A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid ß (Aß) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aß application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aß(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.

Ubiquitin carboxyl-terminal esterase L1 (UCHL1) S18Y polymorphism in patients with cataracts.

BACKGROUND: Cataract is characterized by light-scattering protein aggregates. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. A protective role of the p.S18Y polymorphism of the UCHL1 gene has been shown in Parkinson`s disease. The current study aimed to examine possible effects on cataract formation. METHODS: Patients with cataract (n = 493) and controls (n = 142) were analyzed for the UCHL1 p.S18Y polymorphism using dynamic allele-specific hybridization. RESULTS: Significant differences were observed in allele and genotype frequencies of the p.S18Y polymorphism between controls and cataract patients, where a positive UCHL1 allele A carrier status was associated with the cataract diagnosis (adjusted OR 1.7 [95% CI = 1.1-2.6] p = 0.02). No significant differences were seen in genotype distribution when stratifying for type of cataract. Nor did the mean age at cataract surgery differ between genotypes. CONCLUSION: The current study does not support a protective role for the UCHL1 S18Y polymorphism in cataract development, but may instead suggest a disease-promoting effect.

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE epsilon4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD.

No association of VEGF polymorphims with Alzheimer's disease.

The vascular hypothesis of Alzheimer's disease (AD) has brought the vascular endothelial growth factor (VEGF) into focus. The genomic region including the VEGF gene has been linked to AD and single nucleotide polymorphisms (SNPs) of the VEGF have in previous studies been associated with AD risk. To further evaluate these findings, we genotyped two SNPs in the VEGF gene (rs699947 [-2578]) and rs1570360 [-1154]) by TaqMan Allelic Discrimination in a study sample including AD patients (n = 801) and controls (n = 286). In a subgroup of the population these SNPs were analyzed in relation to APOE epsilon4 genotype, to cerebrospinal fluid biomarkers (T-tau, P-tau, and beta(42)-Amyloid) as well as to neuropathological markers for AD (neurofibrillary tangles and senile plaques). No significant associations with risk for AD or any of the studied biomarkers could be found in this study, thus not supporting VEGF as being a major risk gene for AD.

Association of complement factor H Y402H gene polymorphism with Alzheimer's disease.

Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several epidemiological and biochemical features. The present study aimed to assess the possible influence of the AMD-associated complement factor H (CFH) Y402H (1277T > C) polymorphism on the risk of AD. Caucasian subjects (n = 800) meeting the criteria for probable (n = 717) or definite (n = 83) AD and Caucasian non-demented controls (n = 1265) were included in this multi-center case-control study, in which genotype and allele frequencies of the CFH 1277T > C polymorphism were determined and related to diagnosis, APOE genotype, Mini-Mental State Examination score (MMSE) and the cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phospho-tau(181) (P-tau(181)), and beta-amyloid(1-42) (Abeta(1-42)). The AMD-associated CFH genotypes (1277CC and 1277TC) were overrepresented in subjects with AD as compared to control individuals (P = 0.029). Positive C carrier status was associated with an odds ratio (OR) for AD of 1.24 (95% confidence interval [CI] 1.02-1.50). When APOE epsilon4 carrier status was included in the regression model, this association was even stronger (OR 1.34, 95% CI: 1.08-1.65, P = 0.007). Subgroup analysis showed that the association between CFH C allele positivity and AD was only evident for individuals carrying the APOE epsilon4 allele. Positive C carrier status was also associated with lower levels of CSF Abeta(1-42) selectively in the control group in an APOE epsilon4-independent manner (P = 0.003). In conclusion, the CFH 1277T > C polymorphism seems to influence the risk of AD and there appears to be an interaction between CFH 1277C and APOE epsilon4 alleles. The CFH 1277C allele may predispose patients for co-morbidity in AD and AMD.

Methylenetetrahydrofolate reductase genetic polymorphisms in patients with primary open-angle glaucoma.

PURPOSE: Hyperhomocysteinemia has been found in patients with primary open-angle glaucoma. The purpose of the present study was to determine if hyperhomocysteinemia-associated polymorphisms of the methylenetetrahydrofolate reductase gene (MTHFR) are overrepresented in primary open-angle glaucoma. METHODS: Patients with primary open-angle glaucoma (n = 243) and controls (n = 187) were analyzed for the MTHFR 677 C > T and 1298 A > C polymorphisms using minisequencing technique. RESULTS: No significant differences were observed in allele and genotype frequencies of the MTHFR 677C > T and 1298A > C polymorphisms between controls and the primary open-angle glaucoma group. CONCLUSIONS: If hyperhomocysteinemia is important in the pathogenesis of glaucoma, this study does not support a role for MTHFR polymorphisms in this context.

Apolipoprotein E polymorphisms in patients with primary open-angle glaucoma.

PURPOSE: To investigate apolipoprotein E (APOE) polymorphisms, which are known to influence the risk of Alzheimer disease (AD), in patients with primary open-angle glaucoma (POAG). DESIGN: Retrospective case-control association study. METHODS: Patients with POAG (n = 242) and controls (n = 187) were analyzed for the APOE epsilon 2/epsilon 3/epsilon 4 polymorphisms using minisequencing technique. RESULTS: The Alzheimer-associated APOE epsilon 4 allele had similar frequencies in the POAG group and in the control group. There was no difference between cases and controls with regard to APOE genotypes. CONCLUSIONS: If a common pathogenic mechanism exists for the two age-related neurodegenerative diseases, POAG and AD, it does not involve APOE polymorphisms.