Variable Number Of Tandem Repeats Polymorphism Research Articles

Meta-analysis of the association of IL1-RN variable number of tandem repeats polymorphism with osteoarthritis risk

ObjectiveThe aim of this meta-analysis was to clarify the role of Interleukin-1 receptor antagonist gene (IL1-RN) Variable Number of Tandem Repeats (VNTR) polymorphism on the risk of OA by means of meta-analysis. MethodsEligible articles were retrieved from PubMed, Web of science and Google scholar with a total of 1187 OA cases and 2659 controls. The strength of the association between the IL1-RN VNTR polymorphism and the risk of OA was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. ResultsThe meta-analysis of seven published studies retrieved from the literature search showed a significantly increased OA risk in the recessive model analysis (22 vs 2L + LL: Pb = 0.18, I2 = 32.8, OR(95% CI) = 1.50(1.12, 2.02), P = 0.007), the additive model analysis (22 vs LL: Pb = 0.08, I2 = 46.8, OR(95% CI) = 1.56(1.15, 2.12), P = 0.004) and in the allele contrast model (2 vs L: Pb = 0.02, I2 = 58.8, OR(95% CI) = 1.20(1.05, 1.36), P = 0.007). By subgroup analysis, the IL1-RN VNTR polymorphism was found to be significantly associated with OA susceptibility in Caucasian and Hospital based case-control study (HCC) groups. ConclusionThis meta-analysis showed that IL1-RN VNTR polymorphism may increase the susceptibility to OA. More studies with detailed information are needed to validate our conclusion. Level of evidenceLevel III, diagnostic study.

The influence of an IL-4 variable number tandem repeat (VNTR) polymorphism on breast cancer susceptibility.

BackgroundsBreast cancer (BC) is one of the most widespread cancers globally. Understanding the etiology of BC may help in determining the various risk factors involved in its malignancy. Certain genetic mutations are considered to play a key role in increasing the risk of BC.ObjectivesIn this study, we explored the correlation between a variable number tandem repeat (VNTR) polymorphism in the IL-4 gene and BC.MethodsPCR and subsequent gel electrophoresis were used to genotype this variant in 360 Jordanian women (180 BC patients and 180 controls). In addition, phenotype–genotype analysis was carried out.ResultsOur findings illustrate that there is no significant relationship between the variant genotypes in the IL-4 gene and BC among Jordanian females. Other than body mass index and tumor differentiation (p< 0.05), none of the clinical and pathological parameters of BC patients exhibited any association with the variant genotypes.ConclusionsFrom this study, we propose that the IL-4 genetic variant does not impact BC development and progression but that it could influence the disease prognosis.

Association of IL1RN VNTR polymorphism with chikungunya infection: A study from Western India.

Chikungunya, caused by the chikungunya virus (CHIKV) mostly presents as acute and chronic articular inflammatory manifestations. Interleukin 1 receptor antagonist (IL-1RN) is a potent endogenous competitive inhibitor of IL-1α and 1β and has an anti-inflammatory role. The present study evaluated the possible association of IL1RN variable number tandem-repeat (VNTR) alleles and genotypes, and CHIKV stimulated IL-1RN cytokine production with resistance and/or susceptibility to chikungunya infection and disease state in 224 patients withchikungunya (61 patients withacute chikungunya and 163 patients with chronic chikungunya) and 355 healthy controls. Polymerase chain reaction, CHIKV stimulated cytokine assay and luminex platform were used for assessing polymorphism and protein levels respectively. The study revealed a significant association of IL1RN*1/*1 genotype under recessive genetic model with the risk of developing chikungunya infection. Our findings also indicated that IL1RN *2 allele under dominant mode was associated with protection to chronic chikungunya. The results also revealed a higher production of IL-1 RN protein in patients with chronic chikungunya. To conclude, the results suggest the association of ILRN VNTR polymorphism and IL-RN protein levels with chronic chikungunya.

Dopamine transporter genotype modulates brain activity during a working memory task in children with ADHD

Dopamine active transporter gene (DAT1) is a candidate gene associated with attention-deficit/hyperactivity disorder (ADHD). The DAT1 variable number tandem repeat (VNTR)-3’ polymorphism is functional and 9R carriers have been shown to produce more DAT than 10R homozygotes. We used functional magnetic resonance imaging (fMRI) to investigate the effects of this polymorphism on the neural substrates of working memory (WM) in a small but selected population of children with ADHD, naïve of any psychotropic treatment and without comorbidity. MRI and genotype data were obtained for 36 children (mean age: 10,36 +/− 1,49 years) with combined-type ADHD (9R n = 15) and 25 typically developing children (TDC) (mean age: 9,55 +/− 1,25 years) (9R n = 12). WM performance was similar between conditions. We found a cross-over interaction effect between gene (9R vs. 10R) and diagnosis (TDC vs. ADHD) in the orbito-frontal gyrus, cerebellum and inferior temporal lobe. In these areas, WM-related activity was higher for 9R carriers in ADHD subjects and lower in TDC. In ADHD children only, 10R homozygotes exhibited higher WM-related activity than 9R carriers in a network encompassing the parietal and the temporal lobes, the ventral visual cortex, the orbito-frontal gyrus and the head of the caudate nucleus. There was no significant results in TDC group. Our preliminary findings suggest that DAT1 VNTR polymorphism can modulate WM-related brain activity ADHD children.

Associations between Polymorphisms in the Solute Carrier Family 6 Member 3 and the Myelin Basic Protein Gene and Posttraumatic Stress Disorder.

Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity. The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection. No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores. Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.

PER3 variable number tandem repeat (VNTR) polymorphism modulates the circadian variation of the descending pain modulatory system in healthy subjects

We evaluated the circadian pattern of variation of the descending pain modulatory system (DPMS) using a conditioned pain modulation (CPM) paradigm according to the variable-number tandem-repeat (VNTR) of the clock gene PER3 polymorphism. We assessed the relationship between the genotypes PER34/4 and PER35/5 and the temporal pattern of variation across the day using the following measures: the heat pain threshold (HPT), the cold pressure test (CPT), and the serum levels of BDNF and S100-B protein. The ∆-values (from afternoon to morning) of these measures were used for the analysis. The circadian phenotype was according to the mid-point sleep time established by the Munich ChronoType Questionnaire (MCTQ). We included 18 healthy volunteers (15 women) ages 18 to 30. A Generalized Linear Model (GLM) revealed a significant difference in the ∆-CPM-task between Per34/4 and Per35/5 genotypes, with means (SDs) of −0.41 (0.78) vs. 0.67 (0.90) (χ2 = 7.256; df = 1′ P = 0.007), respectively. Both sleep deprivation of at least 2 h/day (B = −0.96, 95% confidence interval (CI) = −1.86 to −0.11)) and the ∆-S100-B protein (−0.03, 95% CI = −0.06 to −0.02) were negatively correlated with the ∆-CPM-task, while the ∆-BDNF was positively correlated with the ∆-CPM-task (0.015, 95% CI = 0.01 to 0.03). We observed a difference in the ∆-CPT between PER34/4 and PER35/5 (0.11 (4.51) vs. 4.00 (2.60), respectively) (χ2 = 22.251; df = 1 P = 0.001). These findings suggest that the polymorphism of PER35/5 is associated with a decrease in the inhibitory function of the DPMS over the course of the day. However, sleep deprivation is an independent factor that also reduces the inhibitory function of the DPMS, regardless of the PER3 VNTR polymorphism.

