Research on aging during the Venezuelan humanitarian crisis: the experience of the Maracaibo aging study.

BACKGROUND: Venezuela is in the throes of a complex humanitarian crisis that is one of the worst in decades to impact any country outside of wartime. This case analysis describes the challenges faced by the ongoing Maracaibo Aging Study (MAS) during the deteriorating conditions in Venezuela. When the MAS began in 1997, it focused on memory-related disorders. Since then, strategic planning and proactive community participation allowed us to anticipate and address logistical, funding, and ethical challenges, and facilitated the enrollment and retention of more than 2500 subjects over 55 years of age. All participants, who are residents of the city of Maracaibo, Venezuela, underwent various assessments on several occasions. Here, we discuss how our approach to implementing a longitudinal, population-based study of age-related conditions has allowed our research program to continue throughout this period of political, economic, and social upheaval. DISCUSSION: As the social context in Venezuela became more complicated, new challenges emerged, and strategies to sustain the study and participation were refined. We identified five main mechanisms through which the evolving humanitarian crisis has affected implementation of the MAS: 1) community dynamics; 2) morale of researchers, staff, and participants; 3) financial feasibility; 4) components of the research process; and 5) impact on the health of staff, participants, and their families. Strategies to compensate for the impact on these components were implemented, based on inputs from community members and staff. Improved communication, greater involvement of stakeholders, broadening the scope of the project, and strengthening international collaboration have been the most useful strategies. Particular demands emerged, related to the increased mortality and comorbidities of participants and staff, and deterioration of basic services and safety. CONCLUSION: Although the MAS has faced numerous obstacles, it has been possible to continue a longitudinal research project throughout the humanitarian crisis, because our research team has engaged the community deeply and developed a sense of mutual commitment, and also because our project has provided funding to help keep researchers employed, somewhat attenuating the brain drain.

Associations of increased physical performance and change in body composition with molecular pathways of heart disease and diabetes risk.

Higher physical activity is associated with a reduced hazard for a plethora of diseases. It has remained unknown how the two primary physical activity-associated health effects, improved physical performance and change in body composition, independently modulate metabolic profiles toward a reduced risk for adverse outcomes. Here, we utilized a prospective cohort of 664 young men undergoing military service. We studied the metabolic associations of changes in muscle performance and body composition during military service (range 6-12 mo). We subsequently replicated our results for body composition change in 234 population-based samples with a 7-yr follow-up. We found that increased physical performance was associated with reduced very-low-density lipoprotein (VLDL)-related measures [change in VLDL cholesterol: beta = -0.135; 95% confidence interval (CI) = -0.217, -0.054, P = 1.2 × 10-3] and lower inflammation (change in glycoprotein acetyls: beta = -0.138, 95% CI = -0.217, -0.059, P = 6.5 × 10-4), independent of change in body composition. Lower body fat percentage, independent of change in muscle performance, was associated with metabolic changes including lower low-density lipoprotein (LDL) cholesterol measures (change in LDL cholesterol: beta = -0.193, 95% CI = -0.295, -0.090; P = 2.5 × 10-4), increased high-density lipoprotein (HDL) cholesterol measures (change in large HDL cholesterol: beta = 0.316, 95% CI = 0.205, 0.427; P = 3.7 × 10-8), and decreased concentrations of amino acids (change in leucine concentration: beta = -0.236, 95% CI = -0.341, -0.132; P = 1.0 × 10-5) that are type 2 diabetes biomarkers. Importantly, all body fat percentage associations were replicated in a general population-based cohort. Our findings indicate that improved muscle performance showed weaker associations on the metabolic profiles than change in body composition and reduction in body fat percentage reduces cardiometabolic risk mediated by atherogenic lipoprotein particles and branched-chain and aromatic amino acid concentrations.

Glaucomatous Optic Neuropathy Associated with Nocturnal Dip in Blood Pressure: Findings from the Maracaibo Aging Study.

PURPOSE: To determine which nocturnal blood pressure (BP) parameters (low levels or extreme dipper status) are associated with an increased risk of glaucomatous damage in Hispanics. DESIGN: Observational cross-sectional study. PARTICIPANTS: A subset (n = 93) of the participants from the Maracaibo Aging Study (MAS) who met the study eligibility criteria were included. These participants, who were at least 40 years of age, had measurements for optical tomography coherence, visual field (VF) tests, 24-hour BP, office BP, and intraocular pressure <22 mmHg. METHODS: Univariate and multivariate logistic regression analyses under the generalized estimating equations (GEE) framework were used to examine the relationships between glaucomatous damage and BP parameters, with particular attention to decreases in nocturnal BP. MAIN OUTCOME MEASURES: Glaucomatous optic neuropathy (GON) based on the presence of optic nerve damage and VF defects. RESULTS: The mean age was 61.9 years, and 87.1% were women. Of 185 eyes evaluated, 19 (26.5%) had signs of GON. Individuals with GON had significantly lower 24-hour and nighttime diastolic BP levels than those without. However, results of the multivariate GEE models indicated that the glaucomatous damage was not related to the average systolic or diastolic BP levels measured over 24 hours, daytime, or nighttime. In contrast, extreme decreases in nighttime systolic and diastolic BP (>20% compared with daytime BP) were significant risk factors for glaucomatous damage (odds ratio, 19.78 and 5.55, respectively). CONCLUSIONS: In this population, the link between nocturnal BP and GON is determined by extreme dipping effects rather than low nocturnal BP levels alone. Further studies considering extreme decreases in nocturnal BP in individuals at high risk of glaucoma are warranted.

Incidence of dementia in elderly Latin Americans: Results of the Maracaibo Aging Study.

INTRODUCTION: There are few longitudinal studies of dementia in developing countries. We used longitudinal data from the Maracaibo Aging Study to accurately determine the age- and sex-specific incidence of dementia in elderly Latin Americans. METHODS: The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) was used to diagnose dementia, which was classified as Alzheimer's disease, vascular dementia, or other. Age- and sex-specific incidence was estimated as the number of new cases of dementia divided by person-years (p-y) of follow-up. RESULTS: The incidence of all dementia diagnoses was 9.10 per 1000 p-y (95% confidence interval [CI] 7.13-11.44; 8026 total p-y), 5.18 for Alzheimer's disease (95% CI 3.72-7.03; 7916 total p-y), and 3.35 for vascular dementia (95% CI 2.19-4.91; 7757 total p-y). DISCUSSION: Among Maracaibo Aging Study participants younger than 65 years, the incidence of dementia was higher than that of US Whites. Among individuals older than 65 years, the incidence was comparable to the mean of previous incidence estimates for other populations worldwide.

PSEUDOMARKER 2.0: efficient computation of likelihoods using NOMAD.

BACKGROUND: PSEUDOMARKER is a software package that performs joint linkage and linkage disequilibrium analysis between a marker and a putative disease locus. A key feature of PSEUDOMARKER is that it can combine case-controls and pedigrees of varying structure into a single unified analysis. Thus it maximizes the full likelihood of the data over marker allele frequencies or conditional allele frequencies on disease and recombination fraction. RESULTS: The new version 2.0 uses the software package NOMAD to maximize likelihoods, resulting in generally comparable or better optima with many fewer evaluations of the likelihood functions. CONCLUSIONS: After being modified substantially to use modern optimization methods, PSEUDOMARKER version 2.0 is more robust and substantially faster than version 1.0. NOMAD may be useful in other bioinformatics problems where complex likelihood functions are optimized.

Association of Variability and Hypertensive Loads in 24-h Blood Pressure With Mortality and Cardiovascular Risk.

