Association study of promoter polymorphisms at the dopamine transporter gene in Attention Deficit Hyperactivity Disorder

<p>Abstract</p> <p>Background</p> <p>Attention deficit hyperactivity disorder (ADHD) is a complex neurobehavioral disorder. The dopamine transporter gene (DAT1/<it>SLC6A3</it>) has been considered a good candidate for ADHD. Most association studies with ADHD have investigated the 40-base-pair variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1. Only few studies have reported association between promoter polymorphisms of the gene and ADHD.</p> <p>Methods</p> <p>To investigate the association between the polymorphisms -67A/T (rs2975226) and -839C/T (rs2652511) in promoter region of DAT1 in ADHD, two samples of ADHD patients from the UK (n = 197) and Taiwan (n = 212) were genotyped, and analysed using within-family transmission disequilibrium test (TDT).</p> <p>Results</p> <p>A significant association was found between the T allele of promoter polymorphism -67A/T and ADHD in the Taiwanese population (<it>P </it>= 0.001). There was also evidence of preferential transmission of the T allele of -67A/T polymorphism in combined samples from the UK and Taiwan (<it>P </it>= 0.003). No association was detected between the -839C/T polymorphism and ADHD in either of the two populations.</p> <p>Conclusion</p> <p>The finding suggests that genetic variation in the promoter region of DAT1 may be a risk factor in the development of ADHD.</p

Molecular Variation at the SLC6A3 Locus Predicts Lifetime Risk of PTSD in the Detroit Neighborhood Health Study

Recent work suggests that the 9-repeat (9R) allele located in the 3′UTR VNTR of the SLC6A3 gene increases risk of posttraumatic stress disorder (PTSD). However, no study reporting this association to date has been based on population-based samples. Furthermore, no study of which we are aware has assessed the joint action of genetic and DNA methylation variation at SLC6A3 on risk of PTSD. In this study, we assessed whether molecular variation at SLC6A3 locus influences risk of PTSD. Participants (n = 320; 62 cases/258 controls) were drawn from an urban, community-based sample of predominantly African American Detroit adult residents, and included those who had completed a baseline telephone survey, had provided blood specimens, and had a homozygous genotype for either the 9R or 10R allele or a heterozygous 9R/10R genotype. The influence of DNA methylation variation in the SLC6A3 promoter locus was also assessed in a subset of participants with available methylation data (n = 83; 16 cases/67 controls). In the full analytic sample, 9R allele carriers had almost double the risk of lifetime PTSD compared to 10R/10R genotype carriers (OR = 1.98, 95% CI = 1.02–3.86), controlling for age, sex, race, socioeconomic status, number of traumas, smoking, and lifetime depression. In the subsample of participants with available methylation data, a significant (p = 0.008) interaction was observed whereby 9R allele carriers showed an increased risk of lifetime PTSD only in conjunction with high methylation in the SLC6A3 promoter locus, controlling for the same covariates. Our results confirm previous reports supporting a role for the 9R allele in increasing susceptibility to PTSD. They further extend these findings by providing preliminary evidence that a “double hit” model, including both a putatively reduced-function allele and high methylation in the promoter region, may more accurately capture molecular risk of PTSD at the SLC6A3 locus

Genetic Determinants of Time Perception Mediated by the Serotonergic System

Background: The present study investigates neurobiological underpinnings of individual differences in time perception. Methodology: Forty-four right-handed Russian Caucasian males (18–35 years old) participated in the experiment. The polymorphism of the genes related to the activity of serotonin (5-HT) and dopamine (DA)-systems (such as 5-HTT, 5HT2a, MAOA, DAT, DRD2, COMT) was determined upon the basis of DNA analysis according to a standard procedure. Time perception in the supra-second range (mean duration 4.8 s) was studied, using the duration discrimination task and parametric fitting of psychometric functions, resulting in individual determination of the point of subjective equality (PSE). Assuming the ‘dual klepsydra model ’ of internal duration representation, the PSE values were transformed into equivalent values of the parameter k (kappa), which is a measure of the ‘loss rate ’ of the duration representation. An association between time representation parameters (PSE and k, respectively) and 5-HT-related genes was found, but not with DArelated genes. Higher ‘loss rate ’ (k) of the cumulative duration representation were found for the carriers of genotypes characterized by higher 5-HT transmission, i.e., 1) lower 5-HT reuptake, known for the 5-HTTLPR SS polymorphism compared with LL, 2) lower 5-HT degradation, described for the ‘low expression ’ variant of MAOA VNTR gene compared with ‘high expression ’ variant, and 3) higher 5-HT2a receptor density, proposed for the TT polymorphism of 5-HT2a T102C gene compared with CC

Does CT colonography have a role for population-based colorectal cancer screening?

Colorectal cancer (CRC) is the second most common cancer and second most common cause of cancer-related deaths in Europe. CRC screening has been proven to reduce disease-specific mortality and several European countries employ national screening programmes. These almost exclusively rely on stool tests, with endoscopy used as an adjunct in some countries. Computed tomographic colonography (CTC) is a potential screening test, with an estimated sensitivity of 88 % for advanced neoplasia ≥10 mm. Recent randomised studies have shown that CTC and colonoscopy have similar yields of advanced neoplasia per screened invitee, indicating that CTC is potentially viable as a primary screening test. However, the evidence is not fully elaborated. It is unclear whether CTC screening is cost-effective and the impact of extracolonic findings, both medical and economic, remains unknown. Furthermore, the effect of CTC screening on CRC-related mortality is unknown, as it is also unknown for colonoscopy. It is plausible that both techniques could lead to decreased mortality, as for sigmoidoscopy and gFOBT. Although radiation exposure is a drawback, this disadvantage may be over-emphasised. In conclusion, the detection characteristics and acceptability of CTC suggest it is a viable screening investigation. Implementation will depend on detection of extracolonic disease and health-economic impact

Patient willingness for repeat screening&nbsp;and preference for CT colonography and&nbsp;optical colonoscopy in ACRIN 6664: the National CT Colonography trial

Ilana F Gareen,1,2 Bettina Siewert,3 David J Vanness,4 Benjamin Herman,2 CD Johnson,5 Constantine Gatsonis2,6 1Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA; 2Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, USA; 3Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 4Population Health Sciences, University of Wisconsin, Madison, WI, USA; 5Mayo Clinic, Scottsdale, AZ, USA; 6Department of Biostatistics, Brown University School of Public Health, Providence, RI, USA Background: Current American Cancer Society recommendations for colon cancer screening include optical colonoscopy every 10 years or computed tomography colonography (CTC) every 5 years. Bowel preparation (BP) is currently required for both screening modalities.Purpose: To compare ACRIN 6664: the National CT Colonography Trial (NCTCT) participant experiences with CTC and optical colonoscopy (OC), procedure preference, and willingness to return for each procedure.Materials and methods: Participants from fifteen NCTCT sites, who underwent CTC followed by OC under sedation, were invited to complete questionnaires 2 weeks postexam, asking about procedure preference, physical discomfort, and embarrassment experienced and whether that discomfort and embarrassment was better or worse than expected during BP, CTC, and OC, as well as willingness to return for repeat CTC and OC at different time intervals.Results: A total of 2,310 of 2,600 patients (89%) returned their questionnaires. Of patients reporting a preference, 1,058 (46.6%) preferred CTC, 569 (25.0%) preferred OC, and 626 (27.6%) reported no preference. Participant-reported discomfort worse than expected differed significantly between CTC (32.9%) and OC (5.0%) (P&lt;0.001). About 79.3% were willing to be screened again with CTC in 5 years, and 96.6% with OC in 10 years. Discomfort and embarrassment worse than expected with OC were associated with increased intention to adhere with CTC in the future. Conversely, embarrassment experienced during CTC and discomfort worse than expected on CTC were associated with increased intention to adhere with OC in the future.Conclusion: While a larger proportion of participants indicated that they preferred CTC to OC, willingness to undergo repeat CTC compared to OC was limited by unanticipated exam discomfort and embarrassment and CTC&rsquo;s shorter screening interval. Keywords: CT colonography, colonoscopy, bowel preparation, adherence, patient preferenc

Comparative Economic Evaluation of Data from the ACRIN National CT Colonography Trial with Three Cancer Intervention and Surveillance Modeling Network Microsimulations

Purpose: To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. Materials and Methods: Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U. S. health care sector perspective, assuming a 3% discount rate. Results: CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: $26300 per life-year gained). CT colonography at 5- and 10-year screening intervals and colonoscopy were net beneficial compared with no screening in all model scenarios. The 5-year screening interval was net beneficial over the 10-year interval except in the MISCAN model when assuming 100$50000 per life-year gained. Conclusion: All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions. (C) RSNA, 201