Effect of MUC1 length polymorphisms on the NLRP3 inflammasome response of human macrophages

Mucin 1 is a cell-membrane associated mucin, expressed on epithelial and immune cells that helps protect against pathogenic infections. In humans, MUC1 is highly polymorphic, predominantly due to the presence of a variable number tandem repeat (VNTR) region in the extracellular domain that results in MUC1 molecules of typically either short or long length. A genetic link is known between these MUC1 polymorphisms and inflammation-driven diseases, although the mechanism is not fully understood. We previously showed that MUC1 on murine macrophages specifically restricts activation of the NLRP3 inflammasome, thereby repressing inflammation. This study evaluated the effect of MUC1 VNTR polymorphisms on activity of the NLRP3 inflammasome in human macrophages, finding that long MUC1 alleles correlated with increased IL-1β production following NLRP3 inflammasome activation. This indicates that the length of MUC1 can influence IL-1β production, thus providing the first evidence of an immune-modulatory role of MUC1 VNTR polymorphisms in human macrophages.

Association between VNTR polymorphism in promoter region of XRCC5 and susceptibility to acute lymphoblastic leukemia risk

BackgroundThe X-ray repair cross complementing group 5 (XRCC5) gene that contains a variable number tandem repeat (VNTR) insertion in its promoter region encodes Ku80. It plays an important role in DNA double-strand break as part of the non-homologous end joining (NHEJ) pathway. This polymorphism is associated with the risk of numerous cancers. Therefore, the present study was investigated the association between the VNTR genetic polymorphism of XRCC5 and risk of acute lymphoblastic leukemia (ALL). Methods and resultsWe analyzed VNTR polymorphism of XRCC5 gene in 100 ALL cases and 200 controls by polymerase chain reaction. Controls had no history of ALL, and they matched by age with cases. The genotypes were determined by using PCR-based methods. Our results showed that for the VNTR XRCC5 polymorphism the 1R/2R genotype and 0R/2R significantly increased the risk of ALL cancer (OR 2.52, 95% CI 1.385–4.588, P = 0.002; OR 4.333, 95% CI 0.914–20.533, P = 0.025) in comparison with the 1R/1R genotype, respectively. The 0R/3R genotype decreased the risk of ALL cancer compared with 1R/1R genotype (Fisher's test P = 0.002). ConclusionsConsequently, the VNTR polymorphism in the promoter region of XRCC5 gene might be risk factor for ALL development.

Structural Asymmetry in the Frontal and Temporal Lobes Is Associated with PCSK6 VNTR Polymorphism.

The nodal cascade influences the development of bodily asymmetries in humans and other vertebrates. The gene PCSK6 has shown a regulatory function during left-right axis formation and is therefore thought to influence bodily left-right asymmetries. However, it is not clear if variation in this gene is also associated with structural asymmetries in the brain. We genotyped an intronic 33bp PCSK6 variable number tandem repeat (VNTR) polymorphism that has been associated with handedness in a cohort of healthy adults. We acquired T1-weighted structural MRI images of 320 participants and defined cortical surface and thickness for each HCP region. The results demonstrate a significant association between PCSK6 VNTR genotypes and gray matter asymmetry in the superior temporal sulcus, which is involved in voice perception. Heterozygous individuals who carry a short (≤ 6 repeats) and a long (≥ 9 repeats) PCSK6 VNTR allele show stronger rightward asymmetry. Further associations were evident in the dorsolateral prefrontal cortex. Here, individuals homozygous for short alleles show a more pronounced asymmetry. This shows that PCSK6, a gene that has been implicated in the ontogenesis of bodily asymmetries by regulating the nodal cascade, is also relevant for structural asymmetries in the human brain.

Investigation of the relationship between ischemic stroke and endothelial nitric oxide synthase gene polymorphisms [G894T, intron 4 VNTR and T786C

Background/aim We aimed to investigate the associations between endothelial nitric oxide synthase (eNOS) gene polymorphisms [G894T (rs1799983)], intron 4 (27-bpTR) variable number tandem repeat (VNTR) and T786C (rs2070744), and ischemic stroke in the Anatolian population.Materials and methods This case-control study included 112 patients with “stroke of undetermined etiology” and 160 controls. Real-time polymerase chain reaction (RT-PCR) analysis was used to analyze these polymorphisms. Between-group frequencies of alleles and genotypes were compared using binary logistic regression analysis.Results No significant difference was observed between the two groups in terms of the genotype and allele distributions of the eNOS G894T (rs1799983) polymorphism (P > 0.05). The a alleles and the 4b/a and 4a/a genotypes of the intron 4 (27-bpTR) VNTR polymorphism had significantly higher frequencies in the patient group than in the control group (OR: 2.715, P < 0.001; OR: 3.396, P < 0.001; OR: 10.631, P = 0.016, respectively). On the contrary, the TC genotype and C alleles of the T786C (rs2070744) polymorphism had a significantly lower frequency in the patient group than in the control group (OR: 0.244, P < 0.001, OR: 0.605, P = 0.006, respectively).Conclusion Our findings indicate that the eNOS G894T and T786C [rs2070744] polymorphisms are not associated with the risk of ischemic stroke, whereas the intron 4 [27-bpTR] VNTR may be a risk factor in the Anatolian population.

Impact of a variable number tandem repeat in the CYP2C9 promoter on warfarin sensitivity and responsiveness in Jordanians with cardiovascular disease.

PurposeThe purpose of this study was to investigate the influence of CYP/CYP450 2C9 (CYP2C9) promoter variable number tandem repeat (p-VNTR) polymorphism on susceptibility to cardiovascular disease and on warfarin sensitivity and responsiveness, in Jordanians with cardiovascular disease during initiation and stabilization phases of therapy.Patients and methodsA total of 211 cardiovascular patients who were being treated with warfarin anticoagulants and 205 healthy individuals were enrolled in this study. PCR-based methods were performed to analyze the effects of CYP2C9 p-VNTR polymorphism on warfarin metabolism. The p-VNTR polymorphism was composed of tandem repeat motifs sorted into three alleles based on the length and structure: short (p-VNTR-S), middle (p-VNTR-M), and long (p-VNTR-L).ResultsWe found that the genotypic and allelic frequencies differ significantly between patients and healthy individuals; therefore, our results suggest that this polymorphism is associated with cardiovascular disease in the Jordanian population. Moreover, during the initiation phase of therapy, 20% of warfarin-sensitive patients were homozygous for a short allele (p-VNTR-S), and 12.2% were heterozygous for this allele (p-VNTR-M/p-VNTR-S). During the stabilization phase, no significant differences were found between these groups and their genotypic frequencies. Additionally, we did not confirm any relationship between the CYP2C9 p-VNTR polymorphism and warfarin response during either the initiation or the stabilization phases of therapy.ConclusionOur data show a significant difference between the CYP2C9 p-VNTR polymorphism and risk of cardiovascular disease, in addition to significant association between this polymorphism and sensitivity to warfarin at the initiation phase of therapy in a Jordanian population. However, there is no correlation between this polymorphism and warfarin response, international normalized ratio (INR) values, or required warfarin dose to achieve a target INR either at the initiation or stabilization phases of therapy. To further corroborate our results, additional studies are required with a larger number of samples and different ethnic groups.

Improvement of Multiple-Locus VNTR Analysis Typing Scheme for Helicobacter pylori

Aims: To improve a multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) assay for Helicobacter pylori typing.&#x0D; Materials and Methods: Polymorphic VNTRs were searched by Gene Expert. The distribution and polymorphism of each VNTR locus were analyzed in 18 H. pylori genomes from the NCBI genome database by BLAST and were compared with a collection of 15 clinical H. pylori strains. The MLVA assay was compared with MLST-typing for discriminating H. pylori isolates.&#x0D; Results: Twelve VNTR loci were identified by bioinformatic screening of H. pylori genomes, and five of them were highly polymorphic. Therefore, an MLVA assay composed of five VNTR loci was developed with greatest discriminatory power.&#x0D; Conclusion: MLVA typing is a faster and more standardized method for studying the genetic relatedness of H. pylori isolates. At preliminary stage it is sufficient to use only 3 VNTR loci for the differentiation of H. pylori strains.

