Variable Number Of Tandem Repeats Polymorphism Research Articles

Abstract 7082: Epidemiology meets epitranscriptomics: Exploring the cancer-related role of a novel TERT-antisense transcript and its regulation by RNA methylation

Abstract Human telomerase reverse transcriptase (TERT) maintains telomeres at chromosome ends and its dysregulation is implicated in various human health conditions. Multiple GWAS signals are detected within the TERT genomic region at chr 5p15.33. As a potential proxy for these signals, we investigated a highly polymorphic variable number tandem repeat (VNTR)2-1 within intron 2 of TERT, with 57-143 copies of a 42 bp repeat unit per allele. By functional annotation of VNTR2-1, we predicted that it generates an intronic transcript antisense to TERT with a variable-size open reading frame (ORF) of 2502-5211 bp (834-2038 aa). Specific to the TERT-antisense transcript, we predicted N6-methyladenosine (m6A) consensus motifs within each 42 bp unit of VNTR2-1, with longer VNTR2-1 regions carrying more m6A motifs. In a stranded RNA-seq dataset of African pediatric Burkitt lymphoma (BL) tumors, which have high TERT expression, we detected the VNTR2-1-containing TERT-antisense transcript in a subset of tumors (n=35/113, 30.9%), confirming the expression of this novel transcript. VNTR2-1 expression was also experimentally validated by 5’-RACE/Nanopore-seq in Raji (BL cell line) and UMUC3 (bladder cancer cell line). Additionally, the VNTR2-1 transcript was visualized in UMUC3 cells using RNA-FISH. The consensus 42 bp VNTR2-1 repeat sequence and its m6A-deficient variants were cloned into a m6A-deficient dual-luciferase reporter vector (m-psiCHECK-2) and expressed in UMUC3 cells, showing an m6A-motif dose-dependent response driving luciferase protein expression. Transient treatment with STM2457, an inhibitor of the m6A writer METTL3, reduced the expression of the luciferase reporter, confirming that m6A motifs within VNTR2-1 are methylated by METTL3. Additionally, Long-term cigarette smoke condensate (CSC) treatment of UMUC3 reduced luciferase expression, suggesting alterations of VNTR2-1 m6A due to smoke exposure. We explored potential peptides produced from VNTR2-1 transcript by analysis of public mass spectrometry datasets using PepQuery and identified several unique VNTR2-1 peptide fragments in human tumors. Next, we cloned a synthetic FLAG-tagged gene containing three VNTR2-1 consensus repeats with native Kozak sequence and translation start/stop codons. Western blotting confirmed the translation of the VNTR2-1 peptide that was ablated by start codon mutation, suggesting that the native Kozak sequence is sufficient for VNTR2-1 translation. These results support VNTR2-1 as a peptide-producing transcript. In conclusion, we identified a novel intronic transcript produced by VNTR2-1 antisense to TERT. This m6A-regulated transcript could function through several mechanisms, such as a lncRNA or translated peptide, potentially regulating TERT expression and telomerase function in health and disease conditions, including cancer. Citation Format: Brenen W. Papenberg, Oscar Florez-Vargas, Michelle Ho, Kaitlin Forsythe, Chi Zhang, Chia-Han Lee, Sam Mbulaiteye, Pedro J. Batista, Ludmila Prokunina-Olsson. Epidemiology meets epitranscriptomics: Exploring the cancer-related role of a novel TERT-antisense transcript and its regulation by RNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7082.

Associated of Variable Number Tandem Repeat (VNTR) Polymorphism in IL 4 with Susceptibility to Breast Cancer in Iraqi Women

Background: Breast cancer (BC) is common disease in the worldwide. Furthermore genetic mutations are known to enhance BC risk. The aim of this research is to examine correlation between the frequency of BC among Iraqi women and a variable number tandem repeat (VNTR) polymorphism in the IL-4 gene.
 Methods: The study included 74 patients and 54 healthy women. To determine the genotypes of the variable number of tandem repeats (VNTR) in the IL-4 gene, a Polymerase Chain Reaction (PCR) technique was employed. Additionally, a complete blood count (CBC) test was conducted. Logistic regression analyses were performed to evaluate the association between genotypes and the occurrence of BC. Measures of association were computed in the form of odds ratios (OR) and 95% confidence intervals (95% CI). The threshold for statistical significance in both CBC analysis and genotyping analysis was established as a p-value below 0.05.
 Results: Among the CBC analysis, only the results of RBC (red blood cell count) and WBC (white blood cell count) showed statistical significance at the p = 0.05 level when comparing the study population. However, our investigation identified no association between IL-4 gene variant genotypes and breast cancer in Iraqi women. Other than tumor differentiation and body mass index(p < 0.05), no clinical or pathological features of BC patients were linked to variant genotypes.
 Conclusion: The study concluded a substantial RBC and WBC relationship between patients and control. However, the IL-4 genetic variation does not appear to affect breast cancer development or progression. However, the IL-4 genetic variation may affect disease prognosis. Thus, more research is needed to determine how IL-4 genetic variation affects breast cancer prognosis.

