Mehmet Emin Erdal

Significance of Serotonin Transporter Gene 5-HTTLPR and Variable Number of Tandem Repeat Polymorphism in Attention Deficit Hyperactivity Disorder

The purpose of this study was to evaluate the relationship between attention deficit hyperactivity disorder (ADHD) and polymorphism of the two regions of the 5-HTT gene [variable number of tandem repeats (VNTR) and 5-HTTLRR] in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 71 patients with ADHD and 128 healthy controls. The 5-HTTLPR S/S genotype was significantly lower in the patients than in the controls (p = 0.018). Homozygous and heterozygous L variant predominated in the ADHD group. But the VNTR STin2.12/12 genotype was significantly less found in the patients than in the controls (p = 0.001). There was no significant difference between the frequency of the short (S), long, 10, and 12 alleles of both groups. The lack of an S/S variant of 5-HTTLPR polymorphism of the STin2.12/12 variant of VNTR polymorphism appears to be associated with an increased risk of ADHD.

Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants

Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.

Cytokine Polymorphism in Patients with Migraine: Some Suggestive Clues of Migraine and Inflammation

OBJECTIVE There are contrasting results obtained in migraineurs concerning the levels and the role of both pro-inflammatory and anti-inflammatory cytokines. In this study, the association of the occurrence and clinical characteristics of migraine with the polymorphisms of tumor necrosis factor alpha (TNF-alpha) -308 G/A (rs1800629), interleukin-1alpha (IL-1alpha) +4845 G/T (rs17561), IL-1beta+3953 C/T (rs1143634) and interleukin-1 receptor antagonist variable number tandem repeat (IL-1RA VNTR) genes were studied. We also investigated the genetic linkage between these genes. DESIGN, SETTING, PATIENTS Sixty-seven patients with migraine without aura (MwoA) and 96 unrelated, age- and sex-matched migraine-free, healthy control subjects from the same geographic area were investigated. RESULTS We observed significant differences in the genotypic distribution of the TNF-alpha-308 G/A and IL-1beta+3953 C/T polymorphism for migraineurs compared with controls (P = 0.004). Frequency of the TNF-alpha-308 GG genotype was higher in the control group than MwoA group (82.1% vs 55.2%). Differences in the distribution of the allele frequencies were also observed, being the TNF-alpha-308 G allele overrepresented in control group and TNF-alpha-308 A allele in MwoA group. In addition, there was a significant increase of the IL-1beta+3953 T allele in MwoA cases compared with controls (P = 0.004). CONCLUSIONS In conclusion, the present results indicate the possible contribution of TNF-alpha and IL-1beta gene polymorphisms to migraine headache generation in MwoA patients.

No Evidence for an Association between the T102C and 1438 G/A Polymorphisms of the Serotonin 2A Receptor Gene in Attention Deficit/Hyperactivity Disorder in a Turkish Population

Disturbances in the serotonergic neurotransmission system have been implicated in the etiology of attenion deficit/hyperactivity disorder (ADHD). As the importance of genetic factors is well established, genes encoding for proteins of the serotonergic pathway are important candidates to unravel the underlying genetic contribution. We previously demonstrated that the polymorphisms of the serotonin transporter gene promoter and regions of variable number of tandem repeats were involved in the pathogenesis of ADHD. The purpose of this study was to examine the relationship between ADHD and two polymorphisms (T102C and 1438 G/A) in the 5-HT2A gene in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 70 patients with ADHD and in 100 healthy controls. There was no significant difference between the frequencies of the T, C, G and A alleles of both groups. No association was found between the studied polymorphisms of the 5-HT2A gene and ADHD in this sample consisting of Turkish children. Overall, our results suggest that the investigated 5-HT2A polymorphisms are not major susceptibility factors in the etiology of ADHD.

The association of olanzapine-induced weight gain with peroxisome proliferator-activated receptor-γ2 Pro12Ala polymorphism in patients with schizophrenia.

