Cardiovascular Risk Factor Trajectories Since Childhood and Cognitive Performance in Midlife The Cardiovascular Risk in Young Finns Study

Background: Cardiovascular risk factors, such as high blood pressure, adverse serum lipids, and elevated body mass index in midlife, may harm cognitive performance. It is important to note that longitudinal accumulation of cardiovascular risk factors since childhood may be associated with cognitive performance already since childhood, but the previous evidence is scarce. We studied the associations of cardiovascular risk factors from childhood to midlife, their accumulation, and midlife cognitive performance. Methods: From 1980, a population-based cohort of 3596 children (3-18 years of age) have been repeatedly followed up for 31 years. Blood pressure, serum lipids, and body mass index were assessed in all follow-ups. Cardiovascular risk factor trajectories from childhood to midlife were identified using latent class growth mixture modeling. Cognitive testing was performed in 2026 participants 34 to 49 years of age using a computerized test. The associations of the cardiovascular risk factor trajectories and cognitive performance were studied for individual cardiovascular risk factors and cardiovascular risk factor accumulation. Results: Consistently high systolic blood pressure (beta=-0.262 SD [95% CI, -0.520 to -0.005]) and serum total cholesterol (beta=-0.214 SD [95% CI, -0.365 to -0.064]) were associated with worse midlife episodic memory and associative learning compared with consistently low values. Obesity since childhood was associated with worse visual processing and sustained attention (beta=-0.407 SD [95% CI, -0.708 to -0.105]) compared with normal weight. An inverse association was observed for the cardiovascular risk factor accumulation with episodic memory and associative learning (P for trend=0.008; 3 cardiovascular risk factors: beta=-0.390 SD [95% CI, -0.691 to -0.088]), with visual processing and sustained attention (P for trend Conclusions: Longitudinal elevated systolic blood pressure, high serum total cholesterol, and obesity from childhood to midlife were inversely associated with midlife cognitive performance. It is important to note that the higher the number of cardiovascular risk factors, the worse was the observed cognitive performance. Therefore, launching preventive strategies against cardiovascular risk factors beginning from childhood might benefit primordial promotion of cognitive health in adulthood.Peer reviewe

Progressive Volume Loss and White Matter Degeneration in Cstb-Deficient Mice: A Diffusion Tensor and Longitudinal Volumetry MRI Study

Peer reviewe

Genetic and observational evidence : No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment

Background Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited. Objectives A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC. Participants/methods Six independent cohorts were included with follow-up data for 14,438 participants to investigate the associations of HDL-related measures with incident CHD (1,570 events). The GWAS of HDL-CEC was carried out in 20,372 participants. Results HDL-CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL-C). In contradiction, almost all HDL-related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL-CEC independent of HDL-C and triglycerides. Conclusion HDL-CEC is not unequivocally associated with CHD in contrast to HDL-C, apolipoprotein A-I, and most of the HDL subclass particle concentrations.Peer reviewe

IgE sensitisation in relation to flow-independent nitric oxide exchange parameters

BACKGROUND: A positive association between IgE sensitisation and exhaled NO levels has been found in several studies, but there are no reports on the compartment of the lung that is responsible for the increase in exhaled NO levels seen in IgE-sensitised subjects. METHODS: The present study comprised 288 adult subjects from the European Community Respiratory Health Survey II who were investigated in terms of lung function, IgE sensitisation (sum of specific IgE), smoking history and presence of rhinitis and asthma. Mean airway tissue concentration of NO (Caw(NO)), airway transfer factor for NO (Daw(NO)), mean alveolar concentration of NO (Calv(NO)) and fractional exhaled concentration of NO at a flow rate of 50 mL s(-1 )(FE(NO 0.05)) were determined using the extended NO analysis. RESULTS: IgE-sensitised subjects had higher levels (geometric mean) of FE(NO 0.05 )(24.9 vs. 17.3 ppb) (p < 0.001), Daw(NO )(10.5 vs. 8 mL s(-1)) (p = 0.02) and Caw(NO )(124 vs. 107 ppb) (p < 0.001) and positive correlations were found between the sum of specific IgE and FE(NO 0.05), Caw(NO )and Daw(NO )levels (p < 0.001 for all correlations). Sensitisation to cat allergen was the major determinant of exhaled NO when adjusting for type of sensitisation. Rhinitis and asthma were not associated with the increase in exhaled NO variables after adjusting for the degree of IgE sensitisation. CONCLUSION: The presence of IgE sensitisation and the degree of allergic sensitisation were related to the increase in airway NO transfer factor and the increase in NO concentration in the airway wall. Sensitisation to cat allergen was related to the highest increases in exhaled NO parameters. Our data suggest that exhaled NO is more a specific marker of allergic inflammation than a marker of asthma or rhinitis

Clinical patterns in asthma based on proximal and distal airway nitric oxide categories

