60 research outputs found
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<sup>-5 </sup>in 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<sup>-7</sup>); LV systolic dimension, rs10504543 (<it>KCNB2</it>, p = 5.18*10<sup>-6</sup>); LV mass, rs10498091 (p = 5.68*10<sup>-6</sup>); Left atrial size, rs1935881 (<it>FAM5C</it>, p = 6.56*10<sup>-6</sup>); exercise heart rate, rs6847149 (<it>NOLA1</it>, p = 2.74*10<sup>-6</sup>); exercise systolic blood pressure, rs2553268 (<it>WRN</it>, p = 6.3*10<sup>-6</sup>); BA baseline flow, rs3814219 (<it>OBFC1</it>, 9.48*10<sup>-7</sup>), and FMD, rs4148686 (<it>CFTR</it>, p = 1.13*10<sup>-5</sup>). 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–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: 1,67–2,55); 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: 1,12–2,33)]. U pacjentów
z zespołem metabolicznym oraz subkliniczną
postacią choroby sercowo-naczyniowej zaobserwowano
zwiększone ryzyko wystąpienia jawnej klinicznie
postaci choroby sercowo-naczyniowej [2,67
(1,62–4,41) 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: 0,87–2,90)].
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 (1,15–3,24)].
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: 0.87–2.90)]. 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
Recommended from our members
Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma
Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease
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 .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the 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
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