BACKGROUND: Evidence shows that high 24-h blood pressure (BP) variability increases cardiovascular risk. We investigated whether 24-h BP variability relates to mortality and cardiovascular risk due to inherent variability and/or hypertensive loads in 24-h BP. METHODS: A total of 1,050 participants from the Maracaibo Aging Study (mean age, 66 years; women, 67.2%) underwent 24-h ambulatory BP monitoring and were followed between 2001 and 2016. To evaluate inherent BP variability, we used average real variability (ARV) as it captures variability among consecutive BP readings. 24-h systolic BP load was the proportion (%) of systolic BP readings ≥130 mm Hg during the daytime and ≥110 during the nighttime. Our primary endpoint was total mortality and major adverse cardiovascular endpoints (MACE). Statistics included Cox proportional models. RESULTS: During a median follow-up of 8.3 years, 299 participants died and 210 experienced MACE. Each +2 mm Hg (corresponding to 1-standard deviation) higher 24-h systolic ARV (mean value, 9.0 ±â€…2.0 mm Hg) was associated with higher hazard ratios (HRs) for mortality by 1.28-fold (95% confidence interval [CI], 1.14-1.43) and for MACE by 1.24-fold (95% CI, 1.08-1.42). Each 30% higher 24-h systolic BP load (median value, 63%) was associated with mortality and MACE with HRs of 1.29 (95% CI, 1.15-1.46) and 1.28 (95% CI, 1.10-1.48); respectively. After models were additionally adjusted by BP level, only ARV was associated with mortality (HR, 1.17; 95% CI, 1.04-1.33) and MACE (HR, 1.16; 95% CI, 1.00-1.34). CONCLUSIONS: High ARV and hypertensive loads in 24-h systolic BP were associated with mortality and cardiovascular risk, however, only ARV is associated independently of the BP level.

Transcriptome profiling and analysis of patients with esophageal squamous cell carcinoma from Kazakhstan.

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer in Central Asia, often diagnosed at advanced stages. Understanding population-specific patterns of ESCC is crucial for tailored treatments. This study aimed to unravel ESCC's genetic basis in Kazakhstani patients and identify potential biomarkers for early diagnosis and targeted therapies. ESCC patients from Kazakhstan were studied. We analyzed histological subtypes and conducted in-depth transcriptome sequencing. Differential gene expression analysis was performed, and significantly dysregulated pathways were identified using KEGG pathway analysis (p-value < 0.05). Protein-protein interaction networks were constructed to elucidate key modules and their functions. Among Kazakhstani patients, ESCC with moderate dysplasia was the most prevalent subtype. We identified 42 significantly upregulated and two significantly downregulated KEGG pathways, highlighting molecular mechanisms driving ESCC pathogenesis. Immune-related pathways, such as viral protein interaction with cytokines, rheumatoid arthritis, and oxidative phosphorylation, were elevated, suggesting immune system involvement. Conversely, downregulated pathways were associated with extracellular matrix degradation, crucial in cancer invasion and metastasis. Protein-protein interaction network analysis revealed four distinct modules with specific functions, implicating pathways in esophageal cancer development. High-throughput transcriptome sequencing elucidated critical molecular pathways underlying esophageal carcinogenesis in Kazakhstani patients. Insights into dysregulated pathways offer potential for early diagnosis and precision treatment strategies for ESCC. Understanding population-specific patterns is essential for personalized approaches to ESCC management.

A balanced translocation truncates Neurotrimin in a family with intracranial and thoracic aortic aneurysm.

