Adiposity, Cardiometabolic Risk, and Vitamin D Status: The Framingham Heart Study

OBJECTIVE: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear. RESEARCH DESIGN AND METHODS: We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT). RESULTS: In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001). CONCLUSIONS: Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC-25195, R01-DK-80739): American Heart Associatio

Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study

BACKGROUND: Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. METHODS: We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001. RESULTS: With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at . CONCLUSION: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC25195); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1); National Institutes of Health (HL064753, HL076784, AG028321, HL71039, 2 K24HL04334, 1K23 HL083102); Doris Duke Charitable Foundation; American Diabetes Association Career Developement Award; National Center for Research Resources (GCRC M01-RR01066); US Department of Agriculture Agricultural Research Service (58-1950-001, 58-1950-401); National Institute of Aging (AG14759

Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study.</p> <p>Methods</p> <p>We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p ≥ 0.001.</p> <p>Results</p> <p>We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at <url>http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007</url>. We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. Overall, p < 10^-5in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (<it>SLIT2</it>, p = 1.17*10^-7); LV systolic dimension, rs10504543 (<it>KCNB2</it>, p = 5.18*10^-6); LV mass, rs10498091 (p = 5.68*10^-6); Left atrial size, rs1935881 (<it>FAM5C</it>, p = 6.56*10^-6); exercise heart rate, rs6847149 (<it>NOLA1</it>, p = 2.74*10^-6); exercise systolic blood pressure, rs2553268 (<it>WRN</it>, p = 6.3*10^-6); BA baseline flow, rs3814219 (<it>OBFC1</it>, 9.48*10^-7), and FMD, rs4148686 (<it>CFTR</it>, p = 1.13*10^-5). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; chromosome 5); the 1.5 LOD support interval included <it>NRG2</it>.</p> <p>Conclusion</p> <p>In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.</p

Prevalence and prognostic impact of subclinical cardiovascular disease in individuals with the metabolic syndrome and diabetes