VNTR polymorphism in the monoamine oxidase A promoter region and cerebrospinal fluid catecholamine concentrations in forensic autopsy cases

Monoamine oxidase A (MAOA) plays important roles in the metabolism of catecholamines and modulates adrenergic, noradrenergic, and dopaminergic signaling. A polymorphic promoter variable number tandem repeat (VNTR) locus (MAOA-uVNTR) is located approximately 1.2 kb upstream from MAOA exon 1. Functional studies revealed that MAOA-uVNTR affects gene expression. In the present study, we examined the frequencies of MAOA-uVNTR alleles in Japanese autopsy cases, in which amphetamines or psychotropic drugs were not detected. In total, 87 males and 35 females were evaluated and investigated for the possible effect of MAOA-uVNTR polymorphisms on cerebrospinal fluid (CSF) catecholamine concentrations. In males, there was no significant association between MAOA-uVNTR polymorphisms and CSF adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) levels. In contrast, females who were homozygous for the 3-repeat allele (i.e., 3/3 genotype carriers) had higher CSF levels of Adr (p = 0.024) and DA (p = 0.035) than individuals who were heterozygous or homozygous for the 4-repeat allele (3/4 and 4/4, respectively). We found no significant association between MAOA-uVNTR polymorphisms and CSF Nad levels in females. Thus, the results of the present study indicated that MAOA-uVNTR polymorphism influences CSF Adr and DA levels in females.

Abstract P1-05-06: Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with breast cancer

Abstract Background: Endothelial nitric oxide synthase (eNOS), also known as NOS3 is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. Nitric oxide (NO) is synthesized from L-arginine by eNOS in the vascular endothelium and plays crucial roles in cellular proliferation. In the present study, it is hypothesized that polymorphisms of the Intron4b/a variable number of tandem repeat (VNTR) polymorphism Intron4b/a in the eNOS gene may be associated with an increased risk in the developing breast cancer. Methods: We included 38 (38 F/Female) patients with breast cancer and 70 (44M/26F) healthy controls. The VNTR polymorphism in intron4 (intron4b/a) was analyzed by PCR. The results were statistically analyzed by calculating the odds ratios (OR) and 95% confidence intervals using the χ2 test. Results: The distributions of genotype and allele frequency was compared among the groups. The bb, ab and aa genotypes were observed in 29 [76.3%], 9 [23.7%], 0 [0%] patients with breast cancer and in 33 [47.1%], 15 [21.4%], 22[31.5%] healthy controls respectively. The b and a alleles were observed in 67 [88.2%], 9 [11.8%] patients with breast cancer and in 81 [57.8%], 59 [42.2%] healthy controls respectively. The susceptibility to patients with breast cancer had significantly higher frequencies in bb genotype (p=0.004 OR=3.613). The patients with breastcancer had significantly lower frequencies in aa genotype (p=0.001,OR=1.458). The frequency of the a allele was significantly lower in the patients with breast cancer (p=0.001, OR=4.070). Comparison of eNOS / VNTR polymorphism between patients with Breast and healthy control subjects.eNOS VNTRBreastHealthy ControlsOR*%95 CI*pGenotypesn=38 (%)n=70 (%) BB29 (76.3)33 (47.1)3.613 a1.494-8.735 a0.004 a 3.065 b1.440-6.520 b0.004 bAB9 (23.7)15 (21.4)0.879 a0.343-2.252 a0.812 a 0.9020.388-2.096 b0.832 bAA0 (0)22 (31.5)1.458 a1.244-1.709 a0.001 a 12.375 b2.764-55.396 b0.001 bAllele B67 (88.2)81 (57.8)5.422 a2.505-11.740 a0.001 aA9 (11.8)59 (42.2)4.070 b2.199-7.533 b0.001 b* Fisher's Exact Test a, comparison of genotype and allele frequencies between breast and healthy control groups Conclusion: We conclude that there was sensible correlation between eNOS gene intron 4b/a VNTR polymorphism and the risk of breast cancer and bb genotype frequency was significantly higher in these patients than healthy controls. Citation Format: Gunaldi M, Isiksacan N, Pehlivan S, Binboga S. Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-05-06.

