs play a vital part in the elimination of cellular ROS or free radicals. The study involves total 300 pregnant women, (150 GDM cases and 150 healthy controls). The polymorphism study of GSTs genes (GSTM1 and GSTT1) was determined by conventional Polymerase Chain Reaction (PCR). The mRNA expression study of GSTM1 and GSTT1 genes analysed by qPCR/ RT-PCR (quantitative PCR/Real-Time PCR) followed by statistical analysis done using Prism8 software (version 8.01). The study revealed statistically significant variations in biochemical parameters between GDM cases and controls. It was found GSTM1-null (GSTM1-/-) polymorphism significantly (P < 0.0001) most prevalent in GDM cases (56.7%) when compared to healthy control (28%). However, no significant difference was observed for GSTT1 null and present polymorphism (P = 0.906). The gene expression levels of both GSTM1 and GSTT1 were found considerably downregulated in individuals with GDM as compared to the control group (P < 0.0001). The downregulation of gene expression has a significant (P<0.0001) association with the null/deletion polymorphism of both GSTM1/ GSTT1 genes respectively. Null/deletion genotype of GSTM1 gene and its expression showed significant association with GDM. Therefore, this gene variant has the potential to be used as a prognostic biomarker for GDM. However, there is need to study this gene variant in larger sample size and different ethnicity.

The role of tissue persistent organic pollutants and genetic polymorphisms in patients with benign and malignant kidney tumors

This study aimed to explore whether there is an association between environmental exposure to POPs and kidney tumor induction, and whether blood POP concentrations reflect kidney tissue concentrations. POP derivatives were determined in blood, tumor tissue, tumor surrounding tissue, and perirenal fat tissue samples taken from patients who underwent surgery for renal tumors. A voluntary control group was recruited for blood and urine samples as well. Urinary excretions of o,o′-dityrosine, chlorotyrosine, nitrotyrosine, and 8-OHdG were measured in the same patients. The possible role of genetic polymorphisms in CYP1A1, GST isozymes P, M, and T, and hOGG1 genes on the predisposition to renal cancer was investigated. Some POPs have been found to be associated with kidney cancer, as evidenced by their significantly high ORs. 8-OHdG levels were significantly higher compared to the control group. The GSTT1 null polymorphism can be a risk factor for malignant but not for benign kidney tumors.

Blood and tissue levels of persistent organic pollutants and genetic susceptibility in patients with breast cancer

We investigated possible associations between the internal concentrations of POPs and correlations between blood and tumor tissue concentrations in patients who underwent surgery for breast cancer and breast reduction as controls. Genetic variations in CYP1A1, GSTP1, GSTM1, and GSTT1 and hOGG1 were evaluated to determine whether they represent risk factors for breast cancer. Certain POPs have been found to be associated with breast cancer development. GST-P1 polymorphism represented a significant risk for breast cancer with unadjusted OR. However, the GSTT1 null polymorphism represented a significant risk for breast cancer when OR adjusted for age and smoking status. CYP1A1 polymorphism was a significant risk factor for breast cancer, regardless of whether the OR was adjusted. These results suggest that exposure to certain POPs, GSTT1 and CYP1A1 polymorphisms, age, and smoking status are risk factors for breast cancer. In addition, the blood concentrations of some POPs represent surrogates for breast tissue concentrations.

The potential influence of GSTT1 null genetic polymorphism on coronary artery disease: A pilot study in a South Indian cohort

BackgroundIndians are known to have the highest rates of coronary artery disease (CAD), with the conventional risk factors failing to explain the increased risk. Possible candidate genes to study both the environmental and genetic risk associated with CAD is the glutathione S-transferase (GST) family, as it is involved in detoxification. MethodsThis case–control assessed the association between GSTM1 and GSTT1 polymorphisms in Indian patients with CAD. Fifty patients with CAD and 50 healthy volunteers were genotyped for the two polymorphisms by polymerase chain reaction. The genotype frequencies between the groups were compared, where a p-value of less than 0.05 was considered as statistically significant. ResultsThere was a significant inverse association between GSTT1 null polymorphism and CAD susceptibility.

Analysis of null deletion polymorphism of glutathione S-transferase theta (GSTT-1), associated with anti-GSTT-1 antibodies development in transplantation.

