Association of vitamin D receptor gene TaqI polymorphism with Alzheimer's disease in a Southeastern European Caucasian population.

The role of vitamin D in Alzheimer's Disease (AD) has been studied over the past years. The results from numerous studies have indicated that the molecular pathways involved in the development of AD are closely related to the molecular pathways of the mechanisms of action of vitamin D. However, only a limited number of studies have described the key role of vitamin D receptor (VDR) in the regulation of the functions of vitamin D and the potential effect of single nucleotide polymorphisms (SNPs) of the VDR gene. Thus, the aim of the present study was to investigate the VDR TaqI polymorphism in relation to AD in a Southeastern European Caucasian (SEC) cohort. Further, the present study aimed to compare the results obtained with those of other AD populations. For this purpose, blood samples from 90 confirmed patients with AD [median age, 74 years; median mini-mental state examination (MMSE) score of 21; median frontal assessment battery (FAB) score of 10] and 103 healthy controls (median age, 57 years) were analyzed to determine the genotypes of TaqI (rs731236) using quantitative PCR. The frequencies (%) of the TaqI TT, TC and CC genotypes in the controls/patients were 34/48.9, 47.6/41.1 and 18.4/10.0, respectively. Statistically significant differences were observed for the TaqI C allele [odds ratio (OR). 0.54; 95% confidence interval (CI), 0.30-0.96; P=0.035], the TaqI TT genotype (OR, 1.86; 95% CI, 1.04-3.32; P=0.035) and the TaqI CC genotype (OR, 0.119; 95% CI, 0.014-0.995; P=0.032,) in relation to the MMSE score <21 in the patient's group. The TaqI TT allele was found to increase the risk of developing AD by 1.86-fold in the SEC population, while the TaqI C allele may act protectively, with a 46% lower risk of developing the disease. Patients with the TaqI CC genotype were found to have an 88% less likelihood of developing severe cognitive impairment based on the MMSE score. On the whole, the present study did not confirm the results of previous studies on the VDR TaqI C allele in patients with AD.

Association of vitamin D receptor gene haplotypes with late-onset Alzheimer's disease in a Southeastern European Caucasian population.

Vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) have been investigated over the past years with the aim of identifying any association with the development of Alzheimer's disease (AD). However, information regarding the potential association of VDR SNP haplotypes with AD is limited. The aim of the present study was to provide additional knowledge on the effects of VDR haplotypes on the development of late-onset AD in a cohort of Southeastern European Caucasians (SECs). The study sample included 78 patients with late-onset AD and 103 healthy subjects as the control group. VDR SNPs that were analyzed were TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570). The CAC (TaqI, BsmI and FokI) haplotype was found to be associated with a 53% lower risk of developing the disease (OR, 0.47; 95% CI, 0.23-0.96; P=0.04) and the TAC (TaqI, BsmI and FokI) haplotype was associated with an ~6-fold greater risk of developing AD (OR, 6.19; 95% CI, 1.91-20.13; P=0.0028). Female subjects carrying the TAC haplotype had a ~9-fold greater risk of developing AD in comparison to female control subjects (OR, 9.27; 95% CI, 1.86-46.28; P<0.05). The TaqI and BsmI polymorphisms were in high linkage disequilibrium (D'=0.9717, r=0.8467) and produced a haplotype with a statistically significant different frequency between the control and AD group. The TA (TaqI and BsmI) haplotype was associated with an ~8-fold greater risk of developing AD (OR, 8.27; 95% CI, 2.70-25.28; P<0.05). Female TA carriers had an ~14-fold greater risk of developing the disease in comparison to female control subjects (OR, 13.93; 95% CI, 2.95-65.87; P<0.05). On the whole, the present study demonstrates that in the SEC population, TAC and TA are risk haplotypes for AD, while the CAC haplotype may act protectively. SEC women carrying the TAC or TA haplotype are at a greater risk of developing AD, thus suggesting that women are markedly affected by the poor utilization of vitamin D induced by the VDR haplotype.

APOE Allele Frequency in Southern Greece: Exploring the Role of Geographical Gradient in the Greek Population.

BACKGROUND: the apolipoprotein e4 allele (APOE4) constitutes an established genetic risk factor for Alzheimer's Disease Dementia (ADD). We aimed to explore the frequency of the APOE isoforms in the Greek population of Southern Greece. METHODS: peripheral blood from 175 Greek AD patients, 113 with mild cognitive impairment (MCI), and 75 healthy individuals. DNA isolation was performed with a High Pure PCR Template Kit (Roche), followed by amplification with a real-time qPCR kit (TIB MolBiol) in Roche's Light Cycler PCR platform. RESULTS: APOE4 allele frequency was 20.57% in the ADD group, 17.69% in the MCI group, and 6.67% in the control group. APOE3/3 homozygosity was the most common genotype, while the frequency of APOE4/4 homozygosity was higher in the AD group (8.60%). APOE4 carrier status was associated with higher odds for ADD and MCI (OR: 4.49, 95% CI: [1.90-10.61] and OR: 3.82, 95% CI: [1.59-9.17], respectively). CONCLUSION: this study examines the APOE isoforms and is the first to report a higher APOE frequency in MCI compared with healthy controls in southern Greece. Importantly, we report the occurrence of the APOE4 allele, related to ADD, as amongst the lowest globally reported, even within the nation, thus enhancing the theory of ethnicity and latitude contribution.

TARDBP p.I383V, a recurrent alteration in Greek FTD patients.

BACKGROUND: A significant proportion of FTD (Frontotemporal Degeneration) cases can be attributed to mutations in major genes such as GRN, MAPT and C9orf72. Our previous report on a Greek FTD cohort revealed the presence of the single nucleotide polymorphism (SNP) p.I383V (rs80356740) in the TARDBP gene in three unrelated patients. Our objective was to develop a novel, fast and accurate method for the detection of this particular SNP and evaluate the assay in a larger cohort. METHODS AND RESULTS: A real-time qPCR-melting curve analysis method was developed, validated and tested in 142 FTD patients and 111 healthy control subjects. The SNP was detected in another two patients raising its yield in FTD patients to 3.5% (5 out of 142 patients) while one in 111 healthy controls was found to be a carrier. However, its frequency in the general population has been reported extremely low in international SNP databases (0.002%). CONCLUSION: This fact along with the indicated pathogenicity of this SNP in some bioinformatics tools, suggest that TARDBP p.I383V is recurrent and likely pathogenic for the Greek FTD population. Our high-throughput method could be used for genotyping in other larger patient cohorts and in other populations. Additionally, functional in vitro studies are required for the final adjudication of this TARDBP alteration as a pathogenic alteration.

Inappropriate Use of Public Hospitals Emergency Departments in Greece: Magnitude and Associated Factors.

The aim of this study was to evaluate the appropriateness of use of the Emergency Departments (EDs) and to identify the reasons for inappropriate use. A study with 805 patients visiting the EDs of four large-scale public hospitals in Athens was conducted using the Hospital Urgencies Appropriateness Protocol (HUAP). 38.1% of the visits (n=307) were estimated as inappropriate, due to several reasons such as increased confidence in hospital rather than primary care services/patients' expectation for improved care in EDs (46.6%), convenience/proximity to patient's residence (44.6%) etc. Ageing, Greek nationality and insurance coverage were related with the appropriate use of EDs (p<0.001, p=0.04 and p=0.005, respectively). The identified distortions must be tackled so as to mitigate ED crowding, waste of resources and increase quality and responsiveness of care.

Frontotemporal dementia spectrum: first genetic screen in a Greek cohort.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1. We also identified 14 variants of unknown significance in other rarer FTD or amyotrophic lateral sclerosis genes that require further segregation and functional analysis. Our genetic screen revealed a high genetic burden in familial Greek FTD cases (30.4%), whereas only two of the sporadic cases (3.5%) carried a likely pathogenic variant. A substantial number of familial cases still remain without an obvious causal variant, suggesting the existence of other FTD genetic causes besides those currently screened in clinical routine.