Variable Number Tandem Repeat Variant Research Articles

PERIOD3 (PER3) VNTR Variant Associated with Seasonal Pattern and Family History in Bipolar Disorder.

Dysregulation of circadian rhythms has been thought to be associated with psychiatric disorders such as bipolar disorder (BD) and depression. We aimed to evaluate the relationship between clinical specifiers of BD, mainly seasonal pattern (SP), and the variable number tandem repeat (VNTR) variant of the PERIOD3 (PER3) gene (rs57875989) in BD patients by comparing genotype distributions with healthy controls considering clinical parameters. A sample of 98 BD patients and 97 healthy volunteers were included in the study. The Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) was administered to all participants. The patients were evaluated with some scales (Sociodemographic and Clinical Data Form, The Young Mania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HAM-D), and The Clinical Global Impression Scale (CGI)) in terms of clinical features and symptom severity. Blood samples were obtained from participants to isolate their DNA. PCR-RFLP was used to determine the PER3 gene variant. The PER3 genotype (4/4, 4/5, 5/5) distribution of BD was found to be significantly different from the control group. There was a statistically significant difference in the PER3 genotype distribution between BD patients with SP and BD patients without SP. Again, the PER3 allele (4, 5) distributions of BD patients with the SP were statistically different from the control group. The BD patients' PER3 genotype distributions with a family history of BD were significantly different from the BD patients without family history or control group. It was found that the VNTR variant of the PER3 gene (rs57875989) may be associated with the SP and family history of BD as well as the BD itself. Further studies with the VNTR variant of the PER3 gene (rs57875989) in different ethnic populations are also required to determine these polymorphisms' exact role in BD.

A circadian rhythm gene (PER3) VNTR variant as possible risk factor in cohort of Turkish females with primary dysmenorrhea

Primary dysmenorrhea (PDM), which is the most prevalent problem related to the menstrual cycle in women of reproductive age, is due to sleep disorders and negative moods. Circadian rhythms, which are the immediate 24-h processes, enable an organism to adapt the suitable physiological responses to the environmental light-dark changes. Disturbed circadian rhythms are closely associated with several diseases, including sleep disorders. It has been reported that variable number tandem repeat (VNTR) variant in the coding region of circadian rhythm gene PERIOD 3 (PER3) affects sleep. Therefore, in the present study, we investigated the association between PDM and PER3 VNTR variant in Turkish females. A sample of 122 females with PDM and 150 healthy females were included in the study. Genoytyping of PER3 VNTR variant was performed on DNA by polymerase chain reaction (PCR) analysis using specific primers. We evaluated the relation between PER3 VNTR variant and PDM by calculating the odds ratios (ORs) and 95% confidence intervals (CIs). In our analyses of genotype data collected from total 272 subjects, we found that the PER3 VNTR variant was associated with development of PDM [codominant model (5/5 vs. 4/4 + 4/5): OR = 0.664; 95% CI, 0.39–1.10; p = 0.05). The three genotypes of the VNTR variant (4/4, 4/5, and 5/5) and their allelic frequencies showed nonsignificant differences between patients and control group (p > 0.05). In summary, PER3 VNTR variant may be associated with PDM in a Turkish female. However, further studies in different ethnic populations are needed to address the full role of this variant in PDM.

Association between monoamine oxidase A promoter polymorphism and the risk of sudden infant death syndrome: a meta-analysis

IntroductionThe etiology of sudden infant death syndrome (SIDS) remains an unsolved problem. The aim of this meta-analysis is to investigate the potential association between monoamine oxidase A (MAOA) promoter variable number tandem repeat (VNTR) polymorphism and SIDS risk.MethodsA systematic review and meta-analysis were conducted on studies from accessible electronic databases. Each VNTR variant was examined in each gender independently by comparing with the pooled results of other alleles.ResultsA total of six independent case–control studies including 1022 SIDS cases and 1839 controls were enrolled in this meta-analysis. In both of the whole populations and Caucasian populations, male infants with the low-MAOA-expression alleles (2R+3R) were found to exhibit a statistically significant increased risk of SIDS, whereas those with a 4R allele exhibited a reduced risk of SIDS. Besides, an increased risk of SIDS was detected in male Caucasian infants with 2R or 3R alleles. However, none of the allele or genotype variants was associated with SIDS in female victims.ConclusionIn male Caucasian infants, the low expression of MAOA promoter VNTR alleles (2R and 3R) is associated with an increased risk of SIDS, and the existence of the 4R allele could be regarded as a protective factor.

