Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Assessing the Association Between Exercise Status and Poor Glycemic Control

Background: Increased physical activity may be associated with greater glycemic control among adults with diabetes mellitus. However, the area is understudied. The objective of the study was to examine the independent association of exercise status with poor glycemic control, adjusting for patient-level covariates. Methods: We studied a population of Kaiser Permanente Northwest members with type 2 diabetes mellitus who were in: 1) good glycemic control (hemoglobin A1c [HbA1c] \u3c 8%; n = 15,891), or 2) poor glycemic control (HbA1c \u3e 9%; n = 3,709). Additional inclusion criteria included an HbA1c test between July 1, 2014, and June 30, 2015, age 18-plus at time of test, and continuous health plan coverage 12 months prior to HbA1c test. The primary independent was current physical activity status — whether an individual exercised 4 or more times per week (yes vs no) — and was assessed as closely as possible to the HbA1c test date. Multiple logistic regression was used to analyze the independent association of exercise status with poor glycemic control, adjusting for demographics, medication adherence, medical comorbidities, health care utilization, receipt of diabetes mellitus care management services and intensity of diabetes mellitus treatments. Results: Those who exercised 4 or more times per week were less likely to have poor glycemic control (odds ratio: 0.75; 95% confidence interval: 0.68–0.82; P \u3c 0.0001) compared with those who exercised 3 or fewer times per week. Conclusion: Increased exercise is independently associated with a lower likelihood of poor glycemic control among an adult population with type 2 diabetes mellitus. Because physical activity is a potentially modifiable factor, further studies are needed to evaluate whether interventions aimed at increasing physical activity result in subsequent gains in glycemic control

Delta Flow Factors Influencing Stray Rate of Escaping Adult San Joaquin River Fall-Run Chinook Salmon (Oncorhynchus tshawytscha)

Adult salmon that stray when they escape into non-natal streams to spawn is a natural phenomenon that promotes population growth and genetic diversity, but excessive stray rates impede adult abundance restoration efforts. Adult San Joaquin River (SJR) Basin fall-run Chinook salmon (Oncorhynchus tshawytscha) that return to freshwater to spawn migrate through the San Francisco Bay and Sacramento–San Joaquin River Delta (Delta). The Delta has been heavily affected by land development and water diversion. During the fall time-period for the years 1979 to 2007 Delta pumping facilities diverted on average 340% of the total inflow volume that entered the Delta from the SJR. The hypothesis tested in this paper is that river flow and Delta exports are not significantly correlated with SJR salmon stray rates. Adult coded-wire-tagged salmon recoveries from Central Valley rivers were used to estimate the percentage of SJR Basin salmon that strayed to the Sacramento River Basin. SJR salmon stray rates were negatively correlated (P = 0.05) with the average magnitude of pulse flows (e.g., 10 d) in mid- to late-October and positively correlated (P = 0.10) with mean Delta export rates. It was not possible to differentiate between the effects of pulse flows in October and mean flows in October and November on stray rates because of the co-linearity between these two variables. Whether SJR-reduced pulse flow or elevated exports causes increased stray rates is unclear. Statistically speaking the results indicate that flow is the primary factor. However empirical data indicates that little if any pulse flow leaves the Delta when south Delta exports are elevated, so exports in combination with pulse flows may explain the elevated stray rates. For management purposes, we developed two statistical models that predict SJR salmon stray rate: (1) flow and export as co-independent variables; and (2) south Delta Export (E) and SJR inflow (I) in the form of an E:I ratio.&nbsp

Delivery System Partnerships Empower Large Pragmatic Trials: The Case of Diabetes Prevention in Kaiser Permanente

Background/Aims: Successful pragmatic trials require close partnership between researchers and health care organizations. We describe the process by which we engaged clinical and operational leaders from three Kaiser Permanente (KP) regions to design a trial to test alternative population-based models for diabetes prevention. Methods: The study leveraged ongoing efforts in each region to develop a populationwide approach to diabetes prevention. Working with clinical leaders from KP Northwest (KPNW), we designed an initial study that we then took to the leadership of KP Southeast and KP Hawaii. We also obtained the endorsement of KP’s national Care Management Institute (CMI). After submitting a successful letter-of-intent to the Patient-Centered Outcomes Research Institute, we worked with our health plan partners to develop a full proposal that is presently under review. Results: Throughout the proposal development process, we consulted key regional and national health plan stakeholders on various design issues. We also included the KPNW lead for diabetes management as a full co-investigator and regular member of our weekly planning meetings. As a direct result of these interactions, we dropped our initial three-arm design in favor of a two-arm design because it became clear that our planned low-intensity arm would likely be obsolete by the time the grant was funded. We also decided to focus our study on those at highest risk for progressing to diabetes since this was where the organization clearly intended to focus its greatest energy. Finally we leveraged an ongoing demonstration project being coordinated by the CMI to evaluate an online diabetes prevention curriculum that was seen as a scalable model for providing a proven lifestyle change program to our members nationwide. We incorporated this program into our intervention design and conducted interviews with patients to better understand their perspective regarding the overall usefulness of the program and barriers to participation. To meet the needs of members who preferred face-face classes, we also partnered with local diabetes programs in our communities to provide this option. Discussion: Our process of stakeholder engagement directly informed the design of the trial and helped to ensure strong institutional support for the study should it be funded

Delivery System Partnerships Empower Large Pragmatic Trials: The Case of Diabetes Prevention in Kaiser Permanente

Background/Aims: Successful pragmatic trials require close partnership between researchers and health care organizations. We describe the process by which we engaged clinical and operational leaders from three Kaiser Permanente (KP) regions to design a trial to test alternative population-based models for diabetes prevention. Methods: The study leveraged ongoing efforts in each region to develop a populationwide approach to diabetes prevention. Working with clinical leaders from KP Northwest (KPNW), we designed an initial study that we then took to the leadership of KP Southeast and KP Hawaii. We also obtained the endorsement of KP’s national Care Management Institute (CMI). After submitting a successful letter-of-intent to the Patient-Centered Outcomes Research Institute, we worked with our health plan partners to develop a full proposal that is presently under review. Results: Throughout the proposal development process, we consulted key regional and national health plan stakeholders on various design issues. We also included the KPNW lead for diabetes management as a full co-investigator and regular member of our weekly planning meetings. As a direct result of these interactions, we dropped our initial three-arm design in favor of a two-arm design because it became clear that our planned low-intensity arm would likely be obsolete by the time the grant was funded. We also decided to focus our study on those at highest risk for progressing to diabetes since this was where the organization clearly intended to focus its greatest energy. Finally we leveraged an ongoing demonstration project being coordinated by the CMI to evaluate an online diabetes prevention curriculum that was seen as a scalable model for providing a proven lifestyle change program to our members nationwide. We incorporated this program into our intervention design and conducted interviews with patients to better understand their perspective regarding the overall usefulness of the program and barriers to participation. To meet the needs of members who preferred face-face classes, we also partnered with local diabetes programs in our communities to provide this option. Discussion: Our process of stakeholder engagement directly informed the design of the trial and helped to ensure strong institutional support for the study should it be funded

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways