Synaptosomal-Associated Protein 25 Gene Polymorphisms Affect Treatment Efficiency of Methylphenidate in Children With Attention-Deficit Hyperactivity Disorder: An fNIRS Study

Methylphenidate (MPH) is the first-line drug for the treatment of children with attention-deficit hyperactivity disorder (ADHD); however, individual curative effects of MPH vary. Many studies have demonstrated that synaptosomal-associated protein 25 (SNAP-25) gene MnlI polymorphisms may be related to the efficacy of MPH. However, the association between SNAP-25MnlI polymorphisms and changes in brain hemodynamic responses after MPH treatment is still unclear. This study used functional near-infrared spectroscopy (fNIRS) to preliminarily investigate the interaction of MPH treatment-related prefrontal inhibitory functional changes with the genotype status of the SNAP-25 gene in children with ADHD. In total, 38 children with ADHD aged 6.76–12.08 years were enrolled in this study and divided into the following two groups based on SNAP-25 gene MnlI polymorphisms: T/T genotype group (wild-type group, 27 children) and G allele carrier group (mutation group, 11 children). The averaged oxygenated hemoglobin concentration changes [Δavg oxy-Hb] and deoxyhemoglobin concentration changes [Δavg deoxy-Hb] in the frontal cortex before MPH treatment and after 1.5 h (post-MPH1.5h) and 4 weeks (post-MPH4w) of MPH treatments were monitored using fNIRS during the go/no-go task. SNAP-IV scores were evaluated both pre-MPH and post-MPH4w treatments. In the T/T genotype group, [Δavg oxy-Hb] in the dorsolateral prefrontal cortex was significantly higher after 4 weeks of MPH (post-MPH4W) treatment than pre-treatment; however, in the G allele group, no significant differences in [Δavg oxy-Hb] were observed between pre- and post-treatments. In the go/no-go task, the accuracy was significantly increased post-MPH4w treatment in the T/T genotype group, while no significant differences were observed in response time and accuracy of the “go” sand no-go task in the G allele group for pre-MPH, post-MPH1.5h, and post-MPH4w treatments. The T/T genotype group exhibited a significant decrease in SNAP-IV scores after MPH treatment, while the G allele group showed no significant difference. In conclusion, fNIRS data combined with SNAP-25 MnlI polymorphism analysis may be a useful biomarker for evaluating the effects of MPH in children with ADHD.

Association between Apoϵ4 allele and cardiometabolic and social risk factors with cognitive impairment in elderly population from Bogota

ABSTRACT Being an ϵ4 carrier in the Apoϵ gene has been suggested as a modifying factor for the interaction between cardio-metabolic, social risk factors, and the development of cognitive impairment. Objective: The main objective of this study was to assess the existence of such interaction in a sample of Bogota’s elderly population. Methods: A cross-sectional study was conducted with 1,263 subjects older than 50 years. Each participant was diagnosed by consensus, after neuropsychological and neuropsychiatric evaluations, under a diagnosis of normal cognition, mild cognitive impairment (MCI) according to Petersen’s criteria, or dementia according to DSM-IV criteria. Apoϵ was typified and an analysis of MoCA test was performed in each group carrying or not ϵ4 allele. Results: Our study showed that 75% were women with a median age of 68 years (interquartile range 62–74 years) and a median schooling for 6 years (interquartile range 4–12 years). Dementia was related to low education level of ≤5 years OR=11.20 (95%CI 4.99–25.12), high blood pressure (HBP) OR=1.45 (95%CI 1.03–2.05), and age over 70 years OR=7.68 (95%CI 3.49–16.90), independently of being or not an ϵ4 allele carrier. Diabetic subjects with dementia carrying ϵ4 allele showed a tendency to exhibit lower scores on the MoCA test, when compared with noncarriers’ diabetic subjects with dementia. Conclusions: The presence of ϵ4 allele does not modify the relationship between cognitive impairment and the different cardio-metabolic and social risk factors, except in diabetic subjects ϵ4 carriers with dementia who showed a tendency to exhibit lower scores of the MoCA test, when compared with noncarriers’ diabetic subjects with dementia.

Association between clinical symptoms and apolipoprotein A1 or apolipoprotein B levels is regulated by apolipoprotein E variant rs429358 in patients with chronic schizophrenia

Background The apolipoprotein E (ApoE) gene polymorphisms are correlated with blood lipid levels and several neuropsychiatric symptoms. Therefore, this study aimed to examine whether the ApoE rs429358 affected the development and clinical symptoms of schizophrenia and to explore the relationship between apolipoproteins levels and clinical symptoms. Methods The ApoE rs429358 was genotyped using a case–control design. The Positive and Negative Syndrome Scale (PANSS) was employed to evaluate the psychopathology of all patients. Results A total of 637 patients with schizophrenia and 467 healthy controls were recruited. We found no significant differences in the genotype and allele distribution between the patient and control groups. A significant correlation between PANSS negative symptoms and ApoA1 levels (p = 0.048) or ApoB levels (p = 0.001) was found in patients with schizophrenia, which was also confirmed by linear regression analyses (p = 0.048 vs. p = 0.001). Interestingly, only in the T homozygote group, ApoA1 and ApoB levels were predictors of the PANSS negative symptom score (p = 0.008 vs. p = 0.012), while in the C allele carrier group, no correlation was observed. Conclusions This study found that the levels of ApoA1 and ApoB were negatively associated with negative symptoms of patients with schizophrenia. Furthermore, the association between ApoA1 or ApoB levels and psychopathology of schizophrenia was regulated by ApoE rs429358.

Association Between CLOCK 3111 T/C Polymorphism with Ghrelin, GLP-1, Food Timing, Sleep and Chronotype in Overweight and Obese Iranian Adults

Background Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, food timing, dietary intake, appetite and chronobiologic characteristics) and hormonal (plasma ghrelin and Glucagon-like peptide-1 concentrations) factors that could explain the previously reported association between the CLOCK 3111T/C SNP and obesity. Methods This cross-sectional study included 403 subjects, overweight and/or obesity, aged 20- 50 years from Iran. The CLOCK rs1801260 data were measured by the PCR-RFLP method. Dietary intake, food timing, sleep duration, appetite and Chrono-type were assessed using validated questionnaires. Ghrelin and GLP-1 were measured by radioimmunoassay in plasma samples. Participants were also divided into three groups based on rs1801260 genotype and BMI. Logistic regression models and general linear regression models were used to assess the association between CLOCK genotype and study parameters. Univariate linear regression models were used to assess the interaction between CLOCK and VAS, Food timing, chronotype and sleep on food intakes. Results After controlling for confounding factors, there was a significant difference between genotypes for physical activity (P=0.001), waist circumference (P˂0.05), BMI (˂0.01), weight (P=0.001), GLP-1 (P= 0.02), ghrelin (P= 0.04), appetite (P˂0.001), chronotype (P˂0.001), sleep (P˂0.001), food timing (P˂0.001), energy (P˂0.05), carbohydrate (P˂0.05) and fat intake (P˂0.001). Our findings also show that people with the minor allele C who ate lunch after 3 PM and breakfast after 9 AM are more prone to obesity (P˂0.05). furthermore, there was significant interactions between C allele carrier group and high appetite on fat intake (Pinteraction=0.041), eat lunch after 3 PM on energy intake (Pinteraction=0.039) and morning type on fat intake (Pinteraction=0.021). Conclusion Sleep reduction, changes in ghrelin and GLP-1 levels, changes in eating behaviors and evening preference that characterized CLOCK 3111C can all contribute to obesity. Furthermore, the data demonstrate a clear relationship between the timing of food intake and obesity. Our results support the hypothesis that the influence of the CLOCK gene may extend to a wide range of variables related to human behaviors.

Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation

Aim: The role of platelets in atherosclerosis remains incompletely understood. Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here we sought to investigate the contribution of platelet sGC to atherosclerosis and the therapeutic potential of targeting sGC in atherosclerosis. Methods and Results: We genetically deleted sGC in platelets of atherosclerosis-prone Ldlr-/- mice. By intravital fluorescence microscopy such Pf4-Cre+Gucy1b1flox/floxLdlr-/- mice displayed enhanced leukocyte adhesion to atherosclerotic plaques in comparison with their litter mates. Moreover, histological and flow cytometry analyses revealed more numerous inflammatory leukocytes and larger plaque sizes in aortic tissue of Ldlr-/- mice lacking sGC in platelets. In vitro, supernatant from activated platelets lacking sGC promoted leukocyte adhesion to endothelial cells (EC) via enhanced EC activation. Using cytokine profiling, we identified reduced angiopoietin-1 release by Pf4-Cre+Gucy1b1flox/flox and human GUCY1A1 risk allele carrier platelets to be responsible for enhanced activation of EC and subsequent leukocyte adhesion. Pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced recruitment of adoptively transferred leukocytes in Ldlr-/- mice fed a Western diet. Pharmacological sGC stimulation further reduced atherosclerotic plaque formation and vascular inflammation. Conclusion: Loss of sGC in platelets contributes to atherosclerotic plaque formation via reduced release of the soluble factor angiopoietin-1 and, subsequently, enhanced leukocyte recruitment. Pharmacological sGC stimulation might represent a novel therapeutic strategy to prevent and treat CAD.

Apolipoprotein E Genetic Variation and Its Association With Cognitive Function in Rural-Dwelling Older South Africans

Apolipoprotein E (APOE) 𝜀4 allele carrier status is well known for its association with an increased likelihood of developing Alzheimer’s disease, but its independent role in cognitive function is unclear. APOE genetic variation is understudied in African populations; hence, this cross-sectional study in a rural South African community examined allele and genotype frequencies, and their associations with cognitive function. Cognitive function was assessed using two different screening methods to produce a total cognition score and four domain-specific cognition scores for verbal episodic memory, executive function, language, and visuospatial ability. Cognitive phenotype and APOE genotype data were used to determine whether APOE variation was significantly associated with cognitive function in this population. Observed allele frequencies for 1776 participants from the HAALSI study [age 40–80years (mean=56.19); 58.2% female] were 58.1% (𝜀3), 25.4% (𝜀4) and 16.5% (𝜀2). Allele distributions were similar to the African super population, but different from all non-African super populations from the 1,000 Genomes Project. The 𝜀3 homozygous genotype was most common (34.9%) and used as the base genotype for comparison in regression models. Four models were tested for each of the five cognitive phenotypes to explore association of APOE variation with cognitive function. In the first model assessing association with all genotypes for all individuals, marginally significant associations were observed for 𝜀2 homozygotes where executive function scored higher by ~0.5 standard deviations (p=0.037, SE=0.23), and for 𝜀3/𝜀4 heterozygotes where visuospatial ability scores were lower (p=0.046, SE=0.14). These did not survive correction for multiple testing. Regional African population differences were observed at the APOE locus. Marginally, significant associations between APOE genotype, and executive function and visuospatial ability indicate the need for larger studies to better examine these associations in African populations. Furthermore, longitudinal data could shed light on APOE genetic association with rate of change, or decline, in cognitive function.