Associations between the dopamine D4 receptor gene polymorphisms and personality traits in elite athletes.

Personality traits and temperament may affect sports performance. Previous studies suggest that dopamine may play an important role in behavior regulation and physical exercise performance. The aim of this study is to determine associations between dopamine D4 receptor gene (DRD4 Ex3) polymorphisms and personality traits (such as neuroticism, extraversion, openness, agreeability and conscientiousness) in elite combat athletes. A total of 302 physically active, unrelated, self-reported Caucasian participants were recruited for this study. The participants consisted of 200 elite male combat athletes and 102 healthy male participants (control group). For personality trait measurements, the NEO Five-Factor Personality Inventory (NEO-FFI) and the State-Trait Anxiety Inventory questionnaires were used. For the genetic assays, blood was collected and all samples were genotyped using the real-time PCR method. A 2 x 3 factorial ANOVA revealed statistically significant differences on the Openness NEO Five Factor Inventory scale for both examined factors, i.e. sport status and genetics DTD4 Ex3. Combat athletes achieved higher scores on the Conscientiousness NEO-FFI scale when compared to controls (7.18 vs 5.98). On the other hand, combat athletes scored lower on the Openness scale in comparison with control group (4.42 vs. 4.63). Subjects with the DRD4 Ex3 s/s genotype had lower results on the openness scale in comparison with participants with the DRD4 Ex3 s/1 genotype (4.01 vs. 4.57) and higher DRD4 Ex3 1/1 genotype (4,01 vs. 3,50). In conclusion, we found an association between the dopamine D4 receptor gene in variable number tandem repeat (VNTR) polymorphisms and athletic status for two NEO-FFI factors: Openness and Conscientiousness. The DRD4 exon 3 polymorphism may be associated with the selected personality traits in combat athletes, thereby modulating athletes’ predisposition to participate in high risk sports.

M32 - PER3 POLYMORPHISMS, MORNINGNESS-EVENINGNESS AND DEPRESSION: PRELIMINARY EVIDENCE IN A BRAZILIAN FAMILY-BASED COHORT, THE BAEPENDI HEART STUDY

Background There is a significant interest in the contribution of the circadian timing system to individual differences in a wider range of behaviour. This is in part because sleep complaints and disturbances of the circadian timing system are common in psychiatric disorders. Based on diurnal preference, people can be divided into chronotypes with demonstrated differences in sleep-wake patterns and a variety of circadian rhythms, behavioral rhythms, and diurnal variation in mood. Specifically, greater eveningness has been related to greater depression. The human PER3 gene contains a variable number tandem repeat (VNTR) which is associated with diurnal preference: the longer allele (five tandem repeats) has been reported to associate with greater morningness, and the shorter allele (four tandem repeats) with greater eveningness. We have investigated the PER3 polymorphism and its relationship to sleep, circadian and depression characteristics in a Brazilian family-based cohort. Methods Baependi is a small rural town in Brazil that provides a window of opportunity to study the influence of sleep circadian patterns in a highly admixed rural population with a conservative lifestyle. Here, we studied 786 subjects (mean age±SD 46.5±16.2, 42% female). Blood samples were collected from all participants. The Per3 length polymorphism was genotyped using PCR followed by gel electrophoresis. We tested for associations between the PER3 polymorphism and sleep characteristics, daytime sleepiness, and chronotype using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Morningness-Eveningness Questionnaire, respectively. Depressive symptoms were assessed using the Beck Depression Inventory [BDI-II]). Results Our genotyping data showed that 36% of the subjects were homozygous for the shorter allele (4/4), 51% of the participants were heterozygous (4/5) and 12% of the subjects were homozygous for the longer allele (5/5). Allele frequency was 0.62 for the 4-repeat and a 0.38 for the 5-repeat. The percentages of the chronotypes Morning type (M-type), Neither type (N-type) and Evening type (E-type) were 5%, 46% and 7%, respectively. We observed an increase of the depression symptoms in evening types [F(2, 1014)=4.8, p=0.007]. On the other hand, no such associations were observed the PER3 genotype. There were no significant differences in the MEQ score [F(2, 317)=0.46, p=0.63], daytime sleepiness [(F(2, 317)=0.23, p=0.79)], sleep efficiency [(F(2, 317)=2.59, p=0.07)] and sleep characteristics [(F(2, 317)=1.92, p=0.14)] between the PER3 genotypes. Discussion We observed an association between eveningness and depression. Identifying factors contributing to individual differences in sleep and to describe how these factors are associated with physiological and psychological profiles may aid our understanding of the role of sleep and the circadian system in mental health. On the other hand, we were not able to replicate the association between the PER3 VNTR polymorphism and chronotype, which has been confirmed independently in multiple populations worldwide (including in Brazil). Neither did we observe any association with depression. CNPq – PVE 400791/2014-5.

Candidate genes for novelty-seeking: a meta-analysis of association studies of DRD4 exon III and COMT Val158Met.

Two widely studied genetic polymorphisms in the dopaminergic system [DRD4 exon III variable number of tandem repeat (VNTR) and COMT Val158Met] have been reported to be associated with novelty-seeking, but the results have been highly inconsistent. Therefore, a meta-analysis of the associations between these two polymorphisms and novelty-seeking was conducted. For DRD4, 24 studies comprising 27 samples and including 4933 participants were selected. Genotype grouping, sex, mean age, ethnicity, and sample characteristics were examined as moderators. For COMT, nine studies comprising 13 samples and including 2633 participants were selected. Sex, mean age, ethnicity, and sample characteristics were included as moderators. We also tested for possible publication bias. The significant association between the DRD4 polymorphism and novelty-seeking was supported, but no association was found between the COMT polymorphism and novelty-seeking. In addition, our findings revealed that sex and age both directly moderate the relationship between DRD4 and novelty-seeking. Meanwhile, ethnicity can interact with age, sex, and genotype grouping, and age and sex can interact with each other, to moderate the association between the DRD4 exon III VNTR polymorphism and novelty-seeking. Our results provide evidence of association between the DRD4 exon III VNTR polymorphism and novelty-seeking, which is inconsistent with the results of previous meta-analysis. Furthermore, several direct and indirect moderators are also identified to explain contradictory results in the existing literature. However, our results regarding COMT are consistent with those of previous meta-analysis.

Novel motif of variable number of tandem repeats in TPMTpromoter region and evolutionary association of variable number of tandem repeats with TPMT*3alleles.

SNPs in the gene for TPMT exemplify one of the most successful translations of pharmacogenomics into clinical practice. This study explains the correlation between common SNPs and variable number of tandem repeats (VNTR) in promoter of the gene. We determined VNTR polymorphisms, as well as TPMT*2 and TPMT*3 SNPs and TPMT activity in Slovenian and Italian individuals and lymphoblastoid cell lines. We observed a previously unreported VNTR allele, AB7C, in a TPMT*3A heterozygous individual. VNTRs with two (AB2C) and three or more (ABnC, n≥3) B motifs were statistically significant in complete linkage disequilibrium (D'=1, r2=1, p<0.0001) with the TPMT*3C and TPMT*3A alleles, respectively. The study provides insights into the stepwise evolution of TPMT*3 alleles from *3C to *3A, with increasing number of B motifs in the VNTR region.

The dopamine transporter VNTR polymorphism moderates the relationship between acute response to alcohol and future alcohol use disorder symptoms.

Alcohol use disorder (AUD) is a genetically influenced disease with peak onset in young adulthood. Identification of factors that predict whether AUD symptoms will diminish or persist after young adulthood is a critical public health need. King and colleagues previously reported that acute response to alcohol predicted future AUD symptom trajectory. Genes associated with brain dopamine signaling, which underlies alcohol's rewarding effects, might influence this finding. This study analyzed whether variation at a variable number tandem repeat polymorphism in DAT1/SLC6A3, the gene encoding the dopamine transporter, moderated the predictive relationships between acute response to alcohol and future AUD symptoms among participants enrolled in the Chicago Social Drinking Project (first two cohorts). Heavy-drinking young adults (N=197) completed an alcohol challenge, in which acute response (liking, wanting, stimulation, and sedation) was measured. Alcohol use disorder symptoms were assessed over the following 6years. DAT1 genotype significantly moderated the interactions between follow-up time and alcohol liking (P=0.006) and wanting (P=0.006) in predicting future AUD symptoms. These predictive effects were strongest among participants who carried the DAT1 9-repeat allele, previously associated with enhanced striatal dopamine tone relative to the 10-repeat allele. Exploratory analyses indicated that DAT1 effects on the relationship between alcohol liking and AUD symptoms appeared stronger for females (n=79) than males (n=118) (P=0.0496). These data suggest that heavy-drinking DAT1 9-repeat allele carriers who display high alcohol-induced reward in young adulthood may be predisposed to persistent AUD symptoms and support combining genotypic and phenotypic information to predict future AUD risk.

Lack of association between interleukin-1 receptor antagonist gene 86-bp VNTR polymorphism and ischemic stroke: A meta-analysis.

The results of published studies which examined the association between variable number tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL-1RN) and ischemic stroke (IS) are conflicting. Thus, we performed a meta-analysis to examine the potential association between IL-1RN VNTR polymorphism and IS risk. A systematic literature search of PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, CQVIP, and WANFANG Database identified 10 studies with 2331 cases and 3335 controls. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to evaluate the strength of the association. Subgroup analysis and meta-regression analysis were used to investigate the potential sources of heterogeneity. Begg funnel plots were used to explore the publication bias. In this study, no enough proof was found to prove the association between IL-1RN 86-bp VNTR polymorphism and IS risk with random-effects model in the homozygous model (1/1 vs 2/2, OR = 0.97, 95% CI = 0.50-1.87, Pheterogeneity = .00), the heterozygous model (1/2 vs 2/2, OR = 0.64, 95% CI = 0.41-1.01, Pheterogeneity = .10), the dominant model (1/1 + 1/2 vs 2/2, OR = 0.85, 95% CI = 0.51-1.42, Pheterogeneity = .02), the recessive model (1/1 vs 1/2 + 2/2, OR = 0.69, 95% CI = 0.46-1.03, Pheterogeneity = .00), and allelic model (1 vs 2, OR = 1.24, 95% CI = 0.89-1.74, Pheterogeneity = .00). A marginally significant negative association was observed between IL-1RN 86-bp VNTR polymorphism and IS risk in the heterozygous model in the fixed-effects model (1/2 vs 2/2, OR = 0.71, 95% CI = 0.53-0.95, Pheterogeneity = .10). In subgroup analyses, similar association was found in the group whose control size was lower than 300. In conclusion, our results suggested that there was no sufficient evidence to support the association between IL-1RN 86-bp VNTR polymorphism and IS. Further large epidemiologic studies need to be done to confirm these findings.