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

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

Common variants associated with plasma triglycerides and risk for coronary artery disease

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P \u3c 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism\u27s effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved

An Overview on Renal and Central Regulation of Blood Pressure by Neuropeptide FF and Its Receptors

Neuropeptide FF (NPFF) is an endogenous octapeptide that was originally isolated from the bovine brain. It belongs to the RFamide family of peptides that has a wide range of physiological functions and pathophysiological effects. NPFF and its receptors, NPFFR1 and NPFFR2, abundantly expressed in rodent and human brains, participate in cardiovascular regulation. However, the expressions of NPFF and its receptors are not restricted within the central nervous system but are also found in peripheral organs, including the kidneys. Both NPFFR1 and NPFFR2 mainly couple to G&alpha;i/o, which inhibits cyclic adenosine monophosphate (cAMP) production. NPFF also weakly binds to other RFamide receptors and the Mas receptor. Relevant published articles were searched in PubMed, Google Scholar, Web of Science, and Scopus. Herein, we review evidence for the role of NPFF in the regulation of blood pressure, in the central nervous system, particularly within the hypothalamic paraventricular nucleus and the brainstem, and the kidneys. NPFF is a potential target in the treatment of hypertension

Approaches to Health Research Priority Setting in the Philippines across the Years

Background. As one of the research councils under the Department of Science and Technology (DOST), health research priority setting has been the mandate of the Philippine Council for Health Research and Development (PCHRD) since its establishment in 1982. The development of the National Unified Health Research Agenda (NUHRA) convenes the major stakeholders for health in the country to establish the priorities for health research. The NUHRA aims to address the most urgent health issues in the country for the generation of solutions to the health concerns of the country.&#x0D; Objectives and Method. Through document review, this paper describes the approaches and lessons learned in research priority setting since the establishment of the Philippine National Health Research System.&#x0D; Results. The Philippines has employed a bottoms-up, top-down, and a combination of both approaches to develop its health research agenda.&#x0D; Conclusion. The health research agenda-setting must consider evolving funding sources, its link to production of researches with high probability of knowledge translation to health technology innovation, and policy formulation. Measuring the impact of the NUHRA to the health systems and health situation of the country is a difficult assessment, but the gradual change in healthcare technology utilization and evidence-informed policies towards health equity can be a subjective measurement of the NUHRA’s success.</jats:p

Abstract 75: Nrf2 Mediates the Antioxidant Effect of D2r Via Dj-1 in the Kidney

Renal dopamine D2 receptor (D2R) dysfunction is associated with increased oxidative stress and high blood pressure. We have reported that DJ-1 is regulated by D2R in the kidney. Nrf2 is a transcription factor that regulates the expression of several antioxidant genes. We hypothesize that Nrf2 is involved in the DJ-1-mediated regulation of reactive oxygen species (ROS) production in the kidney. DJ-1 and Nrf2 co-inmunoprecipitate in mouse kidney. Selective renal silencing of D2R in mice by the renal subcapsular infusion of D2R siRNA (~50%) decreases Nrf2 expression (63.4%±3.4, n=7, P&lt;0.05), and silencing of D2R expression in mouse proximal tubule cells (mRPTCs) decrease Nrf2 promoter activity (53±2%, n=5, P&lt;0.05). Silencing DJ-1 expression in mRPTCs, via siRNA, decreases the expression of DJ-1 (75±4.5%, n=4, P&lt;0.05), Nrf2 (63.2±6%, n=3, P&lt;0.05), NQO1 (71±1%, n=3, P&lt;0.05), and GST Yc-2 (42±1%, n=4, P&lt;0.05) and Nrf2 promoter activity (58±1%, n=5, P&lt;0.05). Selective renal silencing of DJ-1 in mice by renal subcapsular infusion of DJ-1 siRNA decreases expression of DJ-1 (31±2.6%, n=3, P&lt;0.05), Nrf2 (57±7.9%,n=3, P&lt;0.05), NQO1 (46±9.3%, n=3, P&lt;0.05) and GST Yc2 (28±2.2%, n=3, P&lt;0.05) and increases blood pressure (BP). DJ-1 -/- mice also have increased systolic BP (30.7±1%, P&lt;0.01, n=5 under anesthesia) and renal expression of nitro-tyrosine (76.8±13.5%, P&lt;0.05, n=5), and decreases the expression of Nrf2 (46.8±6.8%, n=5, P&lt;0.05) and NQO1 (19.4±2.7%, n=5, P&lt;0.05). Silencing Nrf2 expression mRPTCs via siRNA decreases the expression of Nrf2 (34±1.8%, n=4, P&lt;0.05), NQO1 (29.1±0.5%, n=4, P&lt;0.05), and increases Nox2 (137±23.7%, n=4, P&lt;0.05), but the expression of Nox4 and DJ-1 are not affected. Quinpirole a D2R agonist, does not modify the expression of Nrf2, NQO1, GST Yc-2, and Nrf2 promoter activity in MPCTS. However, in the presence of H 2 O 2 , quinpirole increases Nrf2 promoter activity (220±58.4%, n=5, P&lt;0.05) and an effect that is blocked by pretreatment with D2R antagonist L741,626. Therefore, the inhibitory effect of DJ-1 on renal ROS production is, in part, mediated by positive regulation of Nrf2. Moreover, D2R and DJ-1 are necessary for normal Nrf2 activity to keep a normal redox balance in the kidney. </jats:p