Variants of the cry 1 gene may influence the effect of fat intake on resting metabolic rate in women with overweight of obesity: a cross-sectional study

Background Previous studies have shown that the minor allele (C allele) for Cry 1 rs2287161, may be associated with increased risk of cardiovascular diseases (CVDs). Low resting metabolic rate (RMR) caused by the diet has been shown to have, potentially, unfavorable effects on obesity. This study sought to investigate the interactions between the Cry 1 Gene and fat intake on RMR in women with overweight of obesity. Methods This comparative cross-sectional study was conducted on 377 Iranian women with overweight of obesity. A food frequency questionnaire (FFQ), with 147 items, was used to assess dietary intake. Individuals were categorized into two groups based on the rs2287161 genotype. Body composition, dietary intake, and RMR were assessed for all participants. Results There was a significant difference between genotypes for fasting blood sugar (FBS) (P = 0.04), fat free mass (FFM) (P = 0.0009), RMR per FFM (P = 0.05), RMR per body mass index (BMI) (P = 0.02), and RMR deviation (P = 0.01). Our findings also showed significant interactions between total fat and C allele carrier group on RMR per kg body weight, RMR per body surface area (BSA), RMR per FFM, and RMR deviation (P for interaction < 0.1), in addition to a significant interaction between CC + CG group genotype and polyunsaturated fatty acids (PUFA) intake on RMR per BMI (P for interaction =0.00) and RMR per kg (P for interaction = 0.02) and RMR per BSA (P = 0.07), compared to the GG group, after control for confounder factors. Conclusion These results highlight that dietary compositions, gene variants, and their interaction, should be acutely considered in lower RMR.

False discovery rates for genome-wide association tests in biobanks with thousands of phenotypes

Biobanks housing genetic and phenotypic data for thousands of individuals introduce new opportunities and challenges for genetic association studies. Association testing across many phenotypes increases the multiple-testing burden and correlation between phenotypes makes appropriate multiple-testing correction uncertain. Moreover, analysis including low-frequency variants results in inflated type I error due to the much larger number of tests and the elevated importance of each individual minor allele carrier in those tests. Here we demonstrate that standard Bonferroni and permutation-based methods for multiple testing correction are inadequate for a holistic analysis of biobank data because ideal significance thresholds vary across datasets and minor allele frequencies. We propose a single-iteration permutation method that is computationally feasible and provides false discovery rate (FDR) estimates tailored to individual datasets and variant frequencies. Each dataset’s unique FDR estimates provide customized levels of confidence for association results and enable informed interpretation of genetic association studies across the phenome.

Antioxidative Defense Genes and Brain Structure in Youth Bipolar Disorder

Background Oxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD. Methods SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD=75; healthy controls (HC)=72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (ROI; prefrontal cortex (PFC), caudal anterior cingulate cortex (cACC), hippocampus) and for vertex-wise whole brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume area, and thickness analyses. Result ROI analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for cACC volume and surface area, and PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs. the HC GG genotype group. There was a significant BD diagnosis x GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs. the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions, related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group. Conclusion We found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structure in youth with BD, in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.

A genetic variant of the NAMPT gene rs4730153 as a risk factor for the metabolic syndrome in younger age: a single-centre pilot study in Yogyakarta, Indonesia

Background The genetic variation of nicotinamide phosphoribosyl transferase (NAMPT) gene rs4730153 is reported to be associated with cardiometabolic risk, but the results are inconsistent between populations. Ethnicity, metabolic risk and lifestyle play a role in the association of the genetic variant and the metabolic syndrome (MetS). To the best of our knowledge, no research has yet been published concerning the Javanese population, so this study aimed to investigate the association of rs4730153 with MetS and its interaction with metabolic risk and lifestyle. Results The GG genotype (p = 0.031; OR 95% CI 3.88 [1.13–13.33]), GA+GG genotype (p = 0.048; OR 95% CI 10.52 [1.02–108.01]) and G allele carrier (p = 0.006; OR 95% CI 4.19 [1.51–11.64]) of rs4730153 had a higher risk of the MetS after adjusting for obesity, hypercholesterolemia, smoking and food intake. The risk was statistically significant for the younger age group ≤ 45 years old. Conclusion The GG, GA+GG genotype and G allele carrier of rs4730153 have a higher risk of the MetS, especially those who are obese, hypercholesterolemic and smokers and have a higher food intake in those aged ≤ 45 years old. Further larger, multicentre studies are required to confirm these pilot results.