The Syntaxin-1A gene single nucleotide polymorphism rs4717806 associates with the risk of ischemic heart disease

Ischemic heart disease (IHD) has a genetic predisposition and a number of cardiovascular risk factors are known to be affected by genetic factors. Development of metabolic syndrome and insulin resistance, strongly influenced by lifestyle and environmental factors, frequently occur in subjects with a genetic susceptibility. The definition of genetic factors influencing disease susceptibility would allow to identify individuals at higher risk and thus needing to be closely monitored.To this end, we focused on a complex of soluble-N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), playing an important role in metabolic syndrome and insulin resistance, involved in endothelial dysfunction and heart disease. We assessed if genetic variants of the SNARE genes are associated with IHD.SNAP25 rs363050, Stx-1A rs4717806, rs2293489, and VAMP2 26bp ins/del genetic polymorphisms were analyzed in a cohort of 100 participants who underwent heart surgery; 56 of them were affected by IHD, while 44 were not. A statistical association of plasma glycemia and insulin resistance, calculated as Triglyceride glucose (TyG) index, was observed in IHD (P<.001 and P=.03, respectively) after binomial logistic stepwise regression analysis, adjusted by age, gender, diabetes positivity, waist circumference, and cholesterol plasma level. Among genetic polymorphisms, rs4717806(A) and rs2293489(T), as well as the rs4717806 - rs2293489 (A-T) haplotype were associated with higher risk for IHD (Pc=.02; Pc=.02; P=.04, respectively). Finally, a statistical association of rs4717806(AA) genotype with higher TyG index in IHD patients (P=.03) was highlighted by multiple regression analysis considering log-transformed biochemical parameters as dependent variable and presence of coronary artery disease, age, gender, waist circumference, presence of diabetes as predictors. These results point to a role of the Stx-1A rs4717806 SNP in IHD, possibly due to its influence on Stx-1A expression and, as a consequence, on insulin secretion and glucose metabolism

The evolutionary history of genes involved in spoken and written language : Beyond FOXP2

Humans possess a communication system based on spoken and written language. Other animals can learn vocalization by imitation, but this is not equivalent to human language. Many genes were described to be implicated in language impairment (LI) and developmental dyslexia (DD), but their evolutionary history has not been thoroughly analyzed. Herein we analyzed the evolution of ten genes involved in DD and LI. Results show that the evolutionary history of LI genes for mammals and aves was comparable in vocal-learner species and non-learners. For the human lineage, several sites showing evidence of positive selection were identified in KIAA0319 and were already present in Neanderthals and Denisovans, suggesting that any phenotypic change they entailed was shared with archaic hominins. Conversely, in FOXP2, ROBO1, ROBO2, and CNTNAP2 non-coding changes rose to high frequency after the separation from archaic hominins. These variants are promising candidates for association studies in LI and DD

HLA alleles modulate EBV viral load in multiple sclerosis

Background: The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular, are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS. Methods: HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89). Results: Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution. Conclusions: Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS

REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human primates

The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration

BDNF rs6265 polymorphism methylation in Multiple Sclerosis: A possible marker of disease progression

Introduction Brain-Derived Neurotrophic Factor (BDNF) and its most common polymorphism Val66Met are known to have a role in Multiple Sclerosis (MS) pathogenesis. Evidence is accumulating that there is an involvement of DNA methylation in the regulation of BDNF expression. The aim of this study was to assess in blood samples of MS patients the correlation between the methylation status of the CpG site near BDNF-Val66Met polymorphism and the severity of the disease. Methods We recruited 209 MS patients that were genotyped for the BDNF Val66Met polymorphism. For each patient we quantitatively measured the methylation level of cytosine included in the exonic CpG site that can be created or abolished by the Val66Met BDNF polymorphism. Furthermore, we analyzed the clinical history of each patient and determined the time elapsed since the onset of the disease and an EDSS score of 6.0. Results The genetic analysis identified 122 (58.4%) subjects carrying the Val/Val genotype, 81 (38.8%) with Val/Met genotype, and 6 (2.8%) carrying the Met/Met genotype. When the endpoint of an EDSS score of 6 was taken into account by means of a survival analysis, 52 failures (i.e., reaching an EDSS score of 6) were reported. When the sample was stratified according to the percentage of the BDNF methylation, subjects falling below the median (median methylation = 81%) were at higher risk of failure (IRD = 0.016; 95%CI = 0.0050- 0.0279; p = 0.004). Conclusions In patients with a high disease progression the hypomethylation of the BDNF gene could increase the secretion of the protective neurotrophin, so epigenetic modifications could be the organism response to limit a brain functional reserve loss. Our study suggests that the percentage of methylation of the BDNF gene could be used as a prognostic factor for disease progression toward a high disability in MS patient

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

OBJECTIVE: to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients. METHODS: We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed. RESULTS: HLA-DRB1*15 is associated with OCB+: p\u200a=\u200a0.03, Odds Ratio (OR)\u200a=\u200a1.6, 95% Confidence Limits (CL)\u200a=\u200a1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p\u200a=\u200a0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p\u200a=\u200a9.4 710(-7)) outside the HLA region (65 Mb). DISCUSSION: genetic factors predispose to the development of OCB

SNAP-25 in Serum Is Carried by Exosomes of Neuronal Origin and Is a Potential Biomarker of Alzheimer&apos;s Disease

A loss of synaptic density and connectivity is observed in multiple brain regions of Alzheimer's disease (AD) patients, resulting in a reduced expression of synaptic proteins such as SNAP-25 (synaptosomal-associated-protein-25). SNAP-25 alterations thus could be an index of the degree of synaptic degeneration in the central nervous system (CNS). We isolated from serum of both AD patients and healthy controls (HC) a population of neuron-derived exosomes (NDEs) and measured the concentrations of SNAP-25 contained in such NDEs. The levels of SNAP-25 carried by NDEs were reduced in AD patients (mean 459.05\ua0ng/ml, SD 146.35\ua0ng/ml) compared to HC (mean 686.42\ua0ng/ml, SD 204.08\ua0ng/ml) (p\u2009<\u20090.001). As a further confirmation of these results, ROC (receiver operating characteristic) analyses indicated that the level of SNAP-25 carried by NDEs has the power to discriminate between AD and HC (AUC\u2009=\u20090.826, sensitivity\u2009=\u200987.5%, specificity\u2009=\u200970.6%, p\u2009<\u20090.0001, cut-off value 587.07\ua0ng/ml). Notably, a correlation between the levels of SNAP-25 carried by NDEs and levels and cognitive status measured by MMSE score (r\u2009=\u20090.465, 95% CI 0.11 to 0.714, p\u2009=\u20090.01) was detected. This is the first report of SNAP-25 measurement in serum. These data suggest that NDE-carried SNAP-25 could be an effective and accessible biomarker that reflects synapses integrity in the brain