Glutathione S-transferase theta 1 (GSTT1) is an enzyme involved in phase II biotransformation processes and a member of a multigene family of detoxifying and clearing reactive oxygen species. GSTT1 is polymorphic like other biotransforming enzymes, allowing variability in hepatic conjugation processes. Immunological recognition of the GSTT1 alloantigen, as evidenced by donor-specific antibodies formation, has previously been observed in recipients lacking GSTT1 protein (called GSTT1-, GSTT*0, null phenotype or homozygous for the GSTT1 deletion) who receive liver or kidney transplants from GSTT1+ donors and is a risk factor for the development of de novo hepatitis following liver transplants from a GSTT1 expressing donor. Antibodies against GSTT1 are demonstrated in patients who are GSTT1 null and received a transplant from a GSTT1+ donor. Understanding the local population frequency of the GSTT1 deletion is of value in understanding the potential clinical risk of developing post-transplant complications, which can be attributed to the nonexpression of GSTT1. A population of 173 healthy donors of the Murcia Region in Southeast Spain was evaluated for a null allele of GSTT1 (n=173). DNA was extracted, and GSTT-1 null allele detection was performed by real-time polymerase chain reaction. The frequency of the null GSTT1 genotype (nonexpression or deletion of the homozygous polymorphism of the GSTT1 protein) was 17.9% (n=31 null allele GSTT1/173 total individuals). Our data suggest that the frequency of null GSTT1 mutations in our population in Southeast Spain is 17.9%, lower than in other Caucasoid populations. This would convert our recipient population into more susceptible to nonlocal potential organ donors and less susceptible to local donors. All recipients bearing this GSTT1 deletion homozygous would be without the protein and triggering an alloantigen in the case of transplantation with a donor without deletion.

GSTM1 and GSTT1 polymorphisms associated with pain in a chemotherapy-induced peripheral neuropathy cohort

PurposeChemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN. This study aimed to investigate four markers in these genes for an association in a mixed cancer cohort in relation to CIPN (n = 172).MethodsCIPN was measured using the neuropathy item from the Patient Reported Outcome Common Terminology Criteria for Adverse Event (PRO-CTCAE) assessment. Genotyping for all samples was performed using PCR for the GSTM1 and GSTT1 null variants and restriction fragment length polymorphisms for the GSTP1 and GSTM1 polymorphisms.ResultsNo associations were found for the GST gene markers in relation to CIPN within our study, or CIPN severity. Longitudinal stratification of the CIPN phenotypes to examine links for neuropathy, identified nominally significant protective associations with the GSTM* null allele (p-value = 0.038, OR = 0.55) and the presence of pain at month 2 of treatment, as well as a risk factor for pain related month 2 of treatment for individuals with the GSTT1*null allele (p-value = 0.030, OR = 1.64). Higher severity of pain in patients with CIPN persisted at each time-point compared to those without CIPN.ConclusionNo significant results for an association between CIPN with polymorphisms in GSTM1, GSTT1 and GSTP1 were identified. However, associations for the GSTM1¬-null and GSTT1-null polymorphisms with pain at month 2 following chemotherapy were identified.

Evaluation of genetic instability, oxidative stress, and metabolism-related gene polymorphisms in workers exposed to waste anesthetic gases.

Professionals who work in operating rooms (ORs) may be exposed daily to waste anesthetic gases (WAGs) due to the use of inhalational anesthetics. Considering the controversial findings related to genetic damage and redox status in addition to a lack of knowledge about the effect of polymorphisms in genes related to phase I and II detoxification upon occupational exposure to WAGs, this cross-sectional study is the first to jointly evaluate biomarkers of genetic instability, oxidative stress, and susceptibility genes in professionals occupationally exposed to high trace amounts of halogenated (≥ 7ppm) and nitrous oxide (165ppm) anesthetics in ORs and in individuals not exposed to WAGs (control group). Elevated rates of buccal micronucleus (MN) and nuclear bud (NBUD) were observed in the exposure group and in professionals exposed aged more than 30years. Exposed males showed a higher antioxidant capacity, as determined by the ferric reducing antioxidant power (FRAP), than exposed females; exposed females had higher frequencies of MN and NBUD than nonexposed females. Genetic instability (MN) was observed in professionals with greater weekly WAG exposure, and those exposed for longer durations (years) exhibited oxidative stress (increased lipid peroxidation and decreased FRAP). Polymorphisms in metabolic genes (cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases (GSTs)) did not exert an effect, except for the effects of the GSTP1 (rs1695) AG/GG polymorphism on FRAP (both groups) and GSTP1 AG/GG and GSTT1 null polymorphisms, which were associated with greater FRAP values in exposed males. Minimizing WAG exposure is necessary to reduce impacts on healthcare workers.

