| 1. |
- Chen, Hao Yu, et al.
(author)
-
Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis
- 2020
-
In: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 5:6, s. 694-702
-
Journal article (peer-reviewed)abstract
- Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets.Objective: To identify novel genetic loci and pathways associated with AS.Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019.Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples.Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography.Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]).Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.
|
|
| 2. |
- Chen, H.Y., et al.
(author)
-
Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study
- 2023
-
In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 44:21, s. 1927-1939
-
Journal article (peer-reviewed)abstract
- Aims Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. Methods and results A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2–SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26–1.35; P = 2.7 × 10−51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08–1.37; P = 1.4 × 10−3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90–5.12; P = 2.1 × 10−20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17–1.23; P = 4.8 × 10−73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05–1.9; P = 1.9 × 10−12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. Conclusion Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.
|
|
| 3. |
- Martinsson, Bengt G., et al.
(author)
-
Five-satellite-sensor study of the rapid decline of wildfire smoke in the stratosphere
- 2022
-
In: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 22:6, s. 3967-3984
-
Journal article (peer-reviewed)abstract
- Smoke from western North American wildfires reached the stratosphere in large amounts in August 2017. Limb-oriented satellite-based sensors are commonly used for studies of wildfire aerosol injected into the stratosphere (OMPS-LP (Ozone Mapping and Profiler Suite Limb Profiler) and SAGE III/ISS (Stratospheric Aerosol and Gas Experiment III on the International Space Station)). We find that these methods are inadequate for studies of the first 1-2 months after such a strong fire event due to event termination ("saturation"). The nadir-viewing lidar CALIOP (Cloud-Aerosol LIdar with Orthogonal Polarization) is less affected due to shorter path in the smoke; furthermore, it provides a means to develop a method to correct for strong attenuation of the signal. After the initial phase, the aerosol optical depth (AOD) from OMPS-LP and CALIOP show very good agreement above the 380ĝK isentrope, whereas OMPS-LP tends to produce higher AOD than CALIOP in the lowermost stratosphere (LMS), probably due to reduced sensitivity at altitudes below 17ĝkm. Time series from CALIOP of attenuation-corrected stratospheric AOD of wildfire smoke show an exponential decline during the first month after the fire, which coincides with highly significant changes in the wildfire aerosol optical properties. The AOD decline is verified by the evolution of the smoke layer composition, comparing the aerosol scattering ratio (CALIOP) to the water vapor concentration from MLS (Microwave Limb Sounder). Initially the stratospheric wildfire smoke AOD is comparable with the most important volcanic eruptions during the last 25 years. Wildfire aerosol declines much faster, 80ĝ%-90ĝ% of the AOD is removed with a half-life of approximately 10ĝd. We hypothesize that this dramatic decline is caused by photolytic loss. This process is rarely observed in the atmosphere. However, in the stratosphere this process can be studied with practically no influence from wet deposition, in contrast to the troposphere where this is the main removal path of submicron aerosol particles. Despite the loss, the aerosol particles from wildfire smoke in the stratosphere are relevant for the climate.
|
|
| 4. |
- Sandvik, Oscar S., et al.
(author)
-
Methodology to obtain highly resolved SO2 vertical profiles for representation of volcanic emissions in climate models
- 2021
-
In: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 14:11, s. 7153-7165
-
Journal article (peer-reviewed)abstract
- In this study we describe a methodology to create high-vertical-resolution SO2 profiles from volcanic emissions. We demonstrate the method's performance for the volcanic clouds following the eruption of Sarychev in June 2009. The resulting profiles are based on a combination of satellite SO2 and aerosol retrievals together with trajectory modelling. We use satellite-based measurements, namely lidar backscattering profiles from the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) satellite instrument, to create vertical profiles for SO2 swaths from the Atmospheric Infrared Sounder (AIRS) aboard the Aqua satellite. Vertical profiles are created by transporting the air containing volcanic aerosol seen in CALIOP observations using the FLEXible PARTicle dispersion model (FLEXPART) while preserving the high vertical resolution using the potential temperatures from the MERRA-2 (Modern-Era Retrospective analysis for Research and Application) meteorological data for the original CALIOP swaths. For the Sarychev eruption, air tracers from 75 CALIOP swaths within 9g d after the eruption are transported forwards and backwards and then combined at a point in time when AIRS swaths cover the complete volcanic SO2 cloud. Our method creates vertical distributions for column density observations of SO2 for individual AIRS swaths, using height information from multiple CALIOP swaths. The resulting dataset gives insight into the height distribution in the different sub-clouds of SO2 within the stratosphere. We have compiled a gridded high-vertical-resolution SO2 inventory that can be used in Earth system models, with a vertical resolution of 1g K in potential temperature, 61g g 56g m, or 1.8g g 2.9g mbar.
|
|
| 5. |
- Siaw, Joachim T., et al.
(author)
-
11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
- 2020
-
In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:12
-
Journal article (peer-reviewed)abstract
- High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature'' that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, high-lighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas.
|
|
| 6. |
|
|
