VNTR Variant Research Articles

Effect of obesity and NAFLD on leukocyte telomere length and hTERT gene MNS16A VNTR variant

It is known that telomere length (TL) (evaluated with T/S ratio) is shortened in the presence of obesity. In this study, we aimed to investigate how obesity in adolescents and non-alcoholic liver disease (NAFLD) within the obese group affect TL and the clinical significance of the human telomerase reverse transcriptase (hTERT) gene MNS16A VNTR variant in terms of NAFLD. Adolescents with exogenous obesity and healthy controls (aged 10–19 years) who applied to our adolescent outpatient clinic between May-October 2023 were included in this study. We performed upper abdominal ultrasonography to investigate the presence of NAFLD in adolescents with obesity and divided into two groups: those without hepatosteatosis (obese NAFLD (-)) and those with hepatosteatosis (obese NAFLD (+)). We recorded body weight, height, waist circumference, and blood pressure measurements and measured the T/S ratio (telomere sequence copy number/gene single copy number) by the Quantitative Polymerase Chain Reaction method. The groups were compared using frequentist and Bayesian methods. Eighty-three obese adolescents [63 NAFLD(+) 20 NAFLD(-)] and 69 lean controls were included in the study. Pairwise comparisons revealed that T/S ratio was significantly lower in the obese NAFLD (-) group than the obese NAFLD (+) and the control group (p = 0.025, p = 0.007, respectively). T/S ratio was lower in the LL allele group than in the other alleles (p = 0.022) and slightly higher in the obese group with metabolic syndrome compared to the obese group without metabolic syndrome (p = 0.072). hTERT-MNS16A-VNTR gene variant LL allele had a negative correlation with T/S ratio among the obese adolescent group. Patients with LL alleles had higher ALT, GGT, HOMA-IR, and ALT/AST. Diastolic blood pressure had a significant correlation with the T/S ratio. The T/S ratio was shorter in the obese adolescent group compared to healthy ones but was higher in the NAFLD (+) obese compared to the NAFLD (-) obese. ALT level and ALT/AST ratio were higher, T/S ratio was lower in the hTERT MNS16A VNTR variant LL allele group among obese adolescents. In addition, there was a significant correlation between the T/S ratio and diastolic blood pressure in obese adolescents.

Lack of association between VNTR variant of the circadian gene (PER3) and major depressive disorder in a sample of a Turkish population

Major depressive disorder (MDD), which is a prevalent psychiatric disorder, is characterized by sleep-wake disturbances. An underlying circadian rhythm disorder mainly may cause these disturbances. The study presented here was designed to investigate the existence of Period Circadian Regulator 3 (PER3) gene VNTR variant in MDD patients in Turkish population. A sample of 118 patients with MDD and 150 healthy volunteers were included in the study. The PER3 VNTR genotyping was performed on DNA by polymerase chain reaction (PCR) using specific primers. The prevalence rates of genotypes of 5/5, 5/4, and 4/4 profiles for the PER3 variant were 30.5%, 55.9%, and 13.6%, respectively, in patients with MDD, and 23.3%, 57.3%, and 19.3%, respectively in the control group. No significant difference was observed between the two groups in terms of either genotype distributions or allele frequencies of the VNTR variant of the PER3 gene (p > 0.05). There was no statistically significant association between the patients and the controls in terms of 5/5 + 4/5 versus 4/4 and 5/5 versus 4/5 + 4/4 (p > 0.05). The present results suggest that the PER3 VNTR variant was not associated with MDD in the Turkish population. However, further studies with other gene variants in different ethnic populations are needed to address the exact role of this variant in MDD.

Predicting anxiety-related personality traits by means of serotonergic VNTR variants STin2 and 5-HTTLPR

Polymorphisms of the serotonergic system are amongst the most commonly investigated genetic variants with respect to anxiety-related personality traits and affective disorders. Mostly the prominent 5-HTTLPR, a functional VNTR in the 5-HTT promoter region, is intensively analysed but effect sizes in meta-analyses are small and results are inconsistent. We reinvestigated the association of 5-HTTLPR with harm avoidance (HA) and neuroticism taking another functional 5-HTT-VNTR (STin2) into account, as both VNTRs have transcription regulating properties and research points to combinatorial effects on transcription efficacy. N = 2969 participants, among them 447 inpatients suffering from affective disorders, were genotyped and filled in the TCI, NEO-FFI personality inventories besides the CLEq measuring the extent of experienced stressful life events. Significant main effects for the 5-HTTLPR with inpatients carrying the L+ allele having lower HA scores as well as for the STin2 with healthy controls carrying at least one STin2.12R allele having lower neuroticism scores were observed. Besides no gene-interaction occurred. However, specific haplotype effects were observed in healthy participants as well as in the total sample. More specifically, the 12/L variant was associated with significant lower HA and neuroticism scores. Results highlight the multifactorial interplay of 5-HTT genetic variants and the use of haplotypes in association studies on anxiety-related personality traits with impact on affective disorders.

Association between endothelial nitric oxide synthase (eNOS) gene variants and nitric oxide production in preeclampsia: a case–control study in Ghana

Evidence suggests that a major cause of PE is endothelial dysfunction emanating from the reduced bioavailability of Nitric oxide (NO). Variants of endothelial nitric oxide synthase (eNOS) gene may lead to decreased NO levels. We explored the association between eNOS gene variants and nitric oxide levels among preeclamptic women in the Ghanaian population. This case–control study included 75 preeclamptic women and 75 healthy normotensive pregnant women attending antenatal care at the Nkawie-Toase Government Hospital, Ghana. A well-structured questionnaire was used to collect socio-demographic, obstetric and clinical data. Blood was obtained for DNA extraction; the gene variants were determined using PCR and RFLP. Preeclamptic women had significantly lower NO concentration compared to the normotensives (p < 0.0001) and was significantly different between VNTR variants (p < 0.0001). A significant difference in VNTR intron 4 distribution was also observed between the preeclamptic and normotensive women with 4c4c” (12.0%) and “4a4c” (1.3%) genotypes found predominantly in preeclamptic women (p < 0.0001). There was significantly higher distribution of “TC” genotype in preeclamptic women (44.0%) compared to normotensives (22.7%) (p = 0.019). However, possessing “4a4b” (cOR: 0.17, 95% CI 0.04–0.64) and “4b4b” (cOR: 0.09, 95% CI 0.02–0.38) significantly decreased the likelihood of experiencing preeclampsia by 83% and 91% respectively. Nitric oxide is reduced in preeclamptic women. NO levels in preeclampsia are altered by VNTR intron 4 variants but not T786C variants. Possessing VNTR intron 4 “4b” allele decreases the risk of PE while the “4c” allele increases the risk of PE. There is the need for eNOS variant screening and nitric oxide estimation among pregnant women for early prediction of women at risk of preeclampsia.

Investigating the relationship between the VNTR variant of the interleukin-1 receptor antagonist gene and coronary in-stent restenosis.

This study aimed to examine the association between the interleukin-1 receptor antagonist gene (IL-1RN) and coronary in-stent restenosis (ISR) through the analysis of the VNTR variant based on the previously reported results. The samples were classified into two clearly defined groups: the case group, which comprised 45 patients diagnosed with in-stent restenosis (ISR+), and the control group, which included 60 patients without ISR (ISR-). Polymerase chain reaction (PCR) was performed to examine the 86-bp VNTR variant of the IL-1RN gene. In the analysis of six identified groups consisting of variant alleles of 86 base pairs of VNTR of the IL-1RN gene statistically significant difference was observed for the presence of IL1RN*2 allele between cases and controls (p = 0.04, OR; 0.045). Individuals with allele 2 of the IL-1Ra gene may be more predisposed to ISR. This could be due to an imbalance between IL-1Ra and IL-1β which is crucial in preventing the initiation or advancement of inflammatory diseases in specific organs. The observed phenomenon can be characterized by increased production of IL-1β and potential reduction of IL-1Ra as a result of functional VNTR variation in IL-RN gene.

Evaluation of a circadian rhythm gene (PER3) VNTR variant in Turkish athletes

Objective Circadian rhythmicity has been shown to contribute to the regulation of key physiological and cognitive processes related to performance. The period homolog 3 (PER3) is expressed in a circadian pattern in the suprachiasmatic nucleus. Therefore, in this study, we aimed to evaluate the role of the variable tandem repeat (VNTR) variant of the PER3 gene in athletic performance in the Turkish population. Methods This study included 223 subjects, which consisted of 123 athletes and 100 sedentary controls. Blood samples were drawn from all subjects. DNA was extracted from whole-blood samples. The PER3 VNTR variant was genotyped using the polymerase chain reaction-restriction method (PCR). The results of the analyses were evaluated for statistical significance. Results The mean ages of athletes and controls were 22 ± 2.814 and 23 ± 3.561, respectively. Endurance athletes in the group were 21.1%, and sprint athletes were 78.9%. There was no statistical significance in terms of PER3 VNTR genotype distribution or allele frequency. In the recessive model, a statistically significant association was observed when the athletes were compared with the controls according to 4/4 + 4/5 versus 5/5 genotype (p = 0.020). Conclusion In this case-control study, for the first time in our country, we obtained findings suggesting that the PER3 VNTR variant may affect sports performance in the Turkish population. Results need to be replicated in different ethnic and larger samples.

The 3'UTR VNTR SLC6A3 Genetic Variant and Major Depressive Disorder: A Systematic Review.

Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the SLC6A3 gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the SLC6A3 (DAT1) 3'UTR VNTR (rs28363170) gene variant's SS (9R/9R) genotype and S (9R) allele frequency fluctuation and its influence on the modulation of pharmacotherapy in MDD. For this purpose, we searched different databases, and after applying the eligibility criteria, six articles were selected. Studies have shown an association between the SS (9R/9R) genotypic and S (9R) allelic presence with the risk of developing MDD, in addition to influencing the decrease in response to antidepressant therapy. However, despite the findings, disagreements were observed between other studies. For this reason, further studies with the SLC6A3 3'UTR VNTR (rs28363170) variant in different populations are necessary to understand this polymorphism's role in the onset of this disease.

Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients

Associations of XRCC4, eNOS, and PER3 VNTR variants with Childhood Acute Lymphoblastic Leukemia in Turkish Patients

Association of intron 4 VNTR polymorphism in the NOS3 gene with rapid cycling and treatment resistance in bipolar disorder: a case-control study.

To evaluate the relationship between patients' clinical parameters, especially clinical specifiers, and the intron 4 VNTR variant of the endothelial nitric oxide synthase (NOS3) gene in bipolar disorder (BD) patients. A sample of 95 patients with BD and 95 healthy volunteers were included in the case-control study. The patients consecutively admitted to the outpatient psychiatry clinic for 6 months and were evaluated with some scales for clinical parameters. In addition, PCR was used to determine the NOS3 intron 4 VNTR variant. The NOS3 genotype and allele frequency distributions of rapid cycling BD patients were significantly different from non-rapid cycling BD patients and the control groups. Furthermore, NOS3 genotype and allele frequency distributions of treatment-resistant BD patients were significantly different from treatment-responsive BD patients and the control groups. While BD patients carrying the b/b genotype and b allele had a lower risk of rapid cycling and treatment resistance, having the b/a genotype in BD patients was at higher risk in terms of rapid cycling and treatment resistance. In addition, the number of hospitalizations and the Clinical Global Impression-Improvement Scale scores of the BD group with the b/b genotype were statistically lower than the BD group with b/a and a/a genotypes. We propose that the intron 4 VNTR variant of the NOS3 gene may be associated with rapid cycling and treatment resistance in Turkish patients diagnosed with BD.

Predictive value of KRAS/NRAS, IL-4 VNTR and HPV alterations in metastases of colorectal cancer.

The main aim of the study was to evaluate the potential roles of KRAS/NRAS proto-oncogenes, IL-4 VNTR variants and HPV prevalence in colorectal cancer metastasis. As the second aim, the interactions of the analyzed genes and viral sequences with both clinicopathological variables and each other were targeted. DNA was extracted using AmoyDx FFPE DNA Extraction kit from paraffin-embedded colorectal tumor tissue samples (n = 60). NRAS/KRAS mutational profiles were determined with real-time polymerase chain reaction using AmoyDx KRAS/NRAS Mutation Detection Kit. Genotyping of IL-4 VNTR was made with PCR. HPV detection was analyzed by PCR with both GP5+/GP6+ consensus primers and type-specific primers for HPV-16 and HPV-18. SPSS v22 (IBM) statistics software was used for all statistical analyses. From the demographical/clinicopathological parameters, age and biopsy specimens revealed an association with metastasis. KRAS mutation rate was as high as 65 % in the patients and the most prevalent mutation type was G12D. Metastasis risk was 3.19-fold increased in KRAS-mutated patients compared to KRAS-negative ones. IL-4 VNTR genotypes/alleles were not associated with metastasis in our analysis. The frequency of HPVs in our colorectal cancer cohort was 36.7 %, but HPV positivity was not found to be associated with metastasis. A significant association was found between HPV and NRAS mutations; NRAS wild-type status acted as a protective factor by 7.5-fold for HPV negativity. Our study comprehensively and concomitantly evaluated several potential molecular risk factors. Future studies designed in such combined approaches will substantially contribute to better manage colorectal cancer tumorigenesis from molecular biological perspective (Tab. 6, Fig. 2, Ref. 40).

VEGF and eNOS variants may influence intervertebral disc degeneration

Background: Intervertebral disc degeneration (IDD) is a common and complex condition. Vascular endothelial growth factor (VEGF) is one of the key regulators of angiogenesis and vascular permeability. Nitric oxide (NO) plays a role in various physiological events. The endothelial nitric oxide synthase (eNOS) that catalyses NO generation are crucial for the regulation of NO level. This study aimed to evaluate the association between VEGF/ eNOS gene variants with IDD. Materials and Methods: Two hundred ninety-one subjects (111 IDD patients and 180 controls) were included in the present case-control study. VEGF −2549 insertion/deletion (I/D) and eNOS VNTR variants were analysed by PCR method. The results of this analysis were evaluated for statistical significance. Results: There were no statistically significant differences in genotype and allele distribution of VEGF −2549 I/D/ eNOS VNTR variants between IDD patients and control subjects. We then evaluated the association between the allele frequencies of these variants and clinical features of IDD. Lumber IDD was more common in patients carrying VEGF I/D variant D allele (p < 0.001). Also, patients with lumbar disc herniation, cervical disc herniation, lumbar stenosis, and lumbar IDD had more 4 b allele (p = 0.005, p < 0.001, p < 0.001, and p = 0.03, respectively). Conclusions: In conclusion, this study demonstrates first time that some clinical characteristics of IDD have been associated with allele frequencies of VEGF −2549 I/D/ eNOS VNTR variants.

VNTR Polymorphism in Intron 4 of the eNOS Gene and the Risk of Gastrointestinal Bleeding: A Case-control Study

Background and Aims: Considering the lack of knowledge regarding the influence of the variable number of repeats of 27 pb in intron 4 (4b/4a VNTR - rs61722009) of the endothelial nitric oxide synthase (eNOS) on the drug response, we assessed the influence of this polymorphism for the risk of upper gastrointestinal bleeding (UGIB).&#x0D; Methods: A case-control study, including 200 cases and 706 controls, was conducted in a Brazilian hospital complex. Cases were participants with UGIB diagnosis. Controls were participants admitted to surgical procedures not related to gastrointestinal problems. The 4b/4a VNTR was determined through polymerase chain reaction followed by fragment analysis. Conditional logistic regression models were designed. The additive interaction between the presence of the 4b/4a VNTR variant and the use of low-dose aspirin (LDA) and nonsteroidal anti-inflammatory drugs (NSAIDs) was calculated by fitting the Cox regression model through the parameters of Synergism index (S) and Relative Excess Risk Due To Interaction (RERI).&#x0D; Results: The presence of the 4b/4a VNTR variant did not increase the risk of UGIB: carriers of the 4a/4a genotype (OR=0.37, 95%CI: 0.09-1.45) and of the variant allele “4a” (OR=0.91, 95%CI: 0.55-1.51). The risk of UGIB in LDA users carriers of the wild genotype (OR=4.96, 95%CI: 2.04- 2.06) and the variant allele “4a” (OR=3.49, 95%CI: 1.18-10.38) is similar, as well as for NSAID users carriers of the wild genotype (OR=5.73, 95%CI: 2.61-12.60) and variant allele “4a” (OR=5.51, 95%CI: 1.42-15.82). No additive interaction was identified between the presence of the genetic variant and the use of LDA [RERI: -1.44 (95%CI: -6.02–3.14; S: 0.63 (95%CI: -1.97–1.15)] and NSAIDs [RERI: -0.13 (95%CI: -6.79–6.53; S: 0.97 (95%CI: -0.23–4.19)] on the UGIB risk.&#x0D; Conclusion: Our data suggests that there is no increase in the magnitude of UGIB risk in LDA and NSAIDs users’ carrying the variant allele “4a”.

Association between NOS3 intron 4 VNTR variant and sports performance

Association between NOS3 intron 4 VNTR variant and sports performance

Polymorphisms of interleukin 4 and interleukin 4 receptor genes and bronchial asthma risk among Egyptian children

BackgroundInterleukin 4 (IL4) is a key cytokine that regulates the inflammatory cascade in bronchial asthma. We investigated the association between the IL4 and IL4R polymorphisms and the susceptibility for bronchial asthma among Egyptian children. MethodsIL4 VNTR and IL4R c.1902 A>G p.(Q576R) polymorphisms were investigated among 100 children with bronchial asthma and 100 healthy controls using PCR method. Serum levels of IL4 and immunoglobulin E (IgE) were assessed by ELISA. ResultsThe frequencies of (A1A2 + A2A2) genotypes and A2-allele of the IL4 VNTR variant were significantly higher among asthmatic patients than controls (p = 0.01, OR = 2.34, 95% CI = 1.24–4.44; p = 0.01, OR = 2.27, 95% CI = 1.29–3.99, respectively). The frequencies of (AG + GG) genotypes and G-allele of the IL4R (A1902G) variant were significantly higher among asthmatic patients than controls (p = 0.003, OR = 2.52, 95% CI = 1.39–4.58; p = 0.002, OR = 2.25, 95% CI = 1.35–3.76, respectively). There was a significant association between (A1A2 + A2A2) genotypes of the IL4 VNTR variant and high serum IL4 level among asthmatic patients (p < 0.001). The (AG + GG) genotypes of the IL4R (A1902G) variant were significantly associated with exposure to triggers, atopic dermatitis and higher serum IgE level in asthmatic patients (p = 0.02, 0.04 and 0.01, respectively). ConclusionIL4 VNTR and IL4R (A1902G) polymorphisms could be associated with higher risks of bronchial asthma among Egyptian children.

Impact of Endothelial NOS VNTR Variant on Susceptibility to Diabetic Neuropathy and Type 2 Diabetes Mellitus.

The aim of this study was to evaluate whether the VNTR intron 4b/4a variant in the eNOS gene is associated with type 2 diabetes mellitus (T2DM) and DPN. A total of 598 subjects were enrolled in the study. eNOS VNTR 4b/4a variant was genotyped by polymerase chain reaction (PCR) method. eNOS VNTR intron 4b/4b genotype and b allele increased in patients with both DPN and T2DM compared healthy controls (p=0.0005, OR:1.94, p= 0.000002, OR:4.10, respectively). 4a/4b genotype was more prevalent in controls than in DPN and T2DM patients (p=0.00008, OR:0.46; p=0.000004, OR:0.24, respectively). eNOS VNTR b allele was more common in DPN patients and T2DM patients compared with controls (p=0.007, p=0.00002, respectively). The eNOS VNTR "4b/4b" homozygous genotype and hence "4b"allele as a genetic risk factor for T2DM and DPN, which may serve as a useful marker of increased susceptibility to the risk of these disorders.

PER3 VNTR GENOTYPES MAY PREDICT OVERALL SURVIVAL IN BLADDER CANCER PATIENTS IN THE TURKISH POPULATION

Circadian genes were proven to play significant roles in tumor development and progression via coordinating various cellular processes. Though circadian rhythm disturbances both on the level of expression and genetic variant analysis have been associated with increased risk for many cancer types, none has investigated the potential effect of PER3 VNTR in bladder tumorigenesis yet. In this study, we aimed to assess PER3 VNTR’s effect in terms of creating susceptibility to bladder carcinoma formation. Our second target was to enlighten the possible associations between PER3 genotypes and clinicopathological correlations in bladder carcinoma cohort and thus evaluate outcomes in bladder carcinoma prognosis. In this case-control study, 116 patients and 120 healthy controls were recruited. DNA was isolated from peripheral blood using the standard salting-out procedure and PER3 VNTR variants (ins/del polymorphism) were determined with PCR technique to distinguish the 5-repeats allele (401 bp) from the 4-repeats allele (347 bp). Though this exploratory analysis did not provide evidence supporting the role of PER3 VNTR in the onset of bladder carcinoma, it enabled us to make a risk assessment for the prognosis of bladder carcinoma patients. The survival times of patients decreased in the patient group (progression and cystectomy positive) for PER3 4/4 genotype and (recurrence, progression and cystectomy positive) for PER3 4/5 genotype. Results presented in this study are highly recommended to be investigated and validated in larger samples in different populations and ethnicities to generalize potential clinical utility.

PER3 VNTR variant and susceptibility to smoking status/substance use disorder in a Turkish population

Background Substance use and smoking exert devastating impact on sleep, especially hindering the ease of falling asleep, compromising the sleep maintenance, and distorting the sleep cycles. PERIOD genes are believed to play a role in individual differences in sleep timing by influencing circadian. Objective The aim of this study was to ascertain whether Per3 VNTR variant affects suspectibility of individuals to substance use disorder (SUD) and smoking status in a Turkish population. Methods A total of 549 subjects, including 212 SUD patients, 160 smoker, and 177 healthy controls, matched by ethnicity, age, and gender, were recruited in a case-control study. Genotyping of Per3 variant was performed using PCR method. Results When the SUD, smoker groups and controls were compared in terms of 5R/5R, 5R/4R, 4R/4R genotypes, no significant difference was observed. Besides, allele frequencies of Per3 VNTR were similar among the groups. Discussion Our data indicate that Per3 VNTR variant is not associated with the risk of SUD and smoking status in our population.

Analysis of Polymorphic Variants of the Dopamine Transporter (DAT1) Gene Polymorphism and Personality Traits Among Athletes.

Personality traits, especially in sport are modulatory factors of athletes’ behavior – his/ her conscientiousness, the will to achieve an aim, perseverance and motivation of activity. Not only are biological predispositions related to anatomical or biochemical traits of success, but they are also largely determined by personality traits that result from genetic factors. In our research we joined tests of athlete’s personality in correlation with genotypes of the dopamine transporter (DAT1) gene polymorphism. The selection of this polymorphism was based on previous reports connecting the influence of dopamine with motivation and numerous arguments supporting its correlation with human behavior. We observed significant differences among polymorphisms DAT 9/9, 9/10, 10/10 in terms of proportion of particular genotypes between athletes and the control group. We also found significant differences in the NEO FFI sten scale for conscientiousness. We noticed that anxiety was related with genotypic variants of DAT1, specifically the 9/10 VNTR variant, which conditioned lower levels of anxiety in the group of tested athletes. By contrast, the lower sten value of agreeability was statistically significant for the group of athletes that were carriers of the 10/10 VNTR genotype. Heterozygous 9/10 VNTR among athletes showed lower levels of anxiety in comparison with the control group, whereas agreeability determined using the NEO FFI scale represented a lower value among athletes that had the 10/10 polymorphism. We may thus conclude that the presence of polymorphic variants of the dopamine transporter gene corresponds to athletes’ personality traits.

DRD4 48\u2009bp multiallelic variants as age-population-specific biomarkers in attention-deficit/hyperactivity disorder

The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/“long” allele was identified as an ADHD risk factor in European-Caucasian populations (d = 1.31, 95%CI: 1.17–1.47, Z = 4.70/d = 1.36, 95%CI: 1.20–1.55, Z = 4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/“short” allele was a protective factor in European-Caucasian and South American populations (d = 0.83, 95%CI: 0.75–0.92, Z = 3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d = 1.20, 95%CI: 0.71–1.69, Z = 4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48 bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression downregulation was found in ADHD specific brain regions (Putamen, Z score = −3.02, P = 0.00252). Overall, our results suggest that DRD4 48 bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated.

Impact of the Functional VNTR Variants of the Interleukin-1 Receptor Antagonist and Interleukin-4 Genes on Oral Squamous Cell Carcinoma

Impact of the Functional VNTR Variants of the Interleukin-1 Receptor Antagonist and Interleukin-4 Genes on Oral Squamous Cell Carcinoma