BACKGROUND: Balanced chromosomal rearrangements occasionally have strong phenotypic effects, which may be useful in understanding pathobiology. However, conventional strategies for characterising breakpoints are laborious and inaccurate. We present here a proband with a thoracic aortic aneurysm (TAA) and a balanced translocation t(10;11) (q23.2;q24.2). Our purpose was to sequence the chromosomal breaks in this family to reveal a novel candidate gene for aneurysm. METHODS AND RESULTS: Intracranial aneurysm (IA) and TAAs appear to run in the family in an autosomal dominant manner: After exploring the family history, we observed that the proband's two siblings both died from cerebral haemorrhage, and the proband's parent and parent's sibling died from aortic rupture. After application of a genome-wide paired-end DNA sequencing method for breakpoint mapping, we demonstrate that this translocation breaks intron 1 of a splicing isoform of Neurotrimin at 11q25 in a previously implicated candidate region for IAs and AAs (OMIM 612161). CONCLUSIONS: Our results demonstrate the feasibility of genome-wide paired-end sequencing for the characterisation of balanced rearrangements and identification of candidate genes in patients with potentially disease-associated chromosome rearrangements. The family samples were gathered as a part of our recently launched National Registry of Reciprocal Balanced Translocations and Inversions in Finland (n=2575), and we believe that such a registry will be a powerful resource for the localisation of chromosomal aberrations, which can bring insight into the aetiology of related phenotypes.

Identification of a variant associated with adult-type hypolactasia.

Adult-type hypolactasia, also known as lactase non-persistence (lactose intolerance), is a common autosomal recessive condition resulting from the physiological decline in activity of the lactase-phlorizin hydrolase (LPH) in intestinal cells after weaning. LPH hydrolyzes lactose into glucose and galactose. Sequence analyses of the coding and promoter regions of LCT, the gene encoding LPH, has revealed no DNA variations correlating with lactase non-persistence. An associated haplotype spanning LCT, as well as a distinct difference in the transcript levels of 'non-persistence' and 'persistence' alleles in heterozygotes, suggest that a cis-acting element contributes to the lactase non-persistence phenotype. Using linkage disequilibrium (LD) and haplotype analysis of nine extended Finnish families, we restricted the locus to a 47-kb interval on 2q21. Sequence analysis of the complete region and subsequent association analyses revealed that a DNA variant, C/T-13910, roughly 14 kb upstream from the LCT locus, completely associates with biochemically verified lactase non-persistence in Finnish families and a sample set of 236 individuals from four different populations. A second variant, G/A-22018, 8 kb telomeric to C/T-13910, is also associated with the trait in 229 of 236 cases. Prevalence of the C/T-13910 variant in 1,047 DNA samples is consistent with the reported prevalence of adult-type hypolactasia in four different populations. That the variant (C/T-13910) occurs in distantly related populations indicates that it is very old.

On the validity of the likelihood ratio test and consistency of resulting parameter estimates in joint linkage and linkage disequilibrium analysis under improperly specified parametric models.

It has been shown that parametric analysis of linkage disequilibrium conditional on linkage using an overly deterministic model can be optimal for family-based association analysis. However, if one applies this strategy carelessly, there is a risk of false inference. We analyse properties of such likelihood ratio tests when the assumed disease mode of inheritance is inaccurate. Under some conditions, problems result if one is not careful to consider what null hypothesis is being tested. We show that: (a) tests for which the null hypothesis assumes the absence of both linkage and association are independent of the true mode of inheritance; (b) likelihood ratio tests assuming either linkage or association under the null hypothesis may depend on the true mode of inheritance, leading to inconsistent parameter estimates, in particular under extremely deterministic models; (c) this problem cannot be eliminated by increasing sample size or adding population controls--as sample size increases, the chance of false positive inference goes to 100%; (d) this issue can lead to systematic false positive inference of association in regions of linkage. This is important because highly deterministic models are often used intentionally in model-based analyses because they can have more power than the true model, and are implicit in many model-free analysis methods.

PSEUDOMARKER: a powerful program for joint linkage and/or linkage disequilibrium analysis on mixtures of singletons and related individuals.