The relationship between the aggrecan VNTR polymorphism and its content in lumbar intervertebral discs.

There is a specific polymorphism of the ACAN gene called the variable number of tandem repeats (VNTR), which is particularly interesting in the light of the development of intervertebral disc pathology and associated low back pain. The nucleus pulposus specimens were harvested from the L5/S1 intervertebral discs. The aggrecan content was determined using enzyme- linked immunosorbent assay (ELISA). Moreover, the VNTR polymorphism in the ACAN gene was evaluated. The genotyping of VNTR polymorphism in ACAN gene was successful in 94 tissue samples (48 homozygotes and 46 heterozygotes). The alleles were divided into four groups, in accordance with the number of tandem repeats in the ACAN gene. No difference between groups in the mean aggrecan mass nor in the mean degree of tissue moisture was observed. No relationship between the ACAN gene VNTR polymorphism and the aggrecan content was observed in studied Caucasian cadavers. Such a relationship may be a more complex phenomenon and exists in other populations.

MUC7 VNTR polymorphism and association with bronchial asthma in Egyptian children

Overproduction of mucins in the airways donates largely to airway blockage in asthma patients. Glycoprotein MUC7 plays a role in the clearance of bacteria and has anti-candidacidal criteria. Our goal was to investigate the association between the MUC7 variable number of tandem repeats (VNTR) polymorphism and bronchial asthma among Egyptian children. The MUC7 VNTR polymorphism was investigated among 100 children with bronchial asthma and 100 healthy controls using polymerase chain reaction (PCR) method. Serum levels of immunoglobulin E (IgE), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta1 (TGF-β1) were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The frequencies of 6*5 genotype, 5*5 genotype, (6*5 + 5*5) genotypes, and MUC7*5 allele of the MUC7 VNTR variant were significantly lower among asthmatic patients than controls (p < 0.015, OR = 0.39, 95% CI = 0.19–0.81; p = 0.03, OR = 0.18, 95% CI = 0.04–0.86; p < 0.001, OR = 0.29, 95% CI = 0.15–0.58; p < 0.001, OR = 0.3, 95% CI = 0.17–0.55, respectively). The (6*5 + 5*5) genotypes of the MUC7 VNTR variant were not associated with the clinical manifestations and serum levels of IgE, TNF-α, and TGF-β1 among asthmatic patients (p ˃ 0.05). In conclusion, the (6*5 + 5*5) genotypes of the MUC7 VNTR variant may have a protective role for bronchial asthma in Egyptian children.

Dim light melatonin onset following simulated eastward travel is earlier in young males genotyped as PER35/5 than PER34/4

ABSTRACT Inter-individual variability exists in recovery from jetlag following travel across time zones. Part of this variation may be due to genetic differences at the variable number tandem repeat (VNTR) polymorphism of the PERIOD3 (PER3) gene as this polymorphism has been associated with chronotype and sleep, as well as sensitivity to blue light on melatonin suppression. To test this hypothesis we conducted a laboratory-based study to compare re-entrainment in males genotyped as PER34/4 (n = 8) and PER35/5 (n = 8) following simulated eastward travel across six time zones. The recovery strategy included morning blue-enriched light exposure and appropriately-timed meals during the first 24 h after simulated travel. Dim light melatonin onset (DLMO), sleep characteristics, perceived sleepiness levels (Stanford Sleepiness Scale), and resting metabolic parameters were measured during constant routine periods before and after simulated travel. While DLMO time was similar between the two groups prior to simulated eastward travel (p = .223), it was earlier in the PER35/5 group (17h23 (17h15; 17h37)) than the PER34/4 group (18h05 (17h53; 18h12)) afterwards (p = .046). During resynchronisation, perceived sleepiness and metabolic parameters were similar to pre-travel in both groups but sleep was more disturbed in the PER35/5 group (total sleep time: p = .008, sleep efficiency: p = .008, wake after sleep onset: p = .023). The PER3 VNTR genotype may influence the efficacy of re-entrainment following trans-meridian travel when blue-enriched light exposure is incorporated into the recovery strategy on the first day following travel.