<p>Abstract</p> <p>Background</p> <p>The exhaled nitric oxide (eNO) signal is a marker of inflammation, and can be partitioned into proximal [J'aw_NO(nl/s), maximum airway flux] and distal contributions [CA_NO(ppb), distal airway/alveolar NO concentration]. We hypothesized that J'aw_NOand CA_NOare selectively elevated in asthmatics, permitting identification of four inflammatory categories with distinct clinical features.</p> <p>Methods</p> <p>In 200 consecutive children with asthma, and 21 non-asthmatic, non-atopic controls, we measured baseline spirometry, bronchodilator response, asthma control and morbidity, atopic status, use of inhaled corticosteroids, and eNO at multiple flows (50, 100, and 200 ml/s) in a cross-sectional study design. A trumpet-shaped axial diffusion model of NO exchange was used to characterize J'aw_NOand CA_NO.</p> <p>Results</p> <p>J'aw_NOwas not correlated with CA_NO, and thus asthmatic subjects were grouped into four eNO categories based on upper limit thresholds of non-asthmatics for J'aw_NO(≥ 1.5 nl/s) and CA_NO(≥ 2.3 ppb): Type I (normal J'aw_NOand CA_NO), Type II (elevated J'aw_NOand normal CA_NO), Type III (elevated J'aw_NOand CA_NO) and Type IV (normal J'aw_NOand elevated CA_NO). The rate of inhaled corticosteroid use (lowest in Type III) and atopy (highest in Type II) varied significantly amongst the categories influencing J'aw_NO, but was not related to CA_NO, asthma control or morbidity. All categories demonstrated normal to near-normal baseline spirometry; however, only eNO categories with increased CA_NO(III and IV) had significantly worse asthma control and morbidity when compared to categories I and II.</p> <p>Conclusions</p> <p>J'aw_NOand CA_NOreveal inflammatory categories in children with asthma that have distinct clinical features including sensitivity to inhaled corticosteroids and atopy. Only categories with increase CA_NOwere related to poor asthma control and morbidity independent of baseline spirometry, bronchodilator response, atopic status, or use of inhaled corticosteroids.</p

Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients

Background: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported.Methods: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P< 1 x 10(-5) were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES.Results: In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (beta = - 4.8%, P = 9.6 x 10(-9) for systolic and beta = - 4.3%, P = 2.2 x 10(-6) for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 x 10(-5). The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (beta = - 0.8%, P = 0.4 for systolic and beta = - 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (beta = -7.6 g/m(2), P = 0.02).Conclusions: rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology

Methylation status of VTRNA2-1/nc886 is stable across populations, monozygotic twin pairs and in majority of tissues

Aims & methods: The aim of this study was to characterize the methylation level of a polymorphically imprinted gene, VTRNA2-1/nc886, in human populations and somatic tissues.48 datasets, consisting of more than 30 tissues and >30,000 individuals, were used. Results: nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, whereas similar to 30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle. Conclusion: The nc886 imprint may be established in the oocyte, and, after implantation, the methylation status is stable, excluding a few specific tissues. Tweetable abstract Methylation status of a polymorphically imprinted gene, VTRNA2-1/nc886, is stable in human populations (48 cohorts, n > 30,000) and in somatic tissues, except in cerebellum and skeletal muscle. Twin data suggest it may already be established in the oocyte.Peer reviewe

Sedentary behaviours and obesity in adults : the Cardiovascular Risk in Young Finns Study

Objective: Sedentary behaviour may contribute to the development of obesity. We investigated the relations between different types of sedentary behaviour and adiposity markers in a well-characterised adult population after controlling for a wide range of potential confounders. Design: Cross-sectional study. Setting: The Cardiovascular Risk in Young Finns Multicenter Study. Participants Sedentary time (TV viewing, computer time, reading, music/radio listening and other relaxation) was assessed with a questionnaire for 1084 women and 909 men aged 30-45 years. Other study variables included occupational and leisure-time physical activity, sleep duration, socioeconomic status, smoking, alcohol consumption, energy intake, adherence to the recommended diet, multiple individual food items, age and genetic variants associated with body mass index (BMI). Primary outcome measures BMI in kg/m(2) and waist circumference (WC in cm). Results: Of the different sedentary behaviour types, TV viewing was most consistently related to higher BMI and WC, both in men and women. One additional daily TV hour was associated with a 1.81 +/- 0.44 cm larger WC in women and 2 cm +/- 0.44 cm in men (both p Conclusions: Out of the different types of sedentary behaviour, TV viewing was most consistently associated with adiposity markers in adults. Partial dilution of these associations after adjustments for covariates suggests that the obesogenic effects of TV viewing are partly mediated by other lifestyle factors.Peer reviewe

Strong Association of De Novo Copy Number Mutations with Autism

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized