The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for ...early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.
We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.
The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).
Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.
URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.
Between 1.8 and 1.0 Ga (Grenville-age), a series of subparallel accretionary orogens were added progressively to the southern edge of Laurentia. These belts now extend from Greenland/Labrador to ...southern California and are truncated at late Precambrian passive margins, suggesting that they once extended farther. We propose that Australia and Baltica contain their continuations. Together they comprise a long-lived orogenic system, >10 000 km long, that preserves a record of 800 million years of convergent margin tectonism. This tectonism culminated during Grenvillian continent–continent collisions in the assembly of the supercontinent Rodinia. Our reconstruction of the Australia–western US part of this assembly (AUSWUS) differs from the SWEAT reconstruction in that Australia is adjacent to the southwestern US rather than to northern Canada. The AUSWUS reconstruction is supported by a distinctive ‘fingerprint’ of geologic similarities between Australia and the southwestern US from 1.8 to 1.0 Ga, by numerous possible piercing points, and by an arguably better agreement between 1.45 and 1.0 Ga paleomagnetic poles between Australia and Laurentia. Geologic and paleomagnetic data suggest that separation between Laurentia and Australia took place ∼800–755 Ma and between Laurentia and Baltica ∼610 Ma. The proposed association of Australia, Laurentia, and Baltica, and the long-lived convergent margin they expose, provide a set of testable implications for the tectonic evolution of these cratons, and an important constraint for Proterozoic plate reconstructions.
The Matachewan Large Igneous Province (LIP) is interpreted to have formed during the early stages of mantle plume-induced continental break-up in the early Proterozoic. When the Matachewan LIP is ...reconstructed to its original configuration with units from the Superior Craton and other formerly adjacent blocks (Karelia, Kola, Wyoming and Hearne), the dyke swarms, layered intrusions and flood basalts, emplaced over the lifetime of the province, form one of the most extensive magmatic provinces recognized in the geological record. New geochemical data allow, for the first time, the Matachewan LIP to be considered as a single, coherent entity and show that Matachewan LIP rocks share a common tholeiitic composition and trace element geochemistry, characterized by enrichment in the most incompatible elements and depletion in the less incompatible elements. This signature, ubiquitous in early Proterozoic continental magmatic rocks, may indicate that the Matachewan LIP formed through contamination of the primary magmas with lithospheric material or that the early Proterozoic mantle had a fundamentally different composition from the modern mantle. In addition to the radiating geometry of the dyke swarms, a plume origin for the Matachewan LIP is consistent with the geochemistry of some of the suites; these suites are used to constrain a source mantle potential temperature of c. 1500-1550 degree C. Comparison of these mantle potential temperatures with estimated temperatures for the early Proterozoic upper mantle indicates that they are consistent with a hot mantle plume source for the magmatism. Geochemical data from coeval intrusions suggest that the plume head was compositionally heterogeneous and sampled material from both depleted and enriched mantle. As has been documented with less ancient but similarly vast LIPs, the emplacement of the Matachewan LIP probably had a significant impact on the early Proterozoic global environment. Compilation of the best age estimates for various suites shows that the emplacement of the Matachewan LIP occurred synchronously with the Great Oxidation Event. We explore the potential for the eruption of this LIP and the emission of its associated volcanic gases to have been a driver of the irreversible oxygenation of the Earth.
The goal of this study was to determine the prevalence of worsening renal function (WRF) among hospitalized heart failure (HF) patients, clinical predictors of WRF, and hospital outcomes associated ...with WRF.
Impaired renal function is associated with poor outcomes among chronic HF patients.
Chart reviews were performed on 1,004 consecutive patients admitted for a primary diagnosis of HF from 11 geographically diverse hospitals. Cox regression model analysis was used to identify independent predictors for WRF, defined as a rise in serum creatinine of >0.3 mg/dl (26.5 μmol/l). Bivariate analysis was used to determine associations of development of WRF with outcomes (in-hospital death, in-hospital complications, and length of stay).
Among 1,004 HF patients studied, WRF developed in 27%. In the majority of cases, WRF occurred within three days of admission. History of HF or diabetes mellitus, admission creatinine ≥1.5 mg/dl (132.6 μmol/l), and systolic blood pressure >160 mm Hg were independently associated with higher risk of WRF. A point score based on these characteristics and their relative risk ratios predicted those at risk for WRF. Hospital deaths (adjusted risk ratio ARR 7.5; 95% confidence intervals CI 2.9, 19.3), complications (ARR 2.1; CI 1.5, 3.0), and length of hospitalizations >10 days (ARR 3.2, CI 2.2, 4.9) were greater among patients with WRF.
Worsening renal function occurs frequently among hospitalized HF patients and is associated with significantly worse outcomes. Clinical characteristics available at hospital admission can be used to identify patients at increased risk for developing WRF.
Background: Worsening renal function in patients hospitalized for heart failure portends a poor prognosis. However, criteria used to define worsening renal function are arbitrary, and the ...implications of different definitions remain unclear. We therefore compared the prognostic importance of various definitions of worsening renal function in 1,002 patients hospitalized for congestive heart failure (CHF). Methods and Results: The patient population was 49% female, aged 67 ± 15 years. Twenty-three percent had a prior history of renal failure, 73% had known depressed ejection fraction, and 63% had known CHF. On admission to the hospital, 47% were receiving ACE inhibitors, 22% β-blockers, 70% diuretics and 6% NAID's. 72% developed increased serum creatinine during the hospitalization, with 20% developing an increase of ≥ 0.5 mg/dL. Worsening renal function predicted both in-hospital mortality and length of stay > 10 days. Even an increased creatinine of 0.1 mg/dL was associated with worse outcome. Sensitivity for death decreased from 92% to 65% as the threshold for increased creatinine was raised from 0.1 to 0.5 mg/dL, with specificity increasing from 28% to 81%. At a threshold of a 0.3 mg/dL increase, sensitivity was 81% and specificity was 62% for death and 64% and 65% for length of stay >10 days. Adding a requirement of final creatinine of ≥ 1.5 mg/dL improved specificity. Conclusions: This analysis demonstrates that any detectable decrease in renal function is associated with increased mortality and prolonged hospital stay. This suggests that therapeutic interventions which improve renal function might be beneficial.
Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice ...site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.
Among patients who are hospitalized with heart failure (HF), worsening renal function (WRF) is associated with worse outcomes. Whether treatment for HF contributes to WRF is unknown. In this study, ...we sought to assess whether acute treatment for patients who were hospitalized with HF contributes to WRF.
Data were collected in a nested case-control study on 382 subjects who were hospitalized with HF (191 patients with WRF, defined as a rise in serum creatinine level >26.5 μmol/L 0.3 mg/dL, and 191 control subjects). The association of medications, fluid intake/output, and weight with WRF was assessed.
Calcium channel blocker (CCB) use and loop diuretic doses were higher in patients on the day before WRF (25% vs 10% for CCB; 199 ± 195 mg vs 143 ± 119 mg for loop diuretics; both
P <.05). There were no significant differences in the fluid intake/output or weight changes in the 2 groups. Angiotensin-converting enzyme (ACE) inhibitor use was not associated with WRF. Other predictors of WRF included elevated creatinine level at admission, uncontrolled hypertension, and history of HF or diabetes mellitus. Higher hematocrit levels were associated with a lower risk. Vasodilator use was higher among patients on the day before WRF (46% vs 35%,
P <.05), but was not an independent predictor in the multivariable analysis.
Several medical strategies, including the use of CCBs and a higher dose of loop diuretics, but not ACE inhibitors, were associated with a higher risk of WRF. Although assessment of inhospital diuresis was limited, WRF could not be explained by greater fluid loss in these patients. Determining whether these interventions are responsible for WRF or are markers of higher risk requires further investigation.
A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene (
) are identified in ...1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia.
To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls.
Rare variants in
were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene (
), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in
was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80-3.26;
=5.50×10
). These variants were associated with higher systolic blood pressure (+3.25 mm Hg; 95% CI, 1.86-4.65;
=5.00×10
) and increased risk of hypertension (adjusted odds ratio 1.31; 95% CI, 1.14-1.51;
=2.00×10
) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk.
Beyond
, we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the
gene.
We report paleomagnetic and rock magnetic data from volcanic, volcaniclastic, and intrusive rocks of the 55–44
Ma Absaroka Volcanic Supergroup (AVS) exposed along the northeastern margin of ...Yellowstone National Park and adjacent areas. Demagnetization behavior and rock magnetic experiments indicate that the remanence in most samples is carried by low-Ti titanomagnetite, although high-coercivity phases are present in oxidized basalt flows. Paleomagnetic demagnetization and rock magnetic characteristics, the presence of normal and reverse polarity sites, consistency with previous results, and positive conglomerate tests suggest that the observed remanences are primary thermoremanent magnetizations of Eocene age (c. 50
Ma). An in situ grand-mean for 22 individual site- or cooling-unit means from this study that yield acceptable data combined with published data from Independence volcano yields a declination of 347.6° and inclination of 59.2° (
k
=
21.8,
α
95
=
6.8°) and a positive reversal test. Averaging 21 virtual geomagnetic poles (VGPs) that are well-grouped yields a mean at 137.1°E, 82.5°N (
K
=
17.6,
A
95
=
7.8°), similar to results previously obtained from published studies from the AVS. Combining the VGPs from our study with published data yields a combined AVS pole at 146.3°E, 83.1°N (
K
=
13.5,
A
95
=
6.2°,
N
=
42 VGPs). Both poles are indistinguishable from c. 50
Ma cratonic and synthetic reference poles for North America, and demonstrate the relative stability of this part of the Cordillera with respect to the craton.
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