Genomic Pattern of GSTM1 and T1 Gene Null polymorphism of Head and Neck Cancer Patients in Eastern India.

Homozygous deletion i.e., null polymorphism of the Glutathione S transferases genes hinders detoxification reactions by altering the sensitization of glutathione s transferases enzymes. Hence, we analysed the association between the GSTM1 and GSTT1 gene polymorphisms and head and neck cancer (HNC). The study consists of 238 healthy controls and 160 diagnosed cases of HNC, who attended the Regional Cancer Centre, Indira Gandhi Institute of Medical Sciences (a tertiary care hospital). DNA was extracted from whole blood of patients and control using Qiagen DNA extraction kit. GSTM1 and GSTT1 gene polymorphisms were examined using PCR and agarose gel electrophoresis. GSTM0 null polymorphism was 26.25% and 15.13% in cases and control respectively. GSTT0 null polymorphism was observed in 18.13% cases and 8.82% in control groups. The GSTM0 null polymorphism was present significantly in case group as compared to control group (OR = 1.997, p = 0.006). There was also significant association of GSTT0 null polymorphism with case group as compared to control group (OR = 2.288, p = 0.006). The combined genotypes were also analysed. GSTM0T1 genotype (n = 27) was found to be most common among HNC group followed next by GSTM0T0 double deletion (n =15). The result indicated that there was strong association of GSTM0 and GSTT0 null polymorphism in those patients. The combined genotypes i.e., GSTM0T1 and GSTM0T0 null polymorphism also showed significant association in HNC patients.

Association of Polymorphisms in Antioxidant Enzyme-Encoding Genes with Diabetic Nephropathy in a Group of Saudi Arabian Patients with Type II Diabetes Mellitus.

IntroductionAn imbalance between reactive oxygen species (ROS) generation and the defence mechanisms underlying the activity of antioxidant enzymes has been demonstrated as the leading pathology in diabetes mellitus (DM)-related microvascular complications.PurposeThis study aims to evaluate the association between polymorphisms in antioxidant enzyme-encoding genes: catalase (CAT); manganese superoxide dismutase (Mn-SOD); glutathione S transferase M1 (GSTM1); and GSTT1 glutathione S transferase T1 (GSTT1), and the risk of type II diabetic nephropathy (DN) in the Saudi population.Patients and MethodsThe present study involved 64 type II DM patients with nephropathy and 64 type II diabetes patients without nephropathy from the King Abdulaziz University (KAU) Hospital. They underwent real-time PCR genotyping for the Mn-SOD and CAT genes. Multiplex PCR was used to detect GSTM1- and GSTT1-null polymorphisms.ResultsA statistically significant difference was observed between the case and control groups with regard to polymorphisms in the CAT gene (P = 0.037), but not for polymorphisms in the Mn-SOD (P = 0.64) gene. In addition, a statistically significant association was observed between null polymorphisms of the GSTT1 and GSTM1 genes and DN in the case and control groups (P = 0.046 and P = 0.035, respectively).ConclusionOur results showed that the genetic ability to combat oxidative stress may play a major role in DN pathogenesis in Saudi type II DM patients. These polymorphisms in antioxidant enzyme-encoding genes could be used as independent genetic markers for the construction of risk prediction models for kidney-related complications in type II DM patients.

Analysis of deletion polymorphism of xenobiotics detoxication system genes in patients with tuberculosis and diabetes mellitus

An analysis of the occurrence of alleles and genotypes of GSTM1 gene in patients with pulmonary tuberculosis and diabetes mellitus regarding the MBT resistance version allowed to establish that under the conditions of pulmonary tuberculosis infection GSTM1 gene deletion mutation can be found in one out of five (21.87% of cases), and the occurrence due to the MBT resistance version is: with NDTB - 17.39%, with MDR-TB 35.0% and - PRTB 20.0% respectively. According to the nature of the distribution of allelic gene GSTM1 a favorable functional 1 allele prevails (73.29%) in the normal inbreeding among patients and deficiency of heterozygosity among healthy people, which generally forms a normal population distribution for the European race. Material and methods. The study involved 100 patients with newly diagnosed pulmonary TB and diabetes mellitus who had been hospitalized in Chernivtsi Regional TB Dispensary. The control group consisted of 50 healthy individuals. Genomic DNA was isolated from the whole venous blood. GSTM1 polymorphic areas were isolated by means of multicomplex polymerase chain reaction, according to the protocol for instantaneous analysis of polymorphism by M. Arana et all (1996). Deletion of gene corresponds to the lack of appropriate strips in the electropherogram. Results and discussion. Despite the fact that the activity of the enzyme glutathione-S-transferase of class M is encoded by five GST genes of class M (M1-M5), the dominant cause of genetically caused dysregulation of antioxidant activity is deletion (null) polymorphism of the gene GSTM1. Conclusion. Among the patients with pulmonary tuberculosis and diabetes mellitus one out of five persons (21,87 % of cases) was diagnosed with deletion mutation of GSTM1 gene; and the occurrence due to MBT resistance variation is: in NDTB-17,39 %, in MDR-TB - 35,0 % and in PRTB- 20,0 % respectively.

Gene-gene and gene-environment interaction: An important predictor of oral cancer among smokeless tobacco users in Karachi.

To determine the risk for oral cancer caused by simultaneous occurrence of more than one of the tested cytochrome P450 CYP1A1 MspI, glutathione S-transferase M1 null gnd Glutathione S-transferases T1 null gene polymorphisms. The cross-sectional case-control study was conducted from December 2011 to October 2016 at the Ziauddin University, Karachi, in collaboration with Dow University of Health Sciences, Karachi, and comprised oral squamous cell carcinoma cases in group A and healthy tobacco habit-matched controls in group B. All investigations were done using standardised laboratory protocols. The outcomes were determined in terms of association of various combinations of cytochrome P450 1A1MspI, glutathione S-transferasesM1 null and glutathione S-transferases T1 null polymorphisms with oral cancer. Data was analysed using SPSS 20. Of the 238 subjects, 140(58.8%) were in group A and 98(41.2%) were in group B. Mean ages in group A and B were 47.1±12.22 and 41.6±14.58 years, respectively. Male/Female ratio in group A was 1.88:1 while 83.4% were using tobacco. When cytochrome P450 1A1MspI homozygous (m2/m2) and glutathione S-transferases M1 null variants occured simultaneously in an individual, an odds ratio of 12.8 (95% confidence interval: 1.20-135.5; p=0.03) among overall tobacco chewers was observed. For glutathione S-transferases M1 not null and glutathione S-transferases T1 null variant combination among overall tobacco users, the conferred odds ratio was 4.58 (95% confidence interval: 0.99-21.2; p=0.05). The other studied gene combinations did not reveal significant associations (p>0.05). A higher risk of oral squamous cell carcinoma was found to be associated with combined-gene polymorphisms of phase I and phase II enzymes than that attributed to a single-gene polymorphism.

Increased Risk of Acute Lymphoblastic Leukemia in Adult Patients with GSTM1 Null Genetic Polymorphism.

PurposeGlutathione S-transferases (GSTT1 and GSTM1) detoxify various endogenous and exogenous compounds and provide cytoprotective role against reactive species. This study aimed to assess the frequency of GSTT1, and GSTM1 polymorphisms in newly diagnosed Sudanese adult patients with acute lymphoblastic leukemia (ALL) and to evaluate the association of these polymorphisms with age, gender and type of ALL.Patients and MethodsThis case–control study included 128 adult Sudanese, untreated newly diagnosed patients with ALL, aged 18 to 74 years and 128 age-gender matched healthy controls. Deletional polymorphisms of GSTT1 and GSTM1 genes were genotyped through a multiplex polymerase chain reaction (PCR) assay using β-globin gene as an internal positive control.ResultsThe genotypic frequency of GSTT1 null polymorphism was 22.7% in cases and 14.8% in controls (OR = 1.68, P = 0.111). Statistically significant differences were noted in the frequencies of GSTM1 null polymorphism in cases and controls (OR = 3.7, P = <0.001). Combined GSTT1 null and GSTM1 null gene polymorphisms showed statistically significant difference in patients with ALL as compared to controls (OR = 6.5, CI 95% = 1.42–29.74, P < 0.001).ConclusionIrrespective of age at diagnosis, gender, and phenotype of ALL, GSTM1 null polymorphism either alone or in combination with GSTT1 null polymorphism poses significantly increased risk of developing ALL in adults.

Susceptibility of Glutathione-S-Transferase Polymorphism to CVD Develo- pment in Type 2 Diabetes Mellitus - A Review.

Metabolic disorder affects normal homeostasis and can lead to the development of diseases. Diabetes mellitus is the most common metabolic disorder, and a cluster of metabolic conditions can lead to cardiovascular disease (CVD) development. Diabetes mellitus and CVD are closely related, with oxidative stress, playing a major role in the pathophysiology. Glutathione-S-Transferases (GST) potentially play an important role by reducing oxidative stress and is found to be the underlying pathophysiology in the development of diabetes, cardiovascular diseases (CVD), etc Background: In this review, the role of GST genetic variant in the development of diabetes mellitus, CVD and diabetic vascular complications has been focused. Objectives: Based on the literature, it is evident that the GST can act as an important biochemical tool providing significant evidence regarding oxidative stress predominant in the development of diseases. Analysis of GST gene status, particularly detection of GSTM1 and GSTT1 null mutations and GSTP1 polymorphism, have clinical importance. Results: The analysis of GST polymorphism may help identify the people at risk and provide proper medical management. Genotyping of GST gene would be a helpful biomarker for early diagnosis of CVD development in DM and also in CVD cases. More studies focusing on the association of GST polymorphism with CVD development in diabetic patients will help us determine the pathophysiology better.

The association of ACTN3 R577X polymorphism with sports specificity in Japanese elite athletes.

The α-actinin-3 proteins regulate muscle function and are located in the Z-line of the fast skeletal muscle. A common null polymorphism of R577X in α-actinin-3 gene (ACTN3) results in its complete absence in fast-twitch muscles. The ACTN3 R577X polymorphism is associated with sprint/power performance in athletes. However, little is known about how this polymorphism impacts sports other than sprint/power-oriented sports in Japanese elite athletes. The aim of our study was to examine the association between ACTN3 R577X polymorphism and elite athlete status in various sports categorized as power/sprint, endurance, artistic, martial arts, and ball game sports. The subjects included 906 Japanese elite athletes and 649 Japanese controls. We analysed the genotype frequency of the ACTN3 R577X polymorphism in sprint/power (n = 120), endurance (n = 150), artistic (n = 45), martial arts (n = 94), and ball game (n = 497) sports athletes. A higher number of sprint/power athletes were R allele carriers compared to the controls, and the endurance and artistic athletes (OR = 1.69, 1.83, and 2.36, 95% CI: 1.02–2.79, 1.02–3.31, and 1.08–5.13, respectively). The frequency of RR genotype was higher in sprint/power, martial arts, and ball game sports athletes (OR = 1.61, 1.84, and 1.39, 95% CI: 1.04–2.50, 1.11–2.95, and 1.05–1.83, respectively) compared to control. Furthermore, there is a significant linear trend with increasing R allele according to athletic status (P for trend < 0.05). The ACTN3 R allele is positively associated with sports performance requiring explosive power such as sprint/power, martial arts, and ball game sports categories.