Dostępne dane dotyczące występowania i znaczenia prognostycznego subklinicznej postaci choroby sercowo-naczyniowej (CVD), u pacjentów z zespołem metabolicznym są ograniczone. W prezentowanej pracy zbadano częstość występowania subklinicznej choroby sercowo-naczyniowej u 1945 uczestników próby Framingham Offspring Study (śr. wieku 58 lat, 59% uczestników stanowiły kobiety) z wykorzystaniem elektrokardiografii, echokardiografii, ultra ultrasonografii tętnic szyjnych, wskaźnika ciśnienia tętniczego kostka&#8211;ramię oraz wydalania albumin z moczem. W pracy oceniono w sposób prospektywny częstość występowania subklinicznej choroby sercowo-naczyniowej związanej z zespołem metabolicznym i cukrzycą, w zależności od obecności subklinicznej postaci tego schorzenia lub jej braku. Przekrojowo u 51% z 581 uczestników z zespołem metabolicznym zdiagnozowano subkliniczną formę choroby sercowo-naczyniowej w przynajmniej jednym z badań dodatkowych, co było częstsze niż u chorych bez zespołu metabolicznego [iloraz szans skorygowany pod względem wielu zmiennych 2,06 (95% CI: 1,67&#8211;2,55); p < 0,0001]. W trakcie dalszej obserwacji klinicznej (śr. 7,2 lat) jawna klinicznie choroba sercowo-naczyniowa rozwinęła się u 139 pacjentów, 59% tej liczby stanowiły osoby z zespołem metabolicznym (10,2%). Uogólniając, występowanie zespołu metabolicznego było związane ze zwiększonym ryzykiem występowania CVD [iloraz ryzyka skorygowany pod względem wielu zmiennych (HR, hazard ratio) 1,61 (95% CI: 1,12&#8211;2,33)]. U pacjentów z zespołem metabolicznym oraz subkliniczną postacią choroby sercowo-naczyniowej zaobserwowano zwiększone ryzyko wystąpienia jawnej klinicznie postaci choroby sercowo-naczyniowej [2,67 (1,62&#8211;4,41) w porównaniu z chorymi bez zdiagnozowanego zespołu metabolicznego, cukrzycy lub subklinicznej formy choroby sercowo-naczyniowej]. Zaobserwowano także mniejszy związek występowania zespołu metabolicznego z rozwinięciem się choroby sercowo-naczyniowej u pacjentów bez subklinicznej postaci CVD [HR 1,59 (95% CI: 0,87&#8211;2,90)]. Podobne zmniejszenie ryzyka wystąpienia choroby sercowo-naczyniowej u pacjentów bez subklinicznej postaci CVD obserwowano u chorych na cukrzycę. Występowanie subklinicznej formy CVD stanowiło istotny predyktor rozwinięcia się jawnej klinicznie choroby sercowo-naczyniowej u pacjentów bez zespołu metabolicznego lub cukrzycy [1,93 (1,15&#8211;3,24)]. W niniejszym populacyjnym badaniu osób z zespołem metabolicznym zaobserwowano częstsze występowanie subklinicznej postaci miażdżycy, co prawdopodobnie przyczynia się do wyższego ryzyka wystąpienia jawnej klinicznie postaci CVD związanej z tym schorzeniem.Data are limited regarding prevalence and prognostic significance of subclinical cardiovascular disease (CVD) in individuals with metabolic syndrome. We investigated prevalence of subclinical CVD in 1,945 Framingham Offspring Study participants (mean age 58 years; 59% women) using electrocardiography, echocardiography, carotid ultrasound, ankle-brachial blood pressure, and urinary albumin excretion. We prospectively evaluated the incidence of CVD associated with metabolic syndrome and diabetes according to presence versus absence of subclinical disease. Cross-sectionally, 51% of 581 participants with metabolic syndrome had subclinical disease in at least one test, a frequency higher than individuals without metabolic syndrome [multivariable- adjusted odds ratio 2.06 (95% CI: 1.67- 2.55); p < 0.0001). On follow-up (mean 7.2 years), 139 individuals developed overt CVD, including 59 with metabolic syndrome (10.2%). Overall, metabolic syndrome was associated with increased CVD risk [multivariableadjusted hazards ratio (HR) 1.61 (95% CI: 1.12-2.33)]. Participants with metabolic syndrome and subclinical disease experienced increased risk of overt CVD [2.67 (1.62-4.41) compared with those without metabolic syndrome, diabetes, or subclinical disease], whereas the association of metabolic syndrome with CVD risk was attenuated in absence of subclinical disease [HR 1.59 (95% CI: 0.87&#8211;2.90)]. A similar attenuation of CVD risk in absence of subclinical disease was observed also for diabetes. Subclinical disease was a significant predictor of overt CVD in participants without metabolic syndrome or diabetes [1.93 (1.15-3.24)]. In our community-based sample, individuals with metabolic syndrome have a high prevalence of subclinical atherosclerosis that likely contributes to the increased risk of overt CVD associated with the condition

p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G1 phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Blood pressure response to renal artery stenting in 901 patients from five prospective multicenter FDA-approved trials

Background Renal artery stent revascularization is commonly used for renovascular hypertension. Clinical predictors associated with blood pressure (BP) improvement after renal artery stent revascularization are not well understood. Methods Patient-level data from 901 patients in five prospective multicenter Food and Drug Administration-approved investigational device exemption studies of renal artery stent revascularization was pooled. BP response was defined as reduction of systolic BP (SBP) by >10 mm Hg. Stent patency was defined within each study. Associations of BP reduction were determined by logistic regression. Results Of 901 patients, complete outcome information was available in 527. Of these, 212/527 (40%) were male, mean age was 63 ± 13 years, 196/544 (36%) were diabetic and 504/527 (96%) had a SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg at baseline. Compared to baseline, 9-month systolic (164 ± 21 mm Hg vs. 146 ± 22 mm Hg, P 150 mm Hg (OR = 4.09, CI = 2.74-6.12, P 150 mm Hg) was strongly associated with BP reduction after the procedure. © 2013 Wiley Periodicals, Inc