A decade ago, there was widespread enthusiasm for the prospects of genome-wide association studies to identify common variants related to common chronic diseases using samples of unrelated individuals from populations. Although technological advancements allow us to query more than a million SNPs across the genome at low cost, a disappointingly small fraction of the genetic portion of common disease etiology has been uncovered. This has led to the hypothesis that less frequent variants might be involved, stimulating a renaissance of the traditional approach of seeking genes using multiplex families from less diverse populations. However, by using the modern genotyping and sequencing technology, we can now look not just at linkage, but jointly at linkage and linkage disequilibrium (LD) in such samples. Software methods that can look simultaneously at linkage and LD in a powerful and robust manner have been lacking. Most algorithms cannot jointly analyze datasets involving families of varying structures in a statistically or computationally efficient manner. We have implemented previously proposed statistical algorithms in a user-friendly software package, PSEUDOMARKER. This paper is an announcement of this software package. We describe the motivation behind the approach, the statistical methods, and software, and we briefly demonstrate PSEUDOMARKER's advantages over other packages by example.

Whole-Genome Sequencing and Genomic Variant Analysis of Kazakh Individuals.

Kazakhstan, the ninth-largest country in the world, is located along the Great Silk Road and connects Europe with Asia. Historically, its territory has been inhabited by nomadic tribes, and modern-day Kazakhstan is a multiethnic country with a dominant Kazakh population. We sequenced and analyzed the genomes of five ethnic Kazakhs at high coverage using the Illumina HiSeq2000 next-generation sequencing platform. The five Kazakhs yielded a total number of base pairs ranging from 87,308,581,400 to 107,526,741,301. On average, 99.06% were properly mapped. Based on the Het/Hom and Ti/Tv ratios, the quality of the genomic data ranged from 1.35 to 1.49 and from 2.07 to 2.08, respectively. Genetic variants were identified and annotated. Functional analysis of the genetic variants identified several variants that were associated with higher risks of metabolic and neurogenerative diseases. The present study showed high levels of genetic admixture of Kazakhs that were comparable to those of other Central Asians. These whole-genome sequence data of healthy Kazakhs could contribute significantly to biomedical studies of common diseases as their findings could allow better insight into the genotype-phenotype relations at the population level.

Subclinical Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Relation to Office and Ambulatory Blood Pressure Measurements.

Background: Twenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or arteriolosclerosis type, cerebral small vessel diseases (CSVD). Methods: A subset of 429 participants from the Maracaibo Aging Study [aged ≥40 years (women, 73.7%; mean age, 59.3 years)] underwent baseline brain magnetic resonance imaging (MRI) to visualize CSVD, which included log-transformed white matter hyperintensities (log-WMH) volume and the presence (yes/no) of lacunes, cerebral microbleeds (CMB), or enlarged perivascular spaces (EPVS). Linear and logistic regression models were applied to examine the association between CSVD and each +10-mmHg increment in the office and ambulatory systolic BP measurements. Improvement in the fit of nested logistic models was assessed by the log-likelihood ratio and the generalized R 2 statistic. Results: Office and ambulatory systolic BP measurements were related to log-WMH (ß-correlation coefficients ≥0.08; P < 0.001). Lacunes and CMB were only associated with ambulatory systolic BP measurements (odds ratios [OR] ranged from 1.31 [95% confidence interval, 1.10-1.55] to 1.46 [1.17-1.84], P ≤ 0.003). Accounted for daytime systolic BP, both the 24-h (ß-correlation, 0.170) and nighttime (ß-correlation, 0.038) systolic BP measurements remained related to log-WMH. When accounted for 24-h or daytime systolic BP levels, the nighttime systolic BP retained the significant association with lacunes (ORs, 1.05-1.06; 95% CIs, ≥1.01 to ≤ 1.13), whereas the 24-h and daytime systolic BP levels were not associated with lacunes after adjustments for nighttime systolic BP (ORs, ≤ 0.88; 95% CI, ≥0.77 to ≤ 1.14). On top of covariables and office systolic BP, ambulatory systolic BP measurements significantly improved model performance (1.05% ≥ R 2 ≤ 3.82%). Compared to 24-h and daytime systolic BP, nighttime systolic BP had the strongest improvement in the model performance; for WMH (1.46 vs. 1.05%) and lacunes (3.06 vs. ≤ 2.05%). Conclusions: Twenty-four-hour and nighttime systolic BP were the more robust BP measurements associated with CSVD, but the nighttime systolic BP level had the strongest association. Controlling ambulatory BP levels might provide additional improvement in the prevention of CSVD.

Open-Angle Glaucomatous Optic Neuropathy Is Related to Dips Rather Than Increases in the Mean Arterial Pressure Over 24-H.

BACKGROUND: Mean arterial pressure (MAP) drives ocular perfusion. Excessive 24-h MAP variability relates to glaucoma, however, whether this is due to dips or increases in the blood pressure (BP) is undocumented. We investigated the association of open-angle glaucoma (OAG) in relation to the 5 largest MAP dips/increases over 24-h, henceforth called dips/blips. METHODS: In the Maracaibo Aging Study (MAS), 93 participants aged ≥40 y (women, 87.1%; mean age, 61.9 y) underwent baseline ophthalmological and 24-h ambulatory BP monitoring assessments. OAG was the presence of optic nerve damage and visual field defects. Statistical methods included logistic regression and the generalized R2 statistic. For replication, 48 OAG cases at the Leuven Glaucoma Clinic were matched with 48 controls recruited from Flemish population. RESULTS: In the MAS, 26 participants had OAG. OAG compared to non-OAG participants experienced longer and deeper dips (116.5 vs. 102.7 minutes; to 60.3 vs. 66.6 mm Hg; -21.0 vs. -18.0 mm Hg absolute or 0.79 vs. 0.81 relative dip compared to the preceding reading). The adjusted odds ratios associated with dip measures ranged from 2.25 (95% confidence interval [CI], 1.31-4.85; P = 0.009) to 3.39 (95% CI, 1.36-8.46; P = 0.008). On top of covariables and 24-MAP level/variability, the dip measures increased the model performance (P ≤ 0.025). Blips did not associate with OAG. The case-control study replicated the MAS observations. CONCLUSIONS: Dips rather than increases in the 24-h MAP level were associated with increased risk for OAG. An ophthalmological examination combined with 24-h BP monitoring might be precautious steps required in normotensive and hypertensive patients at risk of OAG.

Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins.

Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial fat mass loss of 52% (−7.9 ± 1.5 kg) and low body fat (12.7 ± 4.1%), the liquid chromatography-mass spectrometry-based metabolic signature of 24 previously young, healthy, and normal weight female physique athletes was investigated. We observed uniform increases (FDR < 0.05) in bile acids, very-long-chain free fatty acids (FFA), and oxylipins, together with reductions in unsaturated FFAs after weight loss. These widespread changes, especially in the bile acid profile, were most strongly explained (FDR < 0.05) by changes in android (visceral) fat mass. The reported changes did not persist, as all of them were reversed after the subsequent voluntary weight regain period (18.4 ± 2.9 weeks) and were unchanged in non-dieting controls (n = 16). Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects.

Total Plasma Homocysteine and Depressive Symptoms in Older Hispanics.

BACKGROUND: Very few studies have investigated the association between total plasma homocysteine (tHcy) and depressive symptoms in older Hispanics. OBJECTIVE: To test the hypothesis that high tHcy associates with depressive symptoms in older Hispanics. METHODS: A total of 1,418 participants .55 years old from the Maracaibo Aging Study (MAS) underwent standardized neurological, neuropsychiatric, and cardiovascular assessments. The Neuropsychiatric Inventory Depression Subscale (NPId) was used to assess the burden of depressive symptoms. The tHcy levels and other biochemical parameters in blood samples were measured. Univariate and multivariate logistic regression models were applied. RESULTS: Participants with depressive symptoms had higher levels of tHcy than those without (15.1 versus 13.9 µmol/L; p = 0.009). Elevated tHcy levels were associated with depressive symptoms after adjusting for age, sex, education, smoking, diabetes, hypertension, alcohol intake, stroke, and dementia (OR = 1.58; 95% CI, 1.18-2.12). CONCLUSION: Elevated levels of tHcy were associated with depressive symptoms in older Hispanics living under the nutritional and environmental conditions of a developing country.

Normal-tension glaucomatous optic neuropathy is related to blood pressure variability in the Maracaibo Aging Study.

Hypoperfusion of the optic nerve might be involved in the pathogenesis of normal-tension glaucomatous optic neuropathy (GON). Mean arterial pressure (MAP) drives ocular perfusion, but no previous studies have addressed the risk of GON in relation to blood pressure (BP) variability, independent of BP level. In a cross-sectional study, 93 residents of Maracaibo, Venezuela, underwent optical coherence tomography, visual field assessments and 24-h ambulatory BP monitoring between 2011 and 2016. We investigated the association of normal-tension GON with or without visual field defects with reading-to reading variability of 24-h MAP, as captured by variability independent of the MAP level (VIMmap). Odds ratios (ORs) were adjusted for 24-h MAP level and for a propensity score of up to five risk factors. Among the 93 participants (87.1% women; mean age, 61.9 years), 26 had open-angle normal-tension GON at both eyes; 14 had visual field defects; and 19 did not have visual field defects. The OR ratios for normal-tension GON, expressed per 1-SD increment in VIMmap (2 mm Hg), were 2.17 (95% confidence interval, 1.33-3.53) unadjusted; 2.20 (1.35-3.61) adjusted for 24-h MAP level only; 1.93 (1.10-3.41) with additional adjustment for age, educational attainment, high-density lipoprotein (HDL) cholesterol and office hypertension; and 1.95 (1.10-3.45) in models including intraocular pressure. We confirmed our a priori hypothesis that BP variability, most likely operating via hypoperfusion of the optic nerve, is associated with normal-tension GON. 24-H ambulatory BP monitoring might therefore help stratify the risk of normal-tension GON.

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.

ForSim: a tool for exploring the genetic architecture of complex traits with controlled truth.

UNLABELLED: Many important problems in biology involve complex traits affected by multiple coding or regulatory parts of the genome. How well the underlying genetic architecture can be inferred by statistical methods such as mapping and association studies are active research areas. ForSim is a flexible forward evolutionary simulation tool for exploring the consequences of evolution by phenotype, whereby demographic, chance, behavioral and selective effects mold genetic architecture. Simulation is useful for exploring these issues as well as the choice of study design inferential methods. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Linkage analysis of schizophrenia controlling for population substructure.

Etiological heterogeneity and complexity has hampered attempts to identify predisposing genes for schizophrenia. We sought to minimize the number of segregating genes involved by focusing on a population isolate with elevated disease prevalence. We exploited the well-established population history, and searched for disease susceptibility loci in families from two alternative founder lineages. We studied 28 schizophrenia pedigrees (123 nuclear families) from an outlying municipality on the eastern border of Finland. We divided the families based on their genealogy and defined two routes of immigration: southern and northern. We examined the kinship coefficients and allele frequency distributions within each group, and performed a linkage analysis based on 497 microsatellite markers across the genome. A high degree of historical relatedness was demonstrated by higher sharing of alleles than predicted by the relationships we identified within the previous four generations alone, as would be expected. Between the two subpopulations, allele frequencies were significantly different, consistent with their isolated genealogies. The southern families showed some evidence of linkage in a schizophrenia locus at 4q23 (Z = 3.3) near our previous finding with quantitative variation in verbal learning and memory [Paunio et al. (2004); Hum Mol Genet 13: 1693-1702], while the northern pedigrees gave most significant evidence on 10q21 (Z = 2.53). Joint analysis of families from both lineages suggested evidence of linkage only at 3p14 (Z = 3.18). Thus the detailed genealogical information led us to identification of distinct linkage signals for schizophrenia susceptibility loci between the three analyses we performed.