Olanzapine is a second-generation antipsychotic that may cause weight gain and metabolic syndrome in some cases. The peroxisome proliferator-activated receptor (PPAR)-gamma is an important gene in the progress of type II diabetes and metabolic syndrome. In recent studies the polymorphism of the PPAR-gamma has been studied in type II diabetes mellitus, polycystic ovary syndrome, and insulin resistance syndrome. It is aimed to evaluate the association between polymorphism of PPAR-gamma gene and olanzapine-induced weight gain. Our study comprised 95 unrelated subjects who strictly met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for schizophrenia, and all were of Turkish origin. All patients were evaluated with rating scales, and genetic analyses were performed. We found statistically significant differences between pretreatment and posttreatment body mass index and weight change in Pro12Ala polymorphism of PPAR-gamma2. Our results suggest that genetic polymorphism of PPAR might be important in olanzapine-induced weight gain and that genetic variance of people might be considered in antipsychotic medication selection.

Effects of 2.4 GHz radiofrequency radiation emitted from Wi-Fi equipment on microRNA expression in brain tissue

Abstract Purpose: MicroRNAs (miRNA) play a paramount role in growth, differentiation, proliferation and cell death by suppressing one or more target genes. However, their interaction with radiofrequencies is still unknown. The aim of this study was to investigate the long-term effects of radiofrequency radiation emitted from a Wireless Fidelity (Wi-Fi) system on some of the miRNA in brain tissue. Materials and methods: The study was carried out on 16 Wistar Albino adult male rats by dividing them into two groups such as sham (n = 8) and exposure (n = 8). Rats in the exposure group were exposed to 2.4 GHz radiofrequency (RF) radiation for 24 hours a day for 12 months (one year). The same procedure was applied to the rats in the sham group except the Wi-Fi system was turned off. Immediately after the last exposure, rats were sacrificed and their brains were removed. miR-9-5p, miR-29a-3p, miR-106b-5p, miR-107, miR-125a-3p in brain were investigated in detail. Results: The results revealed that long-term exposure of 2.4 GHz Wi-Fi radiation can alter expression of some of the miRNAs such as miR-106b-5p (adj p* = 0.010) and miR-107 (adj p* = 0.005). We observed that mir 107 expression is 3.3 times and miR- 106b-5p expression is 3.65 times lower in the exposure group than in the control group. However, miR-9-5p, miR-29a-3p and miR-125a-3p levels in brain were not altered. Conclusion: Long-term exposure of 2.4 GHz RF may lead to adverse effects such as neurodegenerative diseases originated from the alteration of some miRNA expression and more studies should be devoted to the effects of RF radiation on miRNA expression levels.

Evaluation of several micro RNA (miRNA) levels in children and adolescents with attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent childhood disorders, although disorders etiology and pathogenesis remains unknown, several theories about ADHD development have been proposed and many researchers believe that it is caused by both genetic and environmental factors. In this study we evaluated miR18a-5p, miR22-3p, miR24-3p, miR106b-5p, miR107, miR125b-5p and miR155a-5p levels in child and adolescent ADHD patients. The research sample consisted a group of 52 ADHD patients, and 52 healthy volunteer controls. There was no significant difference in age and sex between the two groups (p>0.05). miRNA 18a-5p, 22-3p, 24-3p, 106b-5p and 107 levels were statistically significantly decreased in ADHD patients(p<0.05). miRNA 155a-5p levels were increased in patients group (p<0.05). The positive predictive value (PPV) and negative predictive value of miR107 was estimated for the cutoff point of 0.4480. PPV was 70% and NPV was 86.5% for the taken cut off point. There could be a close relationship between levels of circulating miRNAs and ADHD. If we could understand how the signaling pathways arranged by miRNAs, impact on CNS development, function and pathology this can improve our knowledge about ADHD etiology and treatment.

Association Among SNAP-25 Gene DdeI and MnlI Polymorphisms and Hemodynamic Changes During Methylphenidate Use A Functional Near-Infrared Spectroscopy Study

Objective: To investigate the interaction of treatment-related hemodynamic changes with genotype status for Synaptosomal associated protein 25 (SNAP-25) gene in participants with attention deficit hyperactivity disorder (ADHD) on and off single dose short-acting methylphenidate treatment with functional near-infrared spectroscopy (fNIRS). Method: A total of 15 right-handed adults and 16 right-handed children with DSM-IV diagnosis of ADHD were evaluated. Ten milligrams of short-acting methylphenidate was administered in a crossover design. Results: Participants with SNAP-25 DdeI T/T genotype had decreased right deoxyhemoglobin ([HHb]) with treatment. SNAP-25 MnlI genotype was also associated with right deoxyhemoglobin ([HbO2]) and [HHb] changes as well as left [HHb] change. When the combinations of these genotypes were taken into account, the participants with [DdeI C/C or T/C and MnlI G/G or T/G] genotype had increased right [HHb] with MPH use whereas the participants with [DdeI T/T and MnlI T/T] or [DdeI T/T and MnlI G/G or T/G] genotypes had decreased right prefrontal [HHb]. Conclusions: These results suggested that SNAP-25 polymorphism might be associated with methylphenidate induced brain hemodynamic changes in ADHD participants.

T102C Polymorphisms at the 5-HT2A Receptor Gene in Turkish Schizophrenia Patients: A Possible Association with Prognosis

Background: Serotonergic system abnormalities have been implicated in the pathogenesis of schizophrenia. The 5-HT2A receptor gene polymorphism has long been implicated to play a role in the pathogenesis of schizophrenia. Aim: In this study, we assessed the relationship of schizophrenia and its subgroups with 5-HT2A receptor gene polymorphism, and attempted to evaluate a possible correlation between the severity and prognosis of the illness and 5-HT2A receptor gene polymorphism. Method: Our study comprised 141 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 79 healthy unrelated controls, all of Turkish origin. A clinical evaluation of all patients was accomplished applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of 5-HT2A receptor gene polymorphism was performed using the polymerase chain reaction technique. Results: Regarding 5-HT2A receptor gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects (p > 0.05). There was no significant difference between the average of BPRS points of the patients and 5-HT2A receptor gene polymorphisms (p > 0.05). Although there was no correlation between the duration of illness and polymorphism (p > 0.05), the frequency of hospitalization was found to be higher in the patients with T/C and T/T genotypes compared with the patients with C/C genotype (p < 0.05). Conclusion: Our findings indicate that the T102C polymorphisms of the 5-HT2A receptor gene does not play a substantial role in schizophrenia nor help evaluate susceptibility to schizophrenia. Since the 5-HT2A receptor gene polymorphism is associated with the frequency of hospitalization of the patients, it may be an indicator of prognosis in schizophrenia or help differentiate the patients who are somewhat refractory to antipsychotic treatment.

Synaptosomal-associated protein 25 gene polymorphisms and antisocial personality disorder: association with temperament and psychopathy.

Objective: The molecular genetic of personality disorders has been investigated in several studies; however, the association of antisocial behaviours with synaptosomal-associated protein 25 (SNAP25) gene polymorphisms has not. This association is of interest as SNAP25 gene polymorphism has been associated with attention-deficit hyperactivity disorder and personality. Methods: We compared the distribution of Ddel and Mnll polymorphisms in 91 young male offenders and in 38 sex-matched healthy control subjects. We also investigated the association of SNAP25 gene polymorphisms with severity of psychopathy and with temperament traits: novelty seeking, harm avoidance, and reward dependence. Results: The Mnll T/T and Ddel T/T genotypes were more frequently present in male subjects with antisocial personality disorder (APD) than in sex-matched healthy control subjects. The association was stronger when the frequency of both Ddel and Mnll T/T were taken into account. In the APD group, the genotype was not significantly associated with the Psychopathy Checklist–Revised scores, measuring the severity of psychopathy. However, the APD subjects with the Mnll T/T genotype had higher novelty seeking scores; whereas, subjects with the Ddel T/T genotype had lower reward dependence scores. Again, the association between genotype and novelty seeking was stronger when both Ddel and Mnll genotypes were taken into account. Conclusion: Ddel and Mnll T/T genotypes may be a risk factor for antisocial behaviours. The association of the SNAP25 Ddel T/T and Mnll T/T genotypes with lower reward dependence and higher novelty seeking suggested that SNAP25 genotype might influence other personality disorders, as well.