Genetic polymorphisms and risk of MALT lymphoma in Greek population

MALT lymphoma is thought to have a genetic component. Genetic studies in the greek population are rare and genetic determinants remain to be established. The current study aimed to seek correlations between genetic polymorphisms and risk of MALT lymphoma in the Greek population. 83 MALT lymphoma patients and 60 age-matched healthy outpatients were recruited. SNPs in TNFa, LTA and CTLA-4 genes and IL1RN-VNTR and GSTT1 and GSTTM1 null polymorphisms were genotyped using published PCR/PCR-RFLP methods, while two novel PCR-RFLP methods were developed for IL-22 rs7314777 and TCF19 rs7750641 SNPs. Part of the results was validated by DNA-sequencing. Statistical analysis was performed using SPSS and the SNPstats bioinformatic tool. The mean age of the patients and controls were 55.9 and 56.2 years respectively. The majority of patients (63) suffered gastric marzinal zone lymphoma (GMZL) and 71.1% were stage I at diagnosis. A statistically significant association was noted for the CTLA-4 49A/ G G variant (OR:2.56,p: 0.006) and the TCF19 rs7750641 SNP T variant (OR: 3.86, p:0.023). Our study confirmed a role for CTLA-4 49A/G and TCF19 rs7750641 SNPs in the Greek population. Additional studies could help confirm these associations and possibly link them to prognosis or response to treatment parameters.

Combined GSTT1 Null, GSTM1 Null and XPD Lys/Lys Genetic Polymorphisms and Their Association with Increased Risk of Chronic Myeloid Leukemia.

PurposeGlutathione S-transferases (GSTT1 and GSTM1) are instrumental in detoxification process of activated carcinogens. Nucleotide excision repair is carried out by DNA helicase encoded by xeroderma pigmentosum group D (XPD) genes and aberrations in the XPD gene predisposes to increased risk of cancer. The present study aimed to investigate GSTT1, GSTM1 and XPD polymorphisms in newly diagnosed chronic myeloid leukemia (CML) patients and to examine the association of these polymorphisms with the risk of developing CML.Patients and MethodsThis case–control study was carried out from June 2019 to August 2021 involving 150 newly diagnosed patients with CML and an equal number of randomly selected age- and sex-matched healthy individuals. A multiplex-PCR assay was used to genotype GSTT1 null and GSTM1 null polymorphisms. XPD gene polymorphism was detected by PCR-RFLP using predesigned gene-specific primers.ResultsGSTT1 and GSTM1 null polymorphisms were detected in 42.7% and 61.3% of cases, respectively, compared to 18% and 35.3% for controls. The combination of both GST null polymorphisms revealed a significant association with CML. Frequencies of XPD Lys751Gln genotypes in cases were 62.7% heterozygous Lys/Gln, 24% homozygous Lys/Lys and 13.3% homozygous Gln/Gln, while in the controls were 74.7%, 20%, and 5.3%, respectively. Significant differences were also noted regarding the combination of GSTT1/GSTM1 null with XPD Lys/Lys, and GSTM1 null with XPD Lys/Lys.ConclusionIn conclusion, GSTT1 null, GSTM1 null and XPD polymorphisms showed positive association with the risk of development of CML. Furthermore, age and gender did not exhibit any association with the studied polymorphisms, while CML phases were associated with GSTT1 null polymorphism.

Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching.

The common null polymorphism (R577X) in the ACTN3 gene is present in over 1.5 billion people worldwide and results in the absence of the protein α-actinin-3 from the Z-discs of fast-twitch skeletal muscle fibres. We have previously reported that this polymorphism is a modifier of dystrophin-deficient Duchenne Muscular Dystrophy. To investigate the mechanism underlying this, we use a double knockout (dk)Actn3KO/mdx (dKO) mouse model, which lacks both dystrophin and sarcomere α-actinin-3. We used dKO mice and mdx dystrophic mice at 12 months (aged) to investigate the correlation between morphological changes to the fast-twitch dKO EDL and the reduction in force deficit produced by an in vitro eccentric contraction protocol. In the aged dKO mouse, we found a marked reduction in fibre branching complexity that correlated with protection from eccentric contraction induced force deficit. Complex branches in the aged dKO EDL fibres (28%) were substantially reduced compared to aged mdx EDL fibres (68%), and this correlates with a graded force loss over three eccentric contractions for dKO muscles (~36% after first contraction, ~66% overall) compared to an abrupt drop in mdx upon the first eccentric contraction (~75% after first contraction, ~89% after three contractions). In dKO, protection from eccentric contraction damage was linked with a doubling of SERCA1 pump density the EDL. We propose that the increased oxidative metabolism of fast-twitch glycolytic fibres characteristic of the null polymorphism (R577X) and increase in SR Ca2+ pump proteins reduces muscle fibre branching and decreases susceptibility to eccentric injury in the dystrophinopathies.