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Understanding the function of human blood serum proteins in disease has been limited by difficulties in monitoring their production, accumulation, and distribution. Emilsson et al. investigated human serum proteins of more than 5000 Icelanders over the age of 65. The composition of blood serum includes a complex regulatory network of proteins that are globally coordinated across most or all tissues. The authors identified modules and functional groups associated with disease and health outcomes and were able to link genetic variants to complex diseases. Science , this issue p. 769 A deep proteome analysis of human serum reveals the relationship between disease and genetics. Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15–18%, at least p  < 0.003) in the highest vs the lowest quintile for circulating long chain (20–22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death. Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.

Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50-179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4-15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.

ObjectiveCarotid plaque and intima-media thickness are non-invasive arterial markers that are used as surrogate end points for cardiovascular disease. The aim was to assess the prevalence and severity of carotid plaque, and examine its determinant risk factors and their association to the common carotid artery intima-media thickness (CCA-IMT) in a general population.MethodsWe examined 6524 participants aged 25–69 years in the population-based REFINE (Risk Evaluation For INfarct Estimates)-Reykjavik study. Plaques at the bifurcation and internal carotid arteries were evaluated. Mean CCA-IMT was measured in the near and far walls of the common carotid arteries.ResultsThe prevalence of minimal, moderate and severe plaque was 35.0%, 8.9% and 1.1%, respectively, and the mean CCA-IMT was 0.73 (SD 0.14) mm. Age, sex, smoking and type 2 diabetes mellitus (T2DM) were the strongest risk factors associated with plaque, followed by systolic blood pressure, total cholesterol, body mass index and family history of myocardial infarct. Low educational level was also strongly and independently associated with plaque. CCA-IMT shared the same risk factors except for a non-significant association with T2DM and family history of myocardial infarction (MI). Participants with T2DM had greater plaque prevalence, 2-fold higher in those <50 years and 17–30% greater in age groups 50–54 to 60–64, and more significant plaques (moderate or severe) were the difference in prevalence was 24% in age group 50–54 and ≥60% in older age groups, compared with non-T2DM.ConclusionsCarotid plaque and CCA-IMT have mostly common determinants. However, T2DM and family history of MI were associated with plaque but not with CCA-IMT. Greater prevalence and more severe plaques in individuals with T2DM raise the concern that with increasing prevalence of T2DM we may expect an increase in atherosclerosis and its consequences.

Activation of blood coagulation and fibrinolysis may be associated with increased risk of coronary heart disease. We aimed to assess associations of circulating tissue plasminogen activator (t-PA) antigen, D-dimer and von Willebrand factor (VWF) with coronary heart disease risk. Prospective case-control study, systematic review and meta-analyses. Measurements were made in 1925 people who had a first-ever nonfatal myocardial infarction or died of coronary heart disease during follow-up (median 19.4 years) and in 3616 controls nested within the prospective population-based Reykjavik Study. Age and sex-adjusted odds ratios for coronary heart disease per 1 standard deviation higher baseline level were 1.25 (1.18, 1.33) for t-PA antigen, 1.01 (0.95, 1.07) for D-dimer and 1.11 (1.05, 1.18) for VWF. After additional adjustment for conventional cardiovascular risk factors, corresponding odds ratios were 1.07 (0.99, 1.14) for t-PA antigen, 1.06 (1.00, 1.13) for D-dimer and 1.08 (1.02, 1.15) for VWF. When combined with the results from previous prospective studies in a random-effects meta-analysis, overall adjusted odds ratios were 1.13 (1.06, 1.21) for t-PA antigen (13 studies, 5494 cases), 1.23 (1.16, 1.32) with D-dimer (18 studies, 6799 cases) and 1.16 (1.10, 1.22) with VWF (15 studies, 6556 cases). Concentrations of t-PA antigen, D-dimer and VWF may be more modestly associated with first-ever CHD events than previously reported. More detailed analysis is required to clarify whether these markers are causal risk factors or simply correlates of coronary heart disease.

This large, prospective study calls into question the value of the C-reactive protein (CRP) concentration in the prediction of coronary events. In contrast to previous research, this study found that the strength of the CRP concentration as a predictor is relatively moderate and that it adds little to the predictive value of standard coronary risk factors, such as the cholesterol concentration, smoking status, and blood pressure. This large study calls into question the value of CRP in the prediction of coronary events. Since atherosclerosis may, in part, be an inflammatory disease, 1 circulating factors related to inflammation may be predictors of cardiovascular disease in general populations. 2 A recent statement from the Centers for Disease Control and Prevention and the American Heart Association concluded that it is reasonable to measure C-reactive protein, a sensitive circulating marker of inflammation, as an adjunct to the measurement of established risk factors in order to assess the risk of coronary heart disease. 3 The report acknowledged, however, that the epidemiologic data to support this view were not entirely consistent and recommended that larger prospective studies be conducted to improve . . .

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10−8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10−8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10−6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10−3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep–wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Associations between circulating markers of dysglycaemia and coronary heart disease (CHD) risk in people without diabetes have not been reliably characterised. We report new data from a prospective study and a systematic review to help quantify these associations. Fasting and post-load glucose levels were measured in 18,569 participants in the population-based Reykjavik study, yielding 4,664 incident CHD outcomes during 23.5 y of mean follow-up. In people with no known history of diabetes at the baseline survey, the hazard ratio (HR) for CHD, adjusted for several conventional risk factors, was 2.37 (95% CI 1.79-3.14) in individuals with fasting glucose > or = 7.0 mmol/l compared to those < 7 mmol/l. At fasting glucose values below 7 mmol/l, adjusted HRs were 0.95 (0.89-1.01) per 1 mmol/l higher fasting glucose and 1.03 (1.01-1.05) per 1 mmol/l higher post-load glucose. HRs for CHD risk were generally modest and nonsignificant across tenths of glucose values below 7 mmol/l. We did a meta-analysis of 26 additional relevant prospective studies identified in a systematic review of Western cohort studies that recorded fasting glucose, post-load glucose, or glycated haemoglobin (HbA(1c)) levels. In this combined analysis, in which participants with a self-reported history of diabetes and/or fasting blood glucose > or = 7 mmol/l at baseline were excluded, relative risks for CHD, adjusted for several conventional risk factors, were: 1.06 (1.00-1.12) per 1 mmol/l higher fasting glucose (23 cohorts, 10,808 cases, 255,171 participants); 1.05 (1.03-1.07) per 1 mmol/l higher post-load glucose (15 cohorts, 12,652 cases, 102,382 participants); and 1.20 (1.10-1.31) per 1% higher HbA(1c) (9 cohorts, 1639 cases, 49,099 participants). In the Reykjavik Study and a meta-analysis of other Western prospective studies, fasting and post-load glucose levels were modestly associated with CHD risk in people without diabetes. The meta-analysis suggested a somewhat stronger association between HbA(1c) levels and CHD risk.

Background Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). Method This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. Results One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16–13.96] P  = 0.03 and age 13 = 2.65[0.69–10.26] P  = 0.16, respectively). Conclusion Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.

The debate whether \"asymptomatic hyperuricemia\" should be treated is still ongoing. The objective of this cross-sectional study was to analyze whether hyperuricema in the elderly is associated with joint pain. Participants in the population-based AGES-Reykjavik Study (males 2195, females 2975, mean age 76(6)) answered standardized questions about joint pain. In addition they recorded intermittent hand joint pain by marking a diagram of the hand. In males, no association was found between hyperuricemia and pain. Females however, showed a positive association between hyperuricemia and joint pain at many sites. After adjustment for age, BMI and hand osteoarthritis however, only intermittent hand joint pain (OR 1.30(1.07-1.58), p = 0.008) and intermittent pain in ≥10 hand joints (OR 1.75(1.32-2.31), p<0.001) remained significant. The best model for describing the relationship between serum uric acid levels (SUA) and intermittent hand joint pain in ≥10 joints was non-linear with a cut-off at 372 μmol/L. The attributable surplus number of symptomatic females with SUA ≥372 μmol/L was approximately 2.0% of the study population for those reporting pain in ≥10 hand joints. Next after having severe hand osteoarthritis, SUA ≥372 was an independent predictive factor of intermittent pain in ≥10 hand joints. Intermittent hand joint pain was also an independent risk factor for worse general health description. Results from this population based study indicate that hyperuricemia in elderly females may be a rather frequent cause of intermittent hand joint pain, often in many joints. The most likely explanation relates to low-grade urate crystal induced inflammation. Our data do not allow for assessment of the severity of symptoms or whether they merit specific treatment, but intermittent hand joint pain was an independent predictor of worse general health. These findings may be an important contribution to the debate on whether hyperuricemia should be treated.