X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease.

BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.

Genetic Variants and Haplotypes of TOMM40, APOE, and APOC1 are Related to the Age of Onset of Late-onset Alzheimer Disease in a Colombian Population.

BACKGROUND: The Apolipoprotein E (APOE) gene is the main risk factor for late-onset Alzheimer disease (LOAD). Genetic variants and haplotypes in regions near the APOE locus may be associated with LOAD in the Colombian population. OBJECTIVE: We evaluated frequencies and risk of genetic variants and haplotypes in APOE, TOMM40, and APOC1 promoters, also in putative regulatory enhancer elements (TOMM40 IVS2-4 and TOMM40 IVS6), and in cis-regulatory elements (ME1 and BCR). MATERIALS AND METHODS: Our case-control association study was carried out in 50 patients with LOAD and 50 controls. We determined frequencies and odd ratios for genetic variants and haplotypes. RESULTS: We found a significant association between LOAD and genetic variants at the TOMM40 promoter, at TOMM40 IVS2-4 and TOMM40 IVS6 regulatory enhancer elements, and at the APOC1 promoter. Particularly, variants of Poly-T and APOC1 promoter could anticipate the age of onset of LOAD in our population. We identified three risk haplotypes in TOMM40 (ACGGAG, ACGGGG, and ATAGGC) related to LOAD's age of onset. We also found other risk or protection haplotypes at the TOMM40 and APOE promoters, at TOMM40 IVS2-4, TOMM40 IVS6 regulatory enhancer elements, and at ME1. CONCLUSION: Genetic variants and haplotypes near the APOE locus are related to LOAD risk and accelerated onset of LOAD in the Colombian population.

Genome-Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients.

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease. METHODS: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. RESULTS: Genome-wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69-10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10-7 ). CONCLUSIONS: We found that although overall genome-wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early-onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome-wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society.

ZNF718, HOXA4, and ZFP57 are differentially methylated in periodontitis in comparison with periodontal health: Epigenome-wide DNA methylation pilot study.

OBJECTIVE: To investigate the differences in the epigenomic patterns of DNA methylation in peripheral leukocytes between patients with periodontitis and gingivally healthy controls evaluating its functional meaning by functional enrichment analysis. BACKGROUND: The DNA methylation profiling of peripheral leukocytes as immune-related tissue potentially relevant as a source of biomarkers between periodontitis patients and gingivally healthy subjects has not been investigated. METHODS: A DNA methylation epigenome-wide study of peripheral leukocytes was conducted using the Illumina MethylationEPIC platform in sixteen subjects, eight diagnosed with periodontitis patients and eight age-matched and sex-matched periodontally healthy controls. A trained periodontist performed the clinical evaluation. Global DNA methylation was estimated using methylation-sensitive high-resolution melting in LINE1. Routine cell count cytometry and metabolic laboratory tests were also performed. The analysis of differentially methylated positions (DMPs) and differentially methylated regions (DMRs) was made using R/Bioconductor environment considering leukocyte populations assessed in both routine cell counts and using the FlowSorted.Blood.EPIC package. Finally, a DMP and DMR intersection analysis was performed. Functional enrichment analysis was carried out with the differentially methylated genes found in DMP. RESULTS: DMP analysis identified 81 differentially hypermethylated genes and 21 differentially hypomethylated genes. Importantly, the intersection analysis showed that zinc finger protein 718 (ZNF718) and homeobox A4 (HOXA4) were differentially hypermethylated and zinc finger protein 57 (ZFP57) was differentially hypomethylated in periodontitis. The functional enrichment analysis found clearly immune-related ontologies such as "detection of bacterium" and "antigen processing and presentation." CONCLUSION: The results of this study propose three new periodontitis-related genes: ZNF718, HOXA4, and ZFP57 but also evidence the suitability and relevance of studying leukocytes' DNA methylome for biological interpretation of systemic immune-related epigenetic patterns in periodontitis.

Differential Methylation Levels in CpGs of the BIN1 Gene in Individuals With Alzheimer Disease.

INTRODUCTION: Late-onset Alzheimer disease (LOAD) is the most common dementia worldwide. APOE-[Latin Small Letter Open E]4 and BIN1 (Bridging Integrator 1) have been implicated in the pathogenesis of this disease, but, although DNA methylation of dinucleotide CpGs in the BIN1 gene influences alterations, it has not been studied in Hispanics. OBJECTIVE: The objective of this study was to evaluate the BIN1 3' intergenic region DNA methylation patterns in a Colombian sample of LOAD patients. METHODS: A case-control study was conducted in 50 individuals with LOAD and 50 age-sex matched controls to determine associations of LOAD with DNA methylation. DNA was isolated from peripheral blood, and methylation levels of 8 CpGs were estimated by bisulfite conversion followed by Sanger sequencing with direct PCR analysis. Logistic regression models adjusted by age, sex, and APOE were used to calculate risk associations between methylation levels and LOAD. RESULTS: Overall, participants with LOAD had significantly lower methylation levels on CpG26 (0.86±0.11 vs. 0.95±0.05; P>0.001), CpG44 (0.84±0.09 vs. 0.94±0.06; P=0.001), and CpG87 (0.64±0.12 vs. 0.82±0.10; P>0.001). Adjusted regression models showed that decreased methylation levels of these CpGs remained as risk factors for LOAD (P<0.05). CONCLUSIONS: Hypomethylation of CpGs in BIN1 might play an important role in the expression of BIN1 and may be a biomarker for identifying individuals at high risk of developing LOAD.

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.

BACKGROUND: Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause. METHODS: We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants. RESULTS: Biallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function. CONCLUSION: Biallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.

Differential Methylation in APOE (Chr19; Exon Four; from 44,909,188 to 44,909,373/hg38) and Increased Apolipoprotein E Plasma Levels in Subjects with Mild Cognitive Impairment.

BACKGROUND: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the APOE gene and apolipoprotein E (ApoE) plasma levels as MCI biomarkers in Colombian subjects with MCI and controls. METHODS: In total, 100 participants were included (71% women; average age, 70 years; range, 43⁻91 years). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Using multivariate logistic regression models adjusted by age and gender, we examined the risk association of MCI with plasma ApoE and APOE methylation. RESULTS: MCI was diagnosed in 41 subjects (average age, 66.5 ± 9.6 years) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (p < 0.05). Higher CpG-227 methylation correlated with lower risk for MCI (p = 0.002). Only CpG-227 was significantly correlated with plasma ApoE levels (correlation coefficient = -0.665; p = 0.008). CONCLUSION: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns require confirmation in larger samples but could potentially be used as biomarkers to identify early stages of MCI.

The p.R47H Variant of TREM2 Gene is Associated With Late-onset Alzheimer Disease in Colombian Population.

OBJECTIVE: We evaluated the association of several single-nucleotide polymorphisms in the triggering receptor expressed on myeloid cells 2 (TREM2) gene in a Colombian sample of late-onset Alzheimer disease (LOAD). METHODS: The p.Q33* (rs104894002), p.R47H (rs75932628), p.R62H (rs143332484), and p.D87N (rs142232675) variants of TREM2 gene were directly genotyped using KASPar technology in 358 cases and 329 healthy controls. Sanger sequencing was used to validate >10% of KASPar's results. The Fisher exact test was used to compare the distribution of allelic and genotype frequency between cases and controls, and the Bonferroni correction was set at P<0.05. RESULTS: The minor allele frequency of rs75932628-T was 0.009 in cases and was not found in any healthy controls which suggests a significant association between rs75932628-T and LOAD risk in our sample (P=0.010). The rs143332484-T variant did not exhibit a significant association (P=0.160), whereas rs104894002 and rs142232675 were not found. CONCLUSIONS: Our findings suggest that the rs75932628-T variant of TREM2 is an important risk factor for LOAD in the Colombian population.

Association Analysis of Polymorphisms in TOMM40, CR1, PVRL2, SORL1, PICALM, and 14q32.13 Regions in Colombian Alzheimer Disease Patients.

OBJECTIVE: We evaluated the association of several single-nucleotide polymorphisms in different genes including APOE, TOMM40, CR1, PVRL2, SORL1, PICALM, and GWA_14q32.13 in a Colombian sample of Late-Onset Alzheimer disease (LOAD) patients. METHODS: A case-control study was conducted in 362 individuals (181 LOADs and 181 controls) to determine the association of single-nucleotide polymorphisms in APOE (e2, e3, and e4), TOMM40 (rs2075650), CR1 (rs665640), PVRL2 (rs6859), SORL1 (rs11218304), PICALM (rs3851179), and GWA_14q32.13 (rs11622883) with LOAD in a sample from Colombia. RESULTS: We were able to confirm the previously reported association of the APOE4 allele with AD. In addition, we report a new significant association with rs2075650 of TOMM40 for LOAD in our sample. We did not detect any significant interaction between TOMM40 and APOE4 carriers (heterozygous or homozygous) for disease risk development. However, Kaplan-Meier survival analyses suggest that AD patients with TOMM40 allele rs2075650-G have an average age of disease onset of 6 years earlier compared with carriers of the A allele. In addition, the age of disease onset is earlier if APOE4/4 is present. CONCLUSION: Our findings suggest that rs2075650 of TOMM40 could be involved in earlier presentation of LOAD in the Colombian population.

Common functional polymorphisms in SLC6A4 and COMT genes are associated with circadian phenotypes in a South American sample.

The molecular study of circadian rhythms in humans could be an excellent approach to understand the relation between genes and behavior. It is possible that variations in genes involved in neurotransmission and/or synaptic plasticity, such as catechol-O-methyltransferase (COMT) and serotonin transporter (SLC6A4) could be of particular interest in understanding human circadian phenotypes. The aim of this study is to analyze the possible and novel associations of the functional polymorphisms in COMT and SLC6A4 genes (Val158Met and 5-HTTLPR) and circadian phenotypes in healthy Colombian subjects. 191 university students were genotyped for two functional polymorphisms in COMT and SLC6A4 genes (rs4680 and rs4795541). We applied two scales to measure phenotypic patterns of human circadian rhythms: Composite Scale of Morningness (CSM) and Epworth Sleepiness Scale (ESS). We found a significant association between 5-HTTLPR polymorphism and morning preference score (CSM) (p = 0.027) using an overdominant genotypic model and association of COMT Val158Met with daytime sleepiness (ESS scores) (p = 0.038) in a genotypic recessive model. These results were supported by differences in genotype frequencies between circadian typologies for SLC6A4 gene (p = 0.007) and categories of diurnal sleepiness for COMT gene (p = 0.032). Our results suggest, for the first time, a significant relationship between functional SLC6A4 and COMT polymorphisms with specific human circadian phenotypes: morning preference and diurnal sleepiness. These results need to be replicated in other populations. Further study of functional polymorphisms in other synaptic genes could be of relevance for the identification of novel candidate genes for circadian phenotypes, and related endophenotypes of neuropsychiatric importance, in healthy humans.

Changes in Bacterial Gut Composition in Parkinson's Disease and Their Metabolic Contribution to Disease Development: A Gut Community Reconstruction Approach.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with the major symptoms comprising loss of movement coordination (motor dysfunction) and non-motor dysfunction, including gastrointestinal symptoms. Alterations in the gut microbiota composition have been reported in PD patients vs. controls. However, it is still unclear how these compositional changes contribute to disease etiology and progression. Furthermore, most of the available studies have focused on European, Asian, and North American cohorts, but the microbiomes of PD patients in Latin America have not been characterized. To address this problem, we obtained fecal samples from Colombian participants (n = 25 controls, n = 25 PD idiopathic cases) to characterize the taxonomical community changes during disease via 16S rRNA gene sequencing. An analysis of differential composition, diversity, and personalized computational modeling was carried out, given the fecal bacterial composition and diet of each participant. We found three metabolites that differed in dietary habits between PD patients and controls: carbohydrates, trans fatty acids, and potassium. We identified six genera that changed significantly in their relative abundance between PD patients and controls, belonging to the families Lachnospiraceae, Lactobacillaceae, Verrucomicrobioaceae, Peptostreptococcaceae, and Streptococcaceae. Furthermore, personalized metabolic modeling of the gut microbiome revealed changes in the predicted production of seven metabolites (Indole, tryptophan, fructose, phenylacetic acid, myristic acid, 3-Methyl-2-oxovaleric acid, and N-Acetylneuraminic acid). These metabolites are associated with the metabolism of aromatic amino acids and their consumption in the diet. Therefore, this research suggests that each individual's diet and intestinal composition could affect host metabolism. Furthermore, these findings open the door to the study of microbiome-host interactions and allow us to contribute to personalized medicine.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson Disease.

Sex differences in Parkinson Disease (PD) risk are well-known. However, it is still unclear the role of sex chromosomes in the development and progression of PD. We performed the first X-chromosome Wide Association Study (XWAS) for PD risk in Latin American individuals. We used data from three admixed cohorts: (i) Latin American Research consortium on the GEnetics of Parkinson's Disease (n=1,504) as discover cohort and (ii) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (iii) Bambui Aging cohort (n= 1,442) as replication cohorts. After developing a X-chromosome framework specifically designed for admixed populations, we identified eight linkage disequilibrium regions associated with PD. We fully replicated one of these regions (top variant rs525496; discovery OR [95%CI]: 0.60 [0.478 - 0.77], p = 3.13 × 10 -5 ; replication OR: 0.60 [0.37-0.98], p = 0.04). rs525496 is an expression quantitative trait loci for several genes expressed in brain tissues, including RAB9B, H2BFM, TSMB15B and GLRA4 . We also replicated a previous XWAS finding (rs28602900), showing that this variant is associated with PD in non-European populations. Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.

Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort.

BACKGROUND: Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts. METHODS: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort. RESULTS: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall. CONCLUSION: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts.

Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): report of three affected sibs.

The Wiedemann-Rautenstrauch syndrome (WRS) (OMIM 264090) is a rare progeroid entity. WRS patients are characterized by premature aging present at birth including pseudohydrocephalus, cranio-facial disproportion, reduced subcutaneous fat, thin skin, rigid and thick joints, and neonatal teeth in some cases. Here we describe three sibs with WRS from unaffected parents and without consanguinity. Our findings support autosomal recessive inheritance in WRS and support the possibility of homozygocity mapping as a good approach to find the causative gene.

Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.

Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration.

The present review explores the role of ceramides in neuronal apoptosis, as well as the recent discovery of the signaling pathways involved in this process placing particular emphasis on the correlation between cellular metabolism and neuronal death. Endogenous levels of ceramides are increased following various pro-apoptotic stimuli which have been identified as potential causes of chronic and acute neurodegenerative diseases. Ceramides induce changes in multiple enzymes and cell signaling components. The early inhibition of the neuronal survival pathway regulated by phosphatidil-inositol-3-kinase/protein kinase B or AKT mediated by ceramide may be a relevant early event in the decision of neuronal survival/death. It may perturb several molecular and metabolic functions. In particular it might decrease glycolysis through rapid modulation of hexokinase activity. This would in turn generate limited amounts of mitochondrial substrates leading to mitochondrial dysfunction and neuronal apoptosis. Subtle and early metabolic alterations caused by inhibition of the PI3K/AKT pathway mediated by ceramide may potentially work with genes associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Together they may be determinant steps in downstream events leading to neuronal apoptosis. Therefore, reinforcement of the PI3K/AKT pathway could constitute an important neuroprotective strategy.

Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis.

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD.

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts.

Recently, mutations in the RNA polymerase III subunit A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A has important roles in transcription regulation of small RNAs, including tRNA, 5S rRNA, and 7SK rRNA. We aim to describe the cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control patient were cultured in vitro. The mutation caused a decrease in the expression of wildtype POLR3A mRNA and POLR3A protein and a sharp increase in mutant protein expression. In addition, there was an increase in the nuclear localization of the mutant protein. These changes were associated with an increase in the number and area of nucleoli and to a high increase in the expression of pP53 and pH2AX. All these changes were associated with premature senescence. The present observations add to our understanding of the differences between Hutchinson-Gilford progeria syndrome and WRS and opens new alternatives to study cell senesce and human aging.

Nighttime Blood Pressure Interacts with APOE Genotype to Increase the Risk of Incident Dementia of the Alzheimer's Type in Hispanics.

BACKGROUND: Dementia of the Alzheimer's type (DAT) impacts Hispanics disproportionately, with almost a twofold elevated risk of developing DAT, as well as earlier onset of the disease, than in non-Hispanic Whites. However, the role of main risk factors for DAT, such as APOE-ɛ4 and blood pressure (BP) levels, remains uncertain among Hispanics. OBJECTIVE: To investigate the association of APOE-ɛ4 and BP levels, measures with 24-h ambulatory BP monitoring, with incidence of DAT in an elderly cohort of Hispanics. METHODS: 1,320 participants from the Maracaibo Aging Study, free of dementia at the baseline, and with ambulatory BP measurements and APOE genotype available were included. Adjusted Cox proportional models were performed to examine 1) the incidence of DAT and 2) the relationship between BP levels and DAT according to APOE genotypes. Models were adjusted by competing risk of death before the onset of DAT. Model performance was assessed by likelihood test. RESULTS: The average follow-up time was 5.3 years. DAT incidence was 5.8 per 1000 person-year. APOE-ɛ4 carriers had a higher risk of DAT. In unadjusted analyses, conventional, 24-h, and nighttime systolic BP levels were significantly higher in participants who developed DAT and of APOE-ɛ4 carriers (p < 0.05). After adjustment for competing risks, only higher nighttime systolic BP was associated with DAT incidence, but only among subjects carrying APOE-ɛ4. CONCLUSION: In this Hispanic population, both APOE-ɛ4 genotype and assessment of nocturnal systolic BP (rather than diurnal or office BP) were necessary to estimate DAT risk.