VNTR Variant of the eNOS Gene and its Relationship with Osteoporosis in Postmenopausal Turkish Women

Osteoporosis (OP) is the most common type of systemic bone disease characterized by low bone mass and micro-structure deterioration of bone tissue, with a consequent increase in bone fragility and fracture risk. Nitric oxide (NO), produced by the enzyme endothelial nitric oxide synthase (eNOS) in endothelial cells, has considerable effects on bone cell function. The objective of this case-control study was to investigate the potential association between the eNOS gene Variable Number Tandem Repeat (VNTR) variant and susceptibility of OP, in Turkish postmenopausal female patients. One hundred and fifty female patients and 100 age-matched healthy females were enrolled in the present study. The eNOS gene VNTR variant was genotyped with a polymerase chain reaction (PCR) method. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The mean age of the patients was 60.32±8.65 years. It was found that the eNOS VNTR variant genotype and allele frequencies were not significantly different between the patient and control groups (p>0.05).

The MIR137 VNTR rs58335419 Is Associated With Cognitive Impairment in Schizophrenia and Altered Cortical Morphology

Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

Analysis of Interleukin-1 Receptor Antagonist Variable Number Tandem Repeat Variant in Recurrent Aphthous Stomatitis.

Recurrent aphthous stomatitis (RAS) is one of the common oral inflammatory diseases. As immunological and genetic factors have been held responsible for the pathogenesis of RAS, the objective of this study was to determine whether the interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) variant is a risk factor for the development of RAS in Turkish patients and to define its contribution to the increased risk. The IL-1Ra VNTR variant was evaluated in 169 RAS patients and 171 healthy controls by the polymerase chain reaction (PCR) method. No statistically significant difference was found in the genotype distributions and allele frequencies of IL-1Ra VNTR variant between RAS patients and healthy controls. Lack of association between IL-1Ra VNTR variant and RAS could indicate that IL-1Ra has no significant role in the pathophysiology of RAS. However, it still appears to be very worthwhile to continue to search for cytokine gene variants in order to predict the development of such disease.

Correlation between a variable number tandem repeat (VNTR) polymorphism in SMYD3 gene and breast cancer: A genotype-phenotype study

Genetic predisposition to breast cancer (BC) has become one of the most studied aspects of the disease. Advances in the field of cancer research have revealed the role of different genetic polymorphisms within genes of interest in the development of BC. This study aimed to explore the impact of a variable number tandem repeat (VNTR) genetic variant found within the SET and MYND domain containing protein 3 (SMYD3) gene on BC risk in Jordan and examine key clinical and pathological prognostic factors. Genotyping of blood samples from 180 cases with breast cancer and 180 healthy individuals from the Jordanian population was carried out via a combination of PCR and agarose gel electrophoresis. A highly significant association was found at level of genotype (P-value = 0.009) and allele (P-value = 0.0001) between BC development and the VNTR variant in the SMYD3 gene among Jordanian women. Moreover, we found that the VNTR of SMYD3 gene may interfere with BC risk among patients with different immunohistochemistry (IHC) profiles (P-value < 0.05). This study reported that there is a significant correlation between BC development and the VNTR in the SMYD3 gene. These findings can help alleviate the burden of BC in developing countries including Jordan and to fill the gaps in current literature. Since this study was carried out on Jordanian Arabs, more studies on the link between BC and the SMYD3 VNTR variant are recommended to determine this polymorphism’s impact on other ethnic groups.

Pharmacogenetic role of dopamine transporter (SLC6A3) variation on response to disulfiram treatment for cocaine addiction.

Disulfiram has been beneficial in treating cocaine addiction in several studies. Patients with two SLC6A3 (DAT1) rs28363170 10-repeat alleles who have with genetically high dopamine transporter (DAT) levels may benefit from increased dopamine levels resulting from disulfiram treatment. After stabilization for 2 weeks on methadone, 70 cocaine and opioid codependent patients were randomized into disulfiram and placebo groups for 12 weeks of treatment. We genotyped the SLC6A3 (DAT1) 40 bp 3'-untranslated region variable number tandem repeat variant and evaluated its role in moderating disulfiram efficacy for cocaine dependence. Among the 10,10-repeat genotype group, cocaine-positive urines dropped from 78% to 48% and from 80% to 75% among the 9-repeat carrier group in the disulfiram group (P = 0.0001, with an effect size of 0.09). No difference was observed in cocaine-positive urines in the placebo group between the 10,10-repeat genotype and the 9-allele carrier patients. We found that patients with genetically higher DAT levels had better treatment outcomes with disulfiram pharmacotherapy of cocaine dependence than those with lower DAT levels. (Am J Addict 2019;28:311-317).

Dopamine D4 Receptor Gene Exon III VNTR Variant Influences Smoking Status in Turkish Population.

Dopaminergic gene variants may affect nicotine dependence through their possible impact on the dopamine reward pathway. The purpose of this study is to investigate the relationship between the variable number tandem repeat (VNTR) variant in exon III of the Dopamine D4 receptor (DRD4) gene and genetic predisposition of smoking status in a Turkish population. We performed a study comparing 154 subjects as the smoker group, and 111 subjects as the non-smoker group. Genotyping for the DRD4 VNTR variant was performed using a PCR method. There was a significant difference between smoker and non-smoker groups regarding the distribution of the alleles and genotypes of the DRD4 gene (p=0.000, p=0.000, respectively). The 2R allele was higher in the non-smoker group compare to the smoker group (p=0.000). We found that the 2/7 and 4/9 genotypes were more common in smokers than non-smoker group (p=0.037, p=0.028, respectively) while 2/4 genotype was more prevalent in non-smokers than smokers (p=0.000). When the number of repeat alleles (48 bp) are accepted as short (S) if six or less, and as long (L) if seven or more, it was found that the frequency of S/S genotype of the DRD4 VNTR variant was lower in the smoker group and S/L genotype was higher in the smoker group (p=0.006, p=0.006, respectively). The subjects carrying the S/L genotype have a 2.25-fold increased risk for smoking than a non-smoker. The results indicated that the subjects carrying DRD4 exon III VNTR S/L genotype have a risk for smoking status in a Turkish population.

Investigation of the role of interleukin-1 receptor antagonist VNTR variant on the Behçet's disease.

Behçet's disease (BD), a chronic multisystem inflammatory disorder, is mainly characterized by relapsing periods of a wide range of clinical symptoms. Several cytokine genes may play important roles in the pathogenesis of BD. Therefore, interleukin-1 receptor antagonist (IL-1Ra) gene 86bp variable number tandem repeat (VNTR) variant was investigated in patients with BD in a Turkish population. One hundred nine patients (60 females, 49 males; the mean age±standard deviation [SD] was 36.56±9.571 years) with BD and one hundred healthy individuals (54 females, 46 males; the mean age±SD was 36.64±2.294 years) were examined in the study. For genotyping, polymerase chain reaction-restriction fragment length polymorphism analysis was employed. Data were analyzed using Statistical Package for Social Sciences (SPSS) 22.0 (IBM Corp.; Armonk, NY, USA) (p<0.05). The genotype distribution and allele frequencies of the IL-1Ra VNTR variant did not differ significantly between the patients and the controls (p>0.05). The frequency of the a1/a1, a1/a2 genotypes and a1, a2 alleles were the most common both in patients and healthy controls (p=0.37, p=0.26, and p=0.53, respectively). Also, no statistically significant difference was found between the IL-1Ra VNTR variant genotypes and clinical characteristics (p>0.05). The results of this study do not support an association between the IL-1Ra VNTR variant and the risk of BD in a Turkish population. However, further studies of this variant with larger sample sizes and different ethnicities are required for confirmation.

The IL-1Ra gene variable number tandem repeat variant is associated with susceptibility to temporomandibular disorders in Turkish population.

Temporomandibular joint disorders (TMD) are a group of disorders involving temporomandibular joint and related structures. Interleukine-1 receptor antagonist (IL-1Ra) is an important anti-inflammatory molecule that competes with other interleukin-1 molecules. This study was designed to investigate the possible association of the IL-1Ra VNTR variant with the risk of TMD in the Turkish population. Peripheral blood samples were collected from 100 patients with TMD (23 males, 77 females) and 110 healthy individuals (35 males, 75 females). Genotyping of IL-1Ra 86bp VNTR variant was evaluated by gel electrophoresis after polymerase chain reaction (PCR). Our results show that there is a statistically significant difference between TMD patients and control group with respect to IL-1Ra genotype distribution and allele frequencies. 1.2, 1.4, and 4.4 genotypes were more common in patients, while 2.2 and 3.3 genotypes were rarer (P<.000). Frequency of alleles 1 and 4 was higher in patient groups (P<.000), whereas alleles 2 and 3 had a lower frequency in patients with TMD (P<.000). This is the first correlation study that evaluates the association between IL-1Ra gene VNTR variant and TMD. The VNTR variant related to IL-1Ra gene showed a strong pattern of association with TMD that may have a potential impact on disease counseling and management. Larger studies with various ethnicities are needed to establish the impact of IL-1Ra VNTR variant on risk of developing TMD.

