Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes ...from the 1000 Genomes Project, we report a GWAS meta-analysis of ~185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a ...social and not a biologic construct.
We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.
In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m
of body-surface area; 95% confidence interval CI, 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m
; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m
; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m
; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m
; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.
New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
On periodically driven AdS/CFT Auzzi, Roberto; Elitzur, Shmuel; Gudnason, Sven Bjarke ...
The journal of high energy physics,
11/2013, Letnik:
2013, Številka:
11
Journal Article
Recenzirano
Odprti dostop
A
bstract
We use the AdS/CFT correspondence to study a thermally isolated conformal field theory in four dimensions which undergoes a repeated deformation by an external periodic time-dependent ...source coupled to an operator of dimension Δ. The initial state of the theory is taken to be at a finite temperature. We compute the energy dissipated in the system as a function of the frequency and of the dimension Δ of the perturbing operator. This is done in the linear response regime. In order to study the details of thermalization in the dual field theory, the leading-order backreaction on the AdS black brane metric is computed. The evolution of the event and the apparent horizons is monitored; the increase of area in each cycle coincides with the increase in the equilibrium entropy corresponding to the amount of energy dissipated. The time evolution of the entanglement entropy of a spherical region and that of the two-points function of a probe operator with a large dimension are also inspected; we find a delay in the thermalization of these quantities which is proportional to the size of the region which is being probed. Thus, the delay is more pronounced in the infrared. We comment on a possible transition in the time evolution of the energy fluctuations.
A
bstract
We present a class of supersymmetric models which address the flavor puzzle and have an inverted hierarchy of sfermions. Their construction involves quiver-like models with link fields in ...generic representations. The magnitude of Standard-Model parameters is obtained naturally and a relatively heavy Higgs boson is allowed without fine tuning. Collider signatures of such models are possibly within the reach of LHC in the near future.
Mediation of supersymmetry breaking in quivers Auzzi, Roberto; Giveon, Amit; Gudnason, Sven Bjarke
The journal of high energy physics,
12/2011, Letnik:
2011, Številka:
12
Journal Article
Recenzirano
Odprti dostop
A
bstract
The soft masses due to SUSY breaking, mediated by gauge fields, are computed for generic matter in quiver gauge theories.
New eGFR equations from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) using creatinine (eGFRcr), cystatin C (eGFRcys), and both ...(eGFRcr-cys) have sufficient accuracy for use in clinical practice, leading to uncertainty in selecting equations for implementation. The authors evaluated performance of equations in an independent population of 4050 adults and evaluated other considerations important for implementation. They found that CKD-EPI and EKFC equations are approaching convergence, with better performance of eGFRcr-cys equations in the overall group and fewer differences among race, sex, and age subgroups than eGFRcr equations. Larger differences among eGFRcr equations reflect regional population differences in creatinine, forcing a trade-off between accuracy and uniformity in global implementation of eGFRcr equations. More widespread use of cystatin C could avoid this trade-off.
New CKD-EPI and EKFC eGFR equations using eGFRcr, eGFRcys, and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global implementation.
We evaluated performance (bias and P 30 ) of equations and methods used for equation development in an independent study population comprising 4050 adults pooled from 12 studies. The mean (SD) measured GFR was 76.4 (29.6) ml/min per 1.73 m 2 and age 57.0 (17.4) years, with 1557 (38%) women and 579 (14%) Black participants.
Coefficients for creatinine, cystatin C, age, and sex in the CKD-EPI and EKFC equations are similar. Performance of the eGFRcr-cys equations in the overall population (bias <±5 ml/min per 1.73 m 2 and P 30 >90%) was better than the eGFRcr or eGFRcys equations, with fewer differences among race, sex, and age subgroups. Differences in performance across subgroups reflected differences in diversity of source populations and use of variables for race and sex for equation development. Larger differences among eGFRcr equations reflected regional population differences in non-GFR determinants of creatinine.
CKD-EPI and EKFC equations are approaching convergence. It is not possible to maximize both accuracy and uniformity in selecting one of the currently available eGFRcr equations for implementation across regions. Decisions should consider methods for equation development in addition to performance. Wider use of cystatin C with creatinine could maximize both accuracy and uniformity of GFR estimation using currently available equations.
Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, ...respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person’s race. β2-Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.
Study of diagnostic test accuracy.
Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants.
Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race.
GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of 51CrEDTA.
Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR 1 − P30 of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 − P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.
No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.
The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.
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Time-dependent stabilization in AdS/CFT Auzzi, Roberto; Elitzur, Shmuel; Gudnason, Sven Bjarke ...
The journal of high energy physics,
08/2012, Letnik:
2012, Številka:
8
Journal Article
Recenzirano
Odprti dostop
A
bstract
We consider theories with time-dependent Hamiltonians which alternate between being bounded and unbounded from below. For appropriate frequencies dynamical stabilization can occur rendering ...the effective potential of the system stable. We first study a free field theory on a torus with a time-dependent mass term, finding that the stability regions are described in terms of the phase diagram of the Mathieu equation. Using number theory we have found a compactification scheme such as to avoid resonances for all momentum modes in the theory. We further consider the gravity dual of a conformal field theory on a sphere in three spacetime dimensions, deformed by a doubletrace operator. The gravity dual of the theory with a constant unbounded potential develops big crunch singularities; we study when such singularities can be cured by dynamical stabilization. We numerically solve the Einstein-scalar equations of motion in the case of a time-dependent doubletrace deformation and find that for sufficiently high frequencies the theory is dynamically stabilized and big crunches get screened by black hole horizons.
Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to ...identify common genetic variants associated with CAC and further investigate their associations with MI.
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
A light stop with flavor in natural SUSY Auzzi, Roberto; Giveon, Amit; Gudnason, Sven Bjarke ...
The journal of high energy physics,
01/2013, Letnik:
2013, Številka:
1
Journal Article
Recenzirano
Odprti dostop
A
bstract
The discovery of a SM-like Higgs boson near 125 GeV and the flavor texture of the Standard Model motivate the investigation of supersymmetric quiver-like BSM extensions. We study the ...properties of such a minimal class of models which deals naturally with the SM parameters. Considering experimental bounds as well as constraints from flavor physics and Electro-Weak Precision Data, we find the following. In a self-contained minimal model — including the full dynamics of the Higgs sector — top squarks below a TeV are in tension with
b
→
s
γ constraints. Relaxing the assumption concerning the mass generation of the heavy Higgses, we find that a stop not far from half a TeV is allowed. The models have some unique properties, e.g. an enhancement of the
h
→
,
decays relative to the
h
→ γγ one, a gluino about 3 times heavier than the stop, an inverted hierarchy of about 3 ÷ 20 between the squarks of the first two generations and the stop, relatively light Higgsino neutralino or stau NLSP, as well as heavy Higgses and a
W
′
which may be within reach of the LHC.
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