Gene locus polymorphisms and expression levels of interleukin-1 in lumbar disc disease: A MOOSE-compliant meta-analysis and immunohistochemical study.

To investigate the association between interleukin (IL)-1α (rs1800587), IL-1β (rs1143634) and IL-1 receptor antagonist (RN) variable number tandem repeat polymorphisms, expression levels and lumbar disc disease (LDD). All relevant articles were searched from 4 databases including PubMed, Embase, Web of Science and China National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to evaluate the association between IL-1 gene locus polymorphisms (rs1800587 in IL-1α, rs1143634 in IL-1β, variable number tandem repeat in interleukin-1 receptor antagonist) and LDD susceptibility. Statistical analysis was conducted by Review Manager (Revman) 5.31 software (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Furthermore, qRT-PCR and immunohistochemistry were performed to evaluate IL-1α, IL-1β and interleukin-1 receptor antagonist expressions in the normal and degenerated disc. A total of 15 case-control studies (1455 cases and 2362 controls) were included in our meta-analysis. The pooled results suggested that IL-1α rs1800587 polymorphism was associated with an increased risk of LDD in overall population (T vs. C, OR = 1.21, 95% CI = 1.04-1.40, P = .01). The subgroup analysis found a significant association between IL-1β rs1143634 polymorphism and LDD in Asian population (T vs. C, OR = 0.61, 95% CI = 0.39-0.96, P = .03). Results of qRT-PCR and immunohistochemistry demonstrated that expressions of IL-1α and IL-1β were significantly increased in the degenerated disc. (all P < .05). IL-1α rs1800587 and IL-1β rs1143634 polymorphisms were significantly associated with LDD in overall population and in Asian population, respectively. The increased expression levels of IL-1α and IL-1β may be the important risk factors for LDD.

Meta-analysis for Association of Interleukin 4 VNTR Polymorphism with Rheumatoid Arthritis Risk and Severity.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by severe joint pain. There are conflicting results for the association of Interleukin 4 (IL4) variable number tandem repeats (VNTR; rs8179190) polymorphism with RA. Therefore, we performed a meta-analysis of the available studies to investigate the association of IL4 VNTR polymorphism with RA risk and severity in the overall populations and Asian, Egyptian, European, and Turkish ethnicities by sub-group analyses. Eight studies involving 1993 RA patients and 1732 controls were included in this meta-analysis. We found increased RA risk for the susceptible "R2R2" genotype and "R2" allele under heterozygous, recessive, and allelic models in the Asian populations (p < 0.00001, p < 0.0001, p = 0.001). We observed a significant association between "R2R2" genotype and "R2" allele for RA protection in the Turkish population under heterozygous, recessive, and allelic models (p = 0.01, p = 0.004, p = 0.002). Disease severity-based analysis revealed significant association for "R2R2" genotype and "R2" allele with RA severity under homozygous, heterozygous, recessive, dominant, and allelic models(p = 0.0004, p = 0.03, p = 0.02, p = 0.003, p = 0.01), specifically in Asian populations (p = 0.009, p = 0.02, p = 0.003, p = 0.03, p = 0.01) and under heterozygous, dominant, and allelic genetic models in Egyptian (p = 0.0001, p < 0.0001, p < 0.0001) and European (p = 0.002, p = 0.0007, p = 0.0006) populations. In silico analysis suggested that the susceptible "R2" allele changes the RNA secondary structure to a stable form by changing minimum free energy(ΔG) from -115.20 to -136.40kcal/mol, which might lead to increased stability of IL-4 in RA patients. Overall, the meta-analysis suggests for the involvement of susceptible "R2" allele with RA risk in the Asian populations, RA severity in the overall populations (specifically in Asian, Egyptian, & European populations), and RA protection in the Turkish population.