A GWAS SNP for Schizophrenia Is Linked to the Internal MIR137 Promoter and Supports Differential Allele-Specific Expression

Single nucleotide polymorphisms (SNPs) within the MIR137 gene locus have been shown to confer risk for schizophrenia through genome-wide association studies (GWAS). The expression levels of microRNA-137 (miR-137) and its validated gene targets have also been shown to be disrupted in several neuropsychiatric conditions, including schizophrenia. Regulation of miR-137 expression is thus imperative for normal neuronal functioning. We previously characterized an internal promoter domain within the MIR137 gene that contained a variable number tandem repeat (VNTR) polymorphism and could alter the in vitro levels of miR-137 in a stimulus-induced and allele-specific manner. We now demonstrate that haplotype tagging-SNP analysis linked the rs1625579 GWAS SNP for schizophrenia to this internal MIR137 promoter through a proxy SNP rs2660304 located at this domain. We postulated that the rs2660304 promoter SNP may act as predisposing factor for schizophrenia through altering the levels of miR-137 expression in a genotype-dependent manner. Reporter gene analysis of the internal MIR137 promoter containing the common VNTR variant demonstrated genotype-dependent differences in promoter activity with respect to rs2660304. In line with previous reports, the major allele of the rs2660304 proxy SNP, which has previously been linked with schizophrenia risk through genetic association, resulted in downregulation of reporter gene expression in a tissue culture model. The genetic influence of the rs2660304 proxy SNP on the transcriptional activity of the internal MIR137 promoter, and thus the levels of miR-137 expression, therefore offers a distinct regulatory mechanism to explain the functional significance of the rs1625579 GWAS SNP for schizophrenia risk.

Association of MAO-A Variant with Complicated Grief in Major Depression

Background/Aims: It has been suggested that monoamine oxidase A (MAO-A) activity is involved in the pathogenesis of major depression. Bereavement-related complicated grief significantly increases the risk of major depression and has been shown to be influenced by serotonergic tonus, possibly conferred by MAO-A activity. Complicated grief – whose inclusion in DSM-V as a separate mental disorder is under discussion – has been shown to be a distinct syndrome with symptoms not seen in depression. Therefore, in the present study, genetic variation in the MAO-A gene was investigated for its influence on complicated grief in major depression. Methods: Sixty-six unrelated Caucasian patients (41 female, 25 male) with major depression and a history of bereavement were evaluated for complicated grief using the Inventory of Complicated Grief (ICG), the posttraumatic stress reaction after the loss by means of the Impact of Event Scale (IES-R) and further psychopathological measures. Patients were additionally genotyped for the functional variable number tandem repeat (VNTR) in the promoter region of the MAO-A gene. Results: The more active longer allele of the MAO-A VNTR was significantly associated with complicated grief in the female subgroup of patients (χ² = 9.471, p = 0.002, OR = 9.208, 95% CI 2.129–38.899, Bonferroni-corrected p = 0.012), whereas there was no such effect in male patients. Higher posttraumatic stress reaction was only nominally associated with the more active longer allele of the MAO-A VNTR in the female subgroup of patients (genotypes: χ² = 5.939, p = 0.015, OR = 5.333, 95% CI 1.366–20.557, Bonferroni-corrected p = 0.087). No significant associations of MAO-A VNTR with the severity of depressive symptoms (Beck Depression Inventory), anxiety symptoms (Spielberger State-Trait Anxiety Inventory), general mental health (Brief Symptom Inventory), or perceived social support (F-SozU) were found (all p > 0.10). Conclusion: The present pilot study for the first time suggests a gender-specific contribution of the more active MAO-A VNTR variant to an increased vulnerability for complicated grief as a potential intermediate phenotype of major depression.

The human melanocortin-1 receptor locus: analysis of transcription unit, locus polymorphism and haplotype evolution

The complete sequence of the MC1R locus has been assembled, the coding region of the gene is intronless and placed within a 12 kb region flanked by the NULP1 and TUBB4 genes. The immediate promoter region has an E-box site with homology to the M-box consensus known to bind the microphthalmia transcription factor (MITF); however, promoter deletion analysis and transactivation studies have failed to show activation through this element by MITF. Polymorphism within the coding region, immediate 5′ promoter region and a variable number tandem repeat (VNTR) minisatellite within the locus have been examined in a collection of Caucasian families and African individuals. Haplotype analysis shows linkage disequilibrium between the VNTR and MC1R coding region red hair variant alleles which can be used to estimate the age of these missense changes. Assuming a mean VNTR mutation rate of 1% and a star phylogeny, we estimate the Arg151Cys variant arose 7500 years before the present day, suggesting these variants may have arisen in the Caucasian population more recently than previously thought.