The serum copper/zinc ratio in childhood and educational attainment: a population-based study

BACKGROUND: Micronutrients are potentially important determinants of adult outcomes such as educational attainment. Copper and zinc have known effects on several medical conditions and cognitive development. Elevated copper and depressed zinc is a common trace metal imbalance. METHODS: We estimate the correlation between the copper/zinc ratio (Cu/Zn) in childhood (year 1980) and educational attainment in adulthood (year 2010). We use the Young Finns Study (YFS) combined with the Finnish Linked Employer-Employee Data (FLEED). The regression models account for confounders such as other biomarkers and parental observables. RESULTS: We report a sizeable, negative correlation between Cu/Zn and educational attainment as measured by education in years, grades as well as the likelihood of completing university education. For example, a one standard deviation increase in Cu/Zn decreases the probability of university education by ∼4%. CONCLUSIONS: The findings are consistent with a Cu/Zn effect influencing cognitive functioning early in life. Future research should explore more deeply the precise mechanisms by which Cu/Zn affects educational attainment

Cardiometabolic Health Among Adult Offspring of Hypertensive Pregnancies: The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Cardiometabolic health among adult offspring of hypertensive disorders of pregnancy (HDP) is relatively unknown. We hypothesized that offspring of HDP would have abnormalities in the retinal microvasculature and cardiac structure by midadulthood. METHODS AND RESULTS: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish university cities. The mean age of participants was 40 years (range 34-49 years) at the time of retinal photography and cardiac assessment. Offspring born ≥37 weeks of gestation and appropriate for gestational age (n=1006) were included. Offspring of HDP had higher systolic blood pressure (β=4.68, P<0.001), body mass index (β=1.25, P=0.009), and waist circumference (β=0.25, P=0.042), compared with offspring of normotensive pregnancies. However, no differences in fasting glucose, insulin, lipid profile, carotid intima media thickness, or brachial artery flow-mediated dilatation were shown. Retinal arteriolar diameters were narrower (β=-0.43, P=0.009) and longer (β=32.5, P=0.023) and the arteriolar length-to-diameter ratio was higher (β=2.32, P=0.006) among offspring of HDP, after adjustment for age and sex. Left atrial volume indexed to body surface area (β=1.34, P=0.040) was increased. Adjustment for the confounding effects of birth weight, body mass index, smoking and socioeconomic status, and the mediating effect of hypertension had little impact on the associations. CONCLUSIONS: Abnormalities of the retinal microvasculature and cardiac structure are seen in offspring of HDP in midadulthood. These findings may need to be considered in future primary prevention strategies of cardiovascular disease among offspring of HDP

Clarifying the terms launch and commercialization : Reflections from theory and practice

AbstractTerms launch and commercialization are used interchangeably and without explicit definitions in the literature making both terms vague. The purpose of this paper is to discuss the similarities and differences between these terms with a help of a critical literature review and illustrative case studies. It is shown that the terms are used to discuss the same broad phenomena, but research issues under them and the empirical data imply that the terms are not exactly the same. As a conclusion, clarification of the terms by utilizing the found differences is encouraged and new directions for research in marketing are proposed.Abstract Terms launch and commercialization are used interchangeably and without explicit definitions in the literature making both terms vague. The purpose of this paper is to discuss the similarities and differences between these terms with a help of a critical literature review and illustrative case studies. It is shown that the terms are used to discuss the same broad phenomena, but research issues under them and the empirical data imply that the terms are not exactly the same. As a conclusion, clarification of the terms by utilizing the found differences is encouraged and new directions for research in marketing are proposed

Metabolic profiling of fatty liver in young and middle-aged adults : Cross-sectional and prospective analyses of the Young Finns Study

Nonalcoholic fatty liver is associated with obesity-related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis-related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty-eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population-based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34-49 years (19% prevalence). Cross-sectional associations as well as 4-year and 10-year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P <0.0007 for 60 measures in age-adjusted and sex-adjusted cross-sectional analyses). The strongest direct associations were observed for extremely large very-low-density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48-6.78), other very-low-density lipoprotein measures, and branched-chain amino acids (e.g., leucine OR = 2.94, 2.51-3.44). Strong inverse associations were observed for high-density lipoprotein measures, e.g., high-density lipoprotein size (OR = 0.36, 0.30-0.42) and several fatty acids including omega-6 (OR = 0.37, 0.32-0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P <0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis. Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491-500).Peer reviewe

Assessing multivariate gene-metabolome associations with rare variants using Bayesian reduced rank regression

Motivation: A typical genome-wide association study searches for associations between single nucleotide polymorphisms (SNPs) and a univariate phenotype. However, there is a growing interest to investigate associations between genomics data and multivariate phenotypes, for example, in gene expression or metabolomics studies. A common approach is to perform a univariate test between each genotype–phenotype pair, and then to apply a stringent significance cutoff to account for the large number of tests performed. However, this approach has limited ability to uncover dependencies involving multiple variables. Another trend in the current genetics is the investigation of the impact of rare variants on the phenotype, where the standard methods often fail owing to lack of power when the minor allele is present in only a limited number of individuals. Results: We propose a new statistical approach based on Bayesian reduced rank regression to assess the impact of multiple SNPs on a high-dimensional phenotype. Because of the method’s ability to combine information over multiple SNPs and phenotypes, it is particularly suitable for detecting associations involving rare variants. We demonstrate the potential of our method and compare it with alternatives using the Northern Finland Birth Cohort with 4702 individuals, for whom genome-wide SNP data along with lipoprotein profiles comprising 74 traits are available. We discovered two genes (XRCC4 and MTHFD2L) without previously reported associations, which replicated in a combined analysis of two additional cohorts: 2390 individuals from the Cardiovascular Risk in Young Finns study and 3659 individuals from the FINRISK study. Availability and implementation: R-code freely available for download at http://users.ics.aalto.fi/pemartti/gene_metabolome/. Contact: [email protected]; [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the &lt;i&gt;LPA&lt;/i&gt; and 1 SNP in the &lt;i&gt;APOE&lt;/i&gt; gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the &lt;i&gt;LPA&lt;/i&gt; , 1 in the &lt;i&gt;APOE&lt;/i&gt; gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, &lt;i&gt;P&lt;/i&gt; = 3.35 × 10 &lt;sup&gt;-30&lt;/sup&gt; ). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the &lt;i&gt;APOE2&lt;/i&gt; -determining allele of rs7412 to be significantly associated with Lp(a) concentrations ( &lt;i&gt;P&lt;/i&gt; = 3.47 × 10 &lt;sup&gt;-10&lt;/sup&gt; ). Each &lt;i&gt;APOE2&lt;/i&gt; allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the &lt;i&gt;TLR2&lt;/i&gt; gene with Lp(a) ( &lt;i&gt;P&lt;/i&gt; = 3.4 × 10 &lt;sup&gt;-4&lt;/sup&gt; ). In summary, we identified a large number of independent SNPs in the &lt;i&gt;LPA&lt;/i&gt; gene region, as well as the &lt;i&gt;APOE2&lt;/i&gt; allele, to be significantly associated with Lp(a) concentrations

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary Disease : The Finnish Guidelines

Peer reviewe

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality

Aims The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. Methods and results We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10−40), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10−40 and rs16899974; P = 1.5 × 10−38) and one in SLC25A45 (rs34400381; P = 2.5 × 10−10). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. Conclusions AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac functio