Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Dopamine D\u3csub\u3e1\u3c/sub\u3e-like receptors regulate the α\u3csub\u3e1A\u3c/sub\u3e-adrenergic receptor in human renal proximal tubule cells and D\u3csub\u3e1\u3c/sub\u3e-like dopamine receptor knockout mice

© 2014 the American Physiological Society. The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D1-like dopamine receptors [dopamine D1 and D5 receptors (D1Rs and D5Rs, respectively)] and the a1A-adrenergic receptor (α1A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na+ transport, i.e., natriuresis (via D1Rs and D5Rs) or antinatriuresis (via α1A-ARs). We tested the hypothesis that the D1R/D5R regulates the α1A-AR. D1-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with ct1A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D1R/D5R agonist fenoldopam resulted in decreased D1R and D5R expression but increased α1A-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na+-K+-ATPase from the plasma membrane to the cytosol that was partially reversed by an α1A-AR agonist, which by itself induced Na+-K+-ATPase translocation from the cytosol to the plasma membrane. The a1A-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na+-K+-ATPase activity. To determine the interaction among D1Rs, D5Rs, and α1A-ARs in vivo, we used phenylephrine and A610603 to decrease Na+ excretion in several D1-like dopamine receptor knockout mouse strains. Phenylephrine and A61603 treatment resulted in a partial reduction of urinary Na+ excretion in wild-type mice and its abolition in D1R knockout, D5R knockout, and D1R-D5R double-knockout mice. Our results demonstrate the ability of the D1-like dopamine receptors to regulate the expression and activity of α1A-AR. Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems

Economic recovery and long-run growth: Agenda for reforms

The package of structural reforms contained in this report addresses the need both for economic recovery in the near-term and stable growth in the long­ run. It is being proposed to the new regime as a possible framework for that preparation of a development plan and for the formulation of more specific policies. The proposals have ·been drawn up with the intention that they (1) be mutually consistent, (2) proceed from a realistic assessment of the situation, and (3) have a common commitment to a set of guiding principles, namely; respect for human rights, social justice and poverty alleviation, a recognition. of the urgency of growth and greater efficiency, and a minimum of government intervention. Certain vital reforms have to be implemented in the short run both to reverse the sharp economic decline ·and to set the stage for implementing a more forward-looking development strategy. The bulk of these reforms aim simply at undoing the biases and penalties carried over from the previous regime. These include: External Debt - The approach· to managing external debt should proceed from what is required for reasonable growth, not what the creditors impose. With a decline in real GNP of 10 percent in the last two years, it is time the government refuse to subordinate growth to an overly burdensome debt service. Monetary Policy - To insure stability and efficiency of the financial system, reforms in monetary policy should be effected including the following: the independence of the Central Bank from political and other interest groups must be reasserted and preserved; Central Bank functions should be limited to the stabilization of prices, interest rates, and exchange rates in the short-run; the Central Bank should not participate in development finance or issue its own interest-bearing bills (e.g. Jobo bills). To promote economic recovery, monetary policy should be expansionary. In the past, monetary policy bad been excessively contractionary -- giving more emphasis on debt servicing rather than on growth. Fiscal Policy - We call for a reduction in the scope of government, which may require government reorganization, a downscaling, abolition, or merger of some offices. We propose a tax structure that relies more on direct than on indirect taxes; local government finance consistent with the spirit of decentralization. Government should intervene only when it can do better. Government Structure - The key reforms proposed, include decentralization i.e. devolution of power and authority (including broadened tax sourcing); checks and balances. Distributive Justice -·Expansion of the scope of land reform to include all natural resources and crops. If distributive justice is to be achieved, the government should commit itself to poverty targets. Monitoring should be undertaken not bythe regular government statistical offices but also by the private sector Population and Basic Services - Education, health, housing and social services call for individual and collective reforms to respond to the poverty alleviation objective and, at the same time, to improve the prospects for recovery and sustained growth. In order to allow greater benefits from growth and to make up for recent slippage, a strong commitment to population policy should be enunciated. Social service should receive a much greater share of the government’s budget. 7. Labor and Employment - Changes in the manner of wage setting are necessary to promote employment. We must do away with mandatory wage setting and opt for wider information access (by both management and labor) as a basis. therefor. We must strengthen collective bargaining and voluntary arbitration as a basis for settling labor-management disputes, For recovery, emergency employment assistance (preferably financed by external donors) should be provided to as in any unemployed to undertake infrastructure work in support of agriculture and rural development. 8. Trade - There should be a more open trade regime, with an exchange rate that reflects the real conditions of the market. Liberalization should be pursued quickly while a battery of consumption taxes is enacted. These reforms intend to achieve a more liberal and more neutral policy regime that allows for growth. Yet leaves it to private initiative to explore and reveal the areas of true economic promise, with a minimum of government direction and intervention. The direct economic role of government is not envisioned to be large, although it will be significant in such areas as social justice, the dissemination of information, and the support of research and technology. As distortions are removed and the debt-burden is reduced, we fully expect formerly penalized sectors to make-a larger contribution to growth. The implementation of these reforms will, therefore, naturally lead to a development strategy that is employment-oriented and rural-based. The government should support this course of evolution by redirecting its infrastructure programs towards the rural areas. In the same manner, for trade and industry, we expect industrial growth and restructuring to occur which rely on competitiveness both at home and abroad, and are supportive of rural development

The role of dietary coconut for the prevention and treatment of Alzheimer's disease: potential mechanisms of action

Coconut, Cocos nucifera L., is a tree that is cultivated to provide a large number of products, although it is mainly grown for its nutritional and medicinal values. Coconut oil, derived from the coconut fruit, has been recognised historically as containing high levels of saturated fat; however, closer scrutiny suggests that coconut should be regarded more favourably. Unlike most other dietary fats that are high in long-chain fatty acids, coconut oil comprises medium-chain fatty acids (MCFA). MCFA are unique in that they are easily absorbed and metabolised by the liver, and can be converted to ketones. Ketone bodies are an important alternative energy source in the brain, and may be beneficial to people developing or already with memory impairment, as in Alzheimer's disease (AD). Coconut is classified as a highly nutritious ‘functional food’. It is rich in dietary fibre, vitamins and minerals; however, notably, evidence is mounting to support the concept that coconut may be beneficial in the treatment of obesity, dyslipidaemia, elevated LDL, insulin resistance and hypertension – these are the risk factors for CVD and type 2 diabetes, and also for AD. In addition, phenolic compounds and hormones (cytokinins) found in coconut may assist in preventing the aggregation of amyloid-ß peptide, potentially inhibiting a key step in the pathogenesis of AD. The purpose of the present review was to explore the literature related to coconut, outlining the known mechanistic physiology, and to discuss the potential role of coconut supplementation as a therapeutic option in the prevention and management of AD