Association of IL-4 and IL-1 Ra Gene Polymorphisms with the Risk of Bladder Cancer

The aim of this study is to evaluate the association of interleukin-4 (IL-4) gene intron 3 and interleukin-1 receptor antagonist (IL-1Ra) gene intron 2 variable number tandem repeat (VNTR) polymorphisms with bladder cancer (BC) susceptibility in Turkish population. A total of 75 BC patients and 126 healthy controls were included in this case-control study. Genotyping for the interested polymorphisms were analyzed through polymerase chain reaction (PCR). The strength of association between both IL-4 and IL-1Ra gene VNTRs and BC susceptibility was estimated utilizing odds ratio (OR) with corresponding 95% confidence interval (CI). In the study, no statistically significant differences were determined in the allele distributions for either in IL-4 gene intron 3 VNTR (OR= 1.33; CI 0.704-2,41, p=0.390) or in IL-1Ra gene intron 2 VNTR polymorphisms (OR= 0.890; CI 0.569-1.394, p=0.346) between BC patients and control groups. The genotype distributions of IL-4 gene were estimated for RP1/RP2 (OR= 1.55; CI 0.11-7.74, p = 0.590) and RP1/RP1 (OR= 2.08; CI 0.48-9.06, p = 0.320), found no difference between BC and control groups. The genotype distributions of IL-1Ra gene were estimated for 2L (OR= 1.401; CI 0.753-2.610, p = 0.287) and 22 (OR=0.908; CI 0.252-3.276, p = 0.883) and found no difference between BC and control groups. This study suggest that there were no statistically significant differences determined either in genotype or allele distributions between BC patients and control groups for both IL-4 intron 3 VNTR and IL-1Ra intron 2 VNTR polymorphisms in Turkish population and therefore there was no association of these variants with BC risk in this population.

TRIB3 promoter 33bp VNTR is associated with the risk of cerebrovascular disease in type 2 diabetic patients.

Previous studies have demonstrated that TRIB3 is closely related to insulin resistance, metabolic disorders and vascular diseases. Recently, it was reported that a 33 bp variable number of tandem repeats (VNTR) located in the TRIB3 promoter could considerably alter its transcriptional activity. Nonetheless, whether the shift of TRIB3 transcriptional activity has the effect of inducing diabetic vascular complications is still unclear. Therefore, in our study, we aimed to explore the relationship between the TRIB3 33bp VNTR and diabetic vascular complications. The TRIB3 33bp VNTR polymorphisms were determined by PCR and Sanger sequencing, a total of 798 eligible Chinese patients with type 2 diabetes (T2DM) were included in our study and then evaluated with clinical data. After adjusting for age, gender, BMI, smoking history, drinking history and duration of diabetes, we found that the high number of 33 bp tandem repeats (repeats>8) was significantly associated with an increase in the risk of cerebrovascular diseases compared with the low number of 33 bp tandem repeats (repeats≤6) in patients with T2DM(OR 2.66, 95% CI 1.29–5.47, p = 0.008). The intermediate number of 33bp tandem repeats (6 < repeat≤8) was markedly associated with a decreased risk of diabetic retinopathy compared with the low number of tandem repeats (OR 0.65, 95% CI 0.46–0.91, p = 0.012). Adjusting for gender, age and BMI, there was a significant difference in DBP levels among patients with the number of different 33 bp tandem repeats (Low vs. Intermediate vs. High, 81.6 ± 12.8 vs. 79.8 ± 12.4 vs. 78.7 ± 12.6 mmHg; p = 0.045). Subgroup analysis found that TRIB3 VNTR was significantly correlated with the difference in systolic blood pressure (SBP) in T2DM patients taking ACEI/ARB drugs (Low vs. Intermediate vs. High, 146.27 ± 18.23 vs. 140.01 ± 19.91 vs. 140.77 ± 18.64 mmHg; p = 0.018). Our results indicated that TRIB3 promoter 33bp VNTR is related to vascular diseases in T2DM patients, and may serve as a new biomarker for individualized prevention and therapy of T2DM.

Polymorphisms of TNF-alpha (− 308), IL-1beta (+ 3954) and IL1-Ra (VNTR) are associated to severe stage of endometriosis in Mexican women: a case control study

BackgroundEndometriosis is an estrogen-dependent and chronic inflammatory disease affecting up to 10% of women. It is the result of a combined interaction of genetic, epigenetic, environmental, lifestyle, reproductive and local inflammatory factors. In this study, we investigated whether single nucleotide polymorphisms (SNPs) mapping to TNF-alpha (TNF, rs1800629) and IL-1beta (IL1B, rs1143634) and variable number tandem repeat polymorphism mapping to IL1-Ra (IL1RN intron 2, rs2234663) genetic loci are associated with risk for endometriosis in a Mexican mestizo population.MethodsThis study included 183 women with confirmed endometriosis (ENDO) diagnosed after surgical laparoscopy and 186 women with satisfied parity and without endometriosis as controls (CTR). PCR/RFLP technique was used for genotyping SNPs (rs1800629 and rs1143634); PCR for genotyping rs2234663.ResultsWe found no statistical differences in age between groups nor among stages of endometriosis and the CTR group. We observed no difference in genotype and allele frequencies, nor carriage rate between groups in none of the three studied polymorphisms. The prevalence of TNF*2-allele heterozygotes (p = 0.025; OR 3.8), TNF*2-allele (p = 0.029; OR 3.4), IL1B*2-allele heterozygotes (p = 0.044; OR 2.69) and its carriage rate (p = 0.041; OR 2.64) in endometriosis stage IV was higher than the CTR group. Surprisingly, the carriage rate of IL1RN*2-allele (ENDO: p = 0.0004; OR 0.4; stage I: p = 0.002, OR 0.38; stage II: p = 0.002, OR 0.35; stage III: p = 0.003, OR 0.33), as well as the IL1RN*2-allele frequencies (ENDO: p = 0.0008, OR 0.55; I: p = 0.037, OR 0.60; II: p = 0.002, OR 0.41; III: p = 0.003, OR 0.38) were lower than the CTR group. Women with endometriosis stage IV (severe) had frequencies more alike to the CTR group in the IL1RN*2 allele frequency (31.2% vs. 27.2%) and carriage rate (37.5% vs. 41.9%).ConclusionAlthough these polymorphisms are not associated with the risk of endometriosis, Mexican mestizo women with severe stage of endometriosis have higher frequencies of TNF*2-, IL1B*2- and IL1RN*2-alleles, which may explain a possible correlation with disease severity rather than predisposition or risk.

Interleukin-1 receptor antagonist (IL-1RA) and interleukin-4 (IL-4) variable number of tandem repeat polymorphisms in schizophrenia and bipolar disorder: an association study in Turkish population

BackgroundPro-inflammatory/anti-inflammatory cytokine imbalance in cerebrospinal fluid or plasma of schizophrenia (SCZ) and bipolar disorder (BD) patients has been documented over the last decade. We aim to examine the interleukin-1 receptor antagonist (IL-1RA) and IL-4 variable number of tandem repeat (VNTR) polymorphisms in SCZ and BD patients by comparing them with healthy controls.MethodsTwo hundred and thirty-four unrelated patients (127 patients with SCZ, 107 patients with BD) and 204 healthy controls were included. The Structured Clinical Interview for DSM-IV Axis I Disorders was used to confirm the diagnosis. In addition, the polymerase chain reaction technique was used to investigate IL-1RA and IL-4 VNTR polymorphisms.ResultsOur results showed that the distributions of IL-1RA and IL-4 genotype and the allele frequencies of SCZ or BD patients were not significantly different from the healthy control group. IL-1RA allele 2 homozygous genotype and IL-1RA allele 2 frequencies were non-significantly higher among SCZ patients than in controls.ConclusionsOur study indicates that the IL-1RA and IL-4 VNTR polymorphisms are not considered risk factors for developing SCZ and BD among Turkish patients.

Relationship of DRD5 and MAO-B VNTR polymorphisms with paranoid and antisocial personality disorders in polydrug users.

Although multiple studies have shown the role genetics plays in personality disorders and in addictions, few have studied the genetic aspects of their comorbidity. Here, we carried out a cross-sectional study in a sample comprising 303 Caucasian polydrug-consuming patients. The presence of personality disorders was evaluated using the International Personality Disorder Examination, and genes related to dopamine, serotonin and monoamine oxidase (MAO) were genotyped. A significant relationship was observed between the bp 279 DRD5 variable number of tandem repeat (VNTR) polymorphism and paranoid personality disorder . The bp 182 and bp 184 alleles of the MAOB VNTR were also associated with antisocial personality disorder. Among patients with addictions, paranoid personality disorder should also be considered in addition to the importance of antisocial and borderline personality disorders. The higher frequency of the bp 279 DRD5 VNTR allele found in patients with paranoid personality disorder, as well as the associations between alleles of the MAOB VNTR and antisocial personality disorder, support the monoaminergic bases of these personality disorders, especially when dealing with patients with addictions.

