| 1. