Association of COX-2 -765G>C and -1195A>G Single Nucleotide Polymorphisms with Bladder Cancer Risk: A Case-Control Study

To explore the association of vitamin-D receptor (VDR) genotypes and haplotypes (variants at the Fok-I, and Taq-I sites) with the risk of bladder cancer, as vitamin D is antiproliferative and reported to induce apoptosis in human bladder tumour cells in vitro. A case-control study using polymerase chain reaction-restriction fragment length polymorphism was conducted in 130 patients with bladder cancer and 346 normal healthy individuals in a north Indian population. Patients were also categorized according to grade and stage of tumour. There was a significant difference in genotype and allelic distribution of VDR (Fok-I) polymorphism in the patients (P = 0.033 and = 0.017, respectively). The FF genotype was associated with twice the risk for bladder cancer (odds ratio 2.042, 95% confidence interval, CI, 0.803-5.193). There was no significant difference in genotypic distribution or allelic frequencies of the VDR (Taq-I) polymorphism (P = 0.477 and 0.230) when compared with the controls. The stage and grade of the bladder tumours had no association with VDR (Fok-I and Taq-I) genotypes. There was a significant difference in the frequency distribution of the haplotypes FT and fT (P < 0.001); these haplotypes had a protective effect in the control group (odds ratio 0.167, 95% CI 0.096-0.291, and 0.079, 0.038-0.164). These data suggest that VDR (Fok-I) polymorphism is associated with the risk of bladder cancer. Further, the results for the haplotype FT and fT indicate that patients with this haplotype have a lower risk of developing bladder cancer than those with other haplotypes.

Several studies examined the impact of miR-34b/c rs4938723 polymorphism and cancer risk, but the findings are inconsistent. However, no study has been conducted to inspect the impact of miR-34b/c polymorphism on bladder cancer. This study aimed to assess possible association between rs4938723 polymorphism and bladder cancer risk. This case-control study was done on 136 pathologically proven bladder cancer patients and 144 controls. Genotyping of Pri-miR-34b/c rs4938723 polymorphism was achieved by using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Our findings did not show any statistically significant differences in genotype and allele frequencies between bladder cancer and controls. Larger sample sizes with diverse ethnicities are required to validate our findings.

Background:Previous studies have investigated the relationship between GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and bladder cancer (BCa) susceptibility, respectively, but the results remain inconsistent. So, we conducted this meta-analysis including 79 case–control studies to explore such relationships.Methods:We searched PubMed, EMBASE, Cochrane library, Web of Science, and CNKI for relevant available studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were implemented to evaluate the intensity of associations. Publication bias was estimated using Begg funnel plots and Egger regression test. To assess the stability of the results, we used sensitivity analysis with the method of calculating the results again by omitting 1 single study each time. Between-study heterogeneity was tested using the I2 statistic.Results:No significant association between GSTA1 polymorphism and BCa susceptibility (OR = 1.05, 95% CI 0.83–1.33) was noted. Besides, meaningful association between individuals who carried the GSTM1 null genotype and increased BCa risk was detected (OR = 1.39, 95%CI 1.28–1.51). When stratified by ethnicity, significant difference was found in both Caucasian (OR = 1.39, 95% CI 1.23–1.58) and Asian populations (OR = 1.45, 95% CI 1.31–1.61). Moreover, in the subgroup analysis by source of controls (SOC), the results were significant in both hospital-based control groups (OR = 1.49, 95% CI 1.35–1.64) and population-based control groups (OR = 1.21, 95% CI = 1.07–1.37). Additionally, the analysis revealed no significant association between GSTP1 polymorphism and BCa risk (OR = 1.07, 95% CI 0.96–1.20). What is more, significant associations between GSTT1 polymorphism and BCa susceptibility were discovered (OR = 1.11, 95% CI 1.00–1.22). In the subgroup analysis by ethnicity, significant associations between GSTT1 null genotype and BCa risk were observed only in Caucasians (OR = 1.25, 95% CI 1.09–1.44). Furthermore, when stratified by SOC, no obvious relationship was found between the GSTT1 null genotype polymorphism with hospital-based population (OR = 1.11, 95% CI 0.97–1.28) or population-based population (OR = 1.10, 95% CI 0.96–1.27).Conclusion:This study suggested that GSTM1 null genotype and GSTT1 null genotype might be related to higher BCa risk, respectively. However, no associations were observed between GSTA1 or GSTP1 polymorphisms and BCa susceptibility.

Simple SummaryThis research aims to understand how gene variations, particularly in the methylenetetrahydrofolate reductase gene (MTHFR), influence bladder cancer development. The study conducted a meta-analysis of seven relevant studies to assess the impact of a specific genetic variant, rs1801133, on bladder cancer susceptibility. The findings indicate a significant association between the MTHFR rs1801133 polymorphism and bladder cancer risk, especially in the Asian population. People with the T-allele or TT genotype had a higher likelihood of developing bladder cancer compared to that of those with the C-allele. This research is vital for the scientific community as it enhances our understanding of genetic factors contributing to bladder cancer. The findings may lead to targeted prevention and personalized treatment strategies. Additionally, the systematic review and meta-analysis provide a comprehensive overview of the existing evidence, adding to the knowledge base on bladder cancer genetics. This could inspire further research into the genetic basis of complex diseases like bladder cancer.The etiology of bladder cancer remains unclear. This study investigates the impact of gene polymorphisms, particularly methylenetetrahydrofolate reductase gene (MTHFR), on bladder cancer susceptibility, focusing on the rs1801133 single-nucleotide polymorphism (SNP). A meta-analysis was conducted after systematically reviewing the MTHFR gene literature, adhering to PRISMA guidelines and registering in PROSPERO (CRD42023423064). Seven studies were included, showing a significant association between the MTHFR C677T (rs1801133) polymorphism and bladder cancer susceptibility. Individuals with the T-allele or TT genotype had a higher likelihood of bladder cancer. In the Asian population, the overall analysis revealed an odds ratio (OR) of 1.15 (95% CI 1.03–1.30; p-value = 0.03) for T-allele versus C-allele and an OR of 1.34 (95% CI 1.04–1.72; p-value = 0.02) for TT genotype versus TC+CC genotype. The CC genotype, however, showed no significant association with bladder cancer. Notably, epigenetic findings displayed low sensitivity but high specificity, indicating reliable identified associations while potentially overlooking some epigenetic factors related to bladder cancer. In conclusion, the MTHFR T-allele and TT genotype were associated with increased bladder cancer risk in the Asian population. These insights into genetic factors influencing bladder cancer susceptibility could inform targeted prevention and treatment strategies. Further research is warranted to validate and expand these findings.

DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.

Epidemiological studies have investigated that functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may play an essential role in bladder carcinogenesis, but the association between these single-nucleotide polymorphisms in the MTHFR gene and the susceptibility of bladder cancer (BC) was inconsistent in previous studies. The objective of this current study was to conduct an update analysis investigating the association between three polymorphisms in the MTHFR gene and the risk of BC. We performed a meta-analysis of 13 publications involving an association between BC and MTHFR gene three polymorphisms (C677T, A1298C, and G1793A). We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). On one hand, we found that the C677T polymorphism was associated with increased BC risk among Asians, however, with decreased BC risk among a mixed population. Interestingly, BC patients who carried the T-allele (TT+TC) had a higher percentage than the individuals who carried the CC genotype (OR=1.38, 95% CI=1.13-1.69, p=0.002). On the other hand, the A1298C polymorphism may increase BC risk among Asians and Africans, but played a decreased association among Europeans. Results from the current update analysis suggested that the C677T and A1298C polymorphisms in the MTHFR gene were associated with BC risk and disease progression.

Single-nucleotide Polymorphisms in Genes Encoding Toll-like Receptor -2, -3, -4, and -9 in a Case–Control Study with Bladder Cancer Susceptibility in a North Indian Population

Objective To investigate the associations between the FAS-1377G ＞ A,-670A ＞ G,and FASL-844T ＞ C polymorphisms with risk of bladder cancer.Methods A total of 174 cases of newly diagnosed bladder transitional cell carcinoma and 252 cancer-free controls were enrolled in this study.We genotyped polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results We found a statistically significantly increased risk of bladder cancer associated with the FASL-844CC genotype [odds ratio (OR) =1.51 ; 95％ confidence interval (CI) 1.03-2.23].And the FAS haplotype genotypes with 2-4 variant alleles were associated with an increased risk of bladder cancer (OR =2.14; 95％ CI 1.10-4.16).Furthermore,when we evaluated these three polymorphisms together,we found that the combined genotypes with 4-6 variant alleles were associated with an increased risk of bladder cancer (OR =1.58; 95％ CI 1.07-2.34),and this increased risk was more pronounced among subgroups of aged ＞50 years (OR=1.70; 95％CI 1.11-2.61) and smokers (OR=1.88; 95％ CI 1.06-3.32).Conclusion FAS and FASL polymorphisms appear to jointly contribute to risk of bladder cancer in Hubei Han population. Key words: FAS; FAS ligand; Gene polymorphism; Bladder cancer

Accumulating evidence suggests that inflammatory process may play a role in bladder carcinogenesis. However, the exact mechanisms of how the inflammatory factors associate with bladder cancer risk are still unknown. In this study, we explored whether polymorphisms (i.e. IL-4 C-590T, IL-4R Ile50Val, IL-4R Ser478Pro, IL-4R Gln551Arg, IL-13 C-1055T and IL-13 Arg130Gln) of IL-4, IL-4R and IL-13 genes predicted Chinese bladder cancer risk in 817 bladder cancer and 1,141 controls. Genotyping was performed by using the TaqMan method. We did not find any overall association between these single nucleotide polymorphisms (SNPs) and bladder cancer susceptibility in a Chinese population. However, in the classification and regression tree (CART) analysis, we found that carriers of IL-13 C-1055T variant genotype in smokers had a 2.57-fold increased bladder cancer risk with a 55% patient rate (OR=2.57; 95% CI=1.93-3.43), comparing with non-smokers. Similar result was also observed in combination of IL-13 C-1055T and IL-13 Arg130Gln in smokers. By multifactor dimensionality reduction (MDR) analysis, the best interaction model was the two-factor model that smokers with the IL-13 C-1055T genotypes were the subgroup to predict bladder cancer risk. The results suggested that the genetic variants in IL-4, IL-4R and IL-13 genes might modulate the bladder cancer risk in a Chinese population.

Objective To investigate the relationship between single nucleotide polymorphisms of excision repair cross-complementing gene (ERCC) 1 (rs3212986) and ERCC2 (rs13181) gene and bladder cancer susceptibility in Chinese population. Methods A total of 194 patients with bladder cancer (case group) and 240 healthy subjects (control group) were enrolled. In the case group, there were 143 males and 51 females, 85 cases under 50 years old and 109 cases over 50 years old, body mass index (BMI) <25 154 cases and BMI ≥25 40 cases, 119 cases without smoking history and 75 cases with smoking history, 122 cases without drinking history and 72 cases with drinking history, 179 cases without family tumor history and 15 cases with family tumor history. In the control group, there were 145 males and 95 females; 121 cases under 50 years old and 119 cases over 50 years old, BMI <25 201 cases and BMI ≥25 39 cases, 176 cases without smoking history and 64 cases with smoking history, 169 cases without drinking history and 71 cases with drinking history, 224 cases without family tumor history and 16 cases with family tumor history. The genotypes of ERCC1 rs3212986 and ERCC2 rs13181 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between each genotype and the risk of bladder cancer was explored. Results There was a statistically significant difference in the distribution of ERCC1 rs3212986 genotype between the two groups (χ2=6.010, P 0.05). Conclusion The ERCC1 rs3212986 gene polymorphism affects the occurrence of bladder cancer in the codominant and recessive models. The ERCC2 rs13181 gene polymorphism is not associated with the risk of bladder cancer. Key words: Bladder cancer; Gene polymorphism; Excision repair cross-complementing gene

Single nucleotide polymorphisms of Ficolin 2 gene in Behçet's disease

Aim: Dopaminergic neurons and dopamine transporters show variations in Attention Deficit Hyperactivity Disorder (ADHD). Furthermore, Ghrelin and leptin, hormones recognized for their neurotrophic effects, are significant in central nervous system regulation, influencing neuronal survival and development. Material and Methods: This study aimed to examine the potential relationship between Attention Deficit Hyperactivity Disorder (ADHD) and polymorphisms in the GHRL (rs34911341) and LEP (rs7799039) genes. The research sample consisted of 29 children diagnosed with ADHD and 24 age-matched healthy controls. Genotypic analysis was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: A significant difference in genotype distribution for the GHRL gene rs34911341 polymorphism was observed between the ADHD group and healthy controls (p = 0.036), whereas allele frequencies did not show a statistically significant difference (p = 0.207). In contrast, analysis of the LEP gene rs7799039 polymorphism revealed no significant differences in either genotype (p = 0.579) or allele frequencies (p = 0.558) between the two groups. Conclusion: These findings suggest a potential role for the GHRL rs34911341 polymorphism in the development or presentation of ADHD. Further research is required to elucidate the mechanisms underlying this association.

The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer

Bladder cancer (BC) is the 10th most common cancer worldwide. Genetic studies estimated 30% heritability in BC risk. Adiponectin is an adipocytokine that has important roles in the regulation of energy metabolism. Recent evidence suggests dysregulation of adiponectin levels in BC tissues. Serum level of adiponectin is influenced by single nucleotide polymorphisms (SNPs) in the ADIPOQ gene. However, limited evidence is available regarding the association between adiponectin serum levels or SNPs in ADIPOQ and BC risk. This study aimed to assess whether adiponectin serum levels or SNPs in ADIPOQ may modify BC risk. In this case-control study, 114 BC patients were recruited along with 114 controls. Study subjects were genotyped for variations in ADIPOQ SNPs, namely rs17300539, rs266729, rs2241766, and rs1501299. Adiponectin levels were measured from the serum of study subjects. Our analysis showed that the G allele and the GG genotype of rs1501299 were significantly more frequent in BC patients compared to those in the control group (p-value < 0.05). Moreover, two ADIPOQ haplotypes containing the above G allele were associated with increased BC risk (p-value < 0.05). Multivariate analysis showed that increased serum adiponectin, smoking or age were all significant predictors of BC (p-value < 0.05). The data supports use of serum adiponectin and the G allele of rs1501299 SNP in ADIPOQ as potential biomarkers and/or targets in BC. To further validate findings in this study, larger populations of various ethnicities and/or genetic backgrounds are required. More investigations on the functional role of adiponectin in BC will also provide better understanding of potential targeting adiponectin for BC treatment.

The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study. Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests. There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05). This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.