Association between interleukin-1 receptor antagonist (IL-1ra) VNTR, gene polymorphism and breast cancer susceptibility in Iranian population: Experimental and web-based analysis.

Breast cancer is one of the leading causes of cancer mortality. Growing evidence indicates that interleukins and its polymorphisms are involved in the pathogenesis of breast cancer. Variable number of tandem repeat (VNTR) polymorphism can affect transcription rate, mRNA stability and also the resulting protein expression and activity. Hence, present study aimed to assess the possible association between interleukin-1 receptor antagonist (IL-1Ra) VNTR polymorphism, and breast cancer susceptibility in Iranian population. A total of 300 Iranian individuals, 150 breast cancer patients and 150 age-matched healthy women, were included in this study. DNA extracted by salting out method and genotyping was done using the polymerase chain reaction. The frequency of the allele 2(5% vs. 22%) and the 2/2 genotype (22% vs. 46%) of IL-1Ra VNTR polymorphism was significantly higher in healthy control compared to breast cancer patient: therefore, A2 allele may play a protective role against breast cancer and its progression (p = .0001 and OR = 0.105, 95% CI: [0.044-0.248]). The allele 2 and 2/2 genotype of the IL-Ra VNTR polymorphism can be a protective factor against breast cancer susceptibility.

Effects of Work Stress and Period3 Gene Polymorphism and Their Interaction on Sleep Quality of Non-Manual Workers in Xinjiang, China: A Cross-Sectional Study.

Work stress has been found to be associated with sleep quality in various occupational groups, and genetic factors such as variable number tandem repeat polymorphism in the Period3 (Per3) gene also influence the circadian sleep-wake process. Therefore, the present study aimed to evaluate the sleep quality status of non-manual workers in Xinjiang, China and to analyse the effects of work stress and Per3 gene polymorphism and their interaction on sleep quality. A cluster sampling method was used to randomly select 1700 non-manual workers in Urumqi, Xinjiang. The work stress and sleep quality of these workers were evaluated using the Effort–Reward Imbalance Inventory (ERI) and the Pittsburgh Sleep Quality Index (PSQI). Next, 20% of the questionnaire respondents were randomly selected for genetic polymorphism analysis. The polymerase chain reaction-restriction fragment length polymorphism technique was used to determine Per3 gene polymorphism. The detection rate of sleep quality problems differed between the different work stress groups (p < 0.05), suggesting that non-manual workers with high levels of work stress are more likely to have sleep quality problems. Regression analysis revealed that the Per3 gene (OR = 3.315, 95% CI: 1.672–6.574) was the influencing factor for poor sleep quality after adjusting for confounding factors, such as occupation, length of service, education, and monthly income. Interaction analysis showed that Per34/5,5/5 × high work stress (OR = 2.511, 95% CI: 1.635–3.855) had a higher risk of developing sleep quality problems as compared to Per34/4 × low work stress after adjusting for confounding factors. The structural equation modelling showed no mediating effect between work stress and Per3 gene polymorphism. The results of this study show that both work stress and Per3 gene polymorphism independently affect sleep quality of nonmanual workers from Xinjiang, and the interaction between these two factors may increase the risk of sleep quality problems. Therefore, to improve sleep quality, individuals with genetic susceptibility should avoid or reduce as much as possible self-stimulation by work-related exposures such as high levels of external work stress.

Frequency of CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism in a Spanish Population: Linkage Disequilibrium with CYP2C9*3 Allele.

Background: A promoter variable number tandem repeat polymorphism (pVNTR) of CYP2C9 is described with three types of fragments: short (pVNTR-S), medium (pVNTR-M) and long (pVNTR-L). The pVNTR-S allele reduces the CYP2C9 mRNA level in the human liver, and it was found to be in high linkage disequilibrium (LD) with the CYP2C9*3 allele in a White American population. The aim of the present study is to determine the presence and frequency of CYP2C9 pVNTR in a Spanish population, as well as analyzing whether the pVNTR-S allele is in LD with the CYP2C9*3 allele in this population. Subjects and Methods: A total of 209 subjects from Spain participated in the study. The CYP2C9 promoter region was amplified and analyzed using capillary electrophoresis. Genotyping for CYP2C9*2 and *3 variants was performed using a fluorescence-based allele-specific TaqMan allelic discrimination assay. Results: The frequencies of CYP2C9 pVNTR-L, M and S variant alleles are 0.10, 0.82 and 0.08, respectively. A high LD between CYP2C9 pVNTR-S and CYP2C9*3 variant alleles is observed (D’ = 0.929, r2 = 0.884). Conclusion: The results from the present study show that both CYP2C9 pVNTR and CYP2C9*3 are in a high LD, which could help to better understand the lower metabolic activity exhibited by CYP2C9*3 allele carriers. These data might be relevant for implementation in the diverse clinical guidelines for the pharmacogenetic analysis of the CYP2C9 gene before treatment with different drugs, such as non-steroidal anti-inflammatory drugs, warfarin, phenytoin and statins.

Association between dopamine transporter gene (DAT1/SLC6A3) variants and infertility in the Turkish females

Objective Worldwide, approximately 10–15% of couples is affected by infertility and infertility is associated with disturbances in female and/or male reproductive systems. The aim of the current study is to investigate the relationship between DAT1 (SLC6A3) VNTR polymorphism with female infertility. Methods Genomic DNA extractions were performed in 98 fertile and 90 infertile females, 3' untranslated region (3’ UTR) variable number tandem repeat (VNTR) polymorphism of DAT1/SLC6A3 was determined by the use of Polymerase Chain Reaction (PCR) method. Results It has been demonstrated that there was no statistically significant difference between female infertile and fertile groups in the terms of DAT1 genotypes (p > .05). Moreover, there was no significant difference regarding the frequencies of 9R and 10R alleles in infertile and fertile groups (p > .05). Conclusion This is the first study for investigating the relationship between DAT1/SLC6A3 gene polymorphism and infertility in females. Our study contributes to the growing awareness of the relationship between dopaminergic system and female infertility despite no significant differences were reported between infertile females and corresponding fertile subjects in DAT1/SLC6A3 gene.

Interleukin-4 gene intron 3 VNTR polymorphism in adult acute myeloid leukemia

BackgroundThe proliferation of acute myeloid leukemia (AML) blast into the bone marrow microenvironment is controlled by cytokines. Interleukin-4 (IL-4) has recently been discovered to suppress the development and persistence of AML cells selectively. Intron three of the Interleukin-4 (IL-4) gene contains a 70-bp minisatellite region polymorphism that may influence gene transcriptional activity and subsequently affect the production level of IL4. We investigated the IL-4 gene intron three variable number tandem repeat (VNTR) polymorphism as a molecular marker in AML associated with clinical and laboratory variables and a prognostic factor for therapeutic response and disease outcome.ResultsIL-4 gene intron three minisatellite regions polymorphism was assessed in 60 adult AML patients and 60 healthy controls, comparable concerning age and gender, using polymerase chain reaction. Three study marker genotypes were detected in AML patients; P1/P1 (3%), P1/P2 (40%), and P2/P2 (56.7%). The frequency of P2 alleles was significantly more in AML patients than in healthy controls (76.7% versus 25%; P < 0.001). Compared to the heterozygous group and P1/P1 carriers, AML patients with the homozygous P2/P2 genotype had a higher total leucocytic count and increased blast percentages in bone marrow or peripheral blood, besides a lower platelet count. P2P2 genotype was also significantly associated with poor therapeutic response, higher susceptibility to disease recurrence and shorter overall survival and disease-free survival.ConclusionThe IL-4 intron 3 VNTR polymorphism could be included in the molecular risk stratification of AML to predict poor disease. This information can be utilized in incorporating biological therapy into the present therapeutic protocols to enhance chemotherapy regimens’ current low response rates.

Significant Association of Variable Number Tandem Repeat Polymorphism rs58335419 in the MIR137 Gene With the Risk of Gastric and Colon Cancers.

The purpose of the article: The MIR137 gene acts as a tumor-suppressor gene in colon and gastric cancers. The aim of this study was to investigate the association of functional variable number tandem repeat (VNTR) polymorphism rs58335419 locating in the upstream of the MIR137 gene with the risk of colon and gastric cancers. Materials and methods: Totally, 429 individuals were contributed in the study, including 154 colon and 120 gastric cancer patients and 155 healthy controls. The target VNTR was genotyped using PCR and electrophoresis for all samples. Statistical analysis was performed using SPSS 21.0 software and by T, χ2 and logistic regression tests. Results: Excluding the rare genotypes, our results showed that genotype 3/5 (95% CI = 1.08–3.73, OR = 2.01, p = 0.026) significantly increased the risk of colon cancer but not gastric cancer (95% CI = 0.88–3.30, OR = 1.70, p = 0.114). Also, in the stratification analysis for VNTRs and sex, genotypes 3/4 (95% CI = 1.00–6.07, OR = 2.46, p = 0.049) and 3/5 (95% CI = 1.25–7.18, OR = 2.99, p = 0.014) significantly increased the risk of colon cancer in men but not in women. In addition, all genotypes including the rare genotypes as a group, significantly increase the risk of gastric (95% CI = 1.14–3.00, OR = 1.85, p = 0.012) and colon (95% CI = 1.38–3.43, OR = 2.17, p = 0.001) cancers compared to the genotype 3/3 as a reference. Conclusion: The results show that increasing the copy of VNTR in the MIR137 gene, increases the risk of colon and gastric cancers and can serve as a marker for susceptibility to colon and gastric cancers.

Association between vitamin D receptor gene polymorphism (rs731236) and aggrecan gene VNTR polymorphism with the risk of lumbar intervertebral disc degeneration.

Background:Low back pain is one of the most common causes of referral to physicians. Lumbar disc degeneration (LDD) is the main cause of back pain in different countries. It seems that genetic factors are more effective than environmental factors in the developing of degenerative phenomena. The aim of this investigation, therefore, was to study the association of the aggrecan gene (ACAN) variable number tandem repeat (VNTR) and the vitamin D receptor (VDR) rs731236 (TaqI) polymorphisms, with lumbar intervertebral disc degeneration in a population in the North of Iran.Methods:In this study, 55 patients with symptomatic intervertebral disk degeneration and 55 control subjects were included. VDR gene polymorphism was genotyped by PCR-based RFLP. The isolated DNA was used to genotype the VNTR of ACAN gene via conventional PCR.Results:For VDR gene polymorphism, the CC genotype (OR=5.337, P=0.019) was significantly higher among the patients compared with the controls, revealing a higher frequency of the C allele in patients compared with controls (OR=2.707, P=0.005). The lower number of frequent repetitions in the VNTR aggrecan gene was associated with a six-time increase of lumbar disc degeneration. Also, high BMI can be considered as an independent factor in the incidence of this disease.Conclusion:Aggrecan gene VNTR polymorphism had an association with degeneration of lumbar intervertebral discs that the shorter VNTR repeats increasing the chance of the disc degeneration in this population in the North of Iran. Moreover, an association between the mutant allele (C) of VDR gene TaqI polymorphism and disc degeneration is found.

VNTR polymorphism in the SLC6A3 gene does not influence dopamine transporter availability measured by [18F]FE-PE2I PET or [123I]FP-Cit SPECT.

To investigate the potential impact of polymorphism in the 3'-untranslated region (3'UTR) of the SLC6A3 gene (DAT1) on normal variation in dopamine transporter (DAT) imaging with [18F]FE-PE2I PET and [123I]FP-Cit SPECT. Thirty-six individuals (mean age 70.4±5.4 years) with normal [18F]FE-PE2I PET and [123I]FP-Cit SPECT were genotyped for variable number of tandem repeats (VNTR) in the 3'UTR of the DAT1 gene. The DAT-availability in the caudate and putamen as measured with [18F]FE-PE2I PET and [123I]FP-Cit SPECT, as well as in the substantia nigra with [18F]FE-PE2I PET were compared between the participants carrying one or two 9-repeat alleles (i.e. 9R+10R or 9R+9R; 47%) and the participants without a 9R allele (i.e. 10R+10R or 10R+11R; 53%). Nonparametric tests, linear regression analysis and mixed model analysis were used to assess any statistical difference in measured DAT availability between the two allele groups. The measured DAT-availability in PET- and SPECT-imaging tended to be slightly higher in the 9R-group; however, the difference did not reach statistical significance in either the caudate or the putamen or the substantia nigra. Instead, age did have a significant effect on the DAT level (P < 0.05) notwithstanding the genotype. No significant effect of DAT1-genotype was detectable in imaging with [18F]FE-PE2I PET or [123I]FP-Cit, instead, age accounted for the normal variation in DAT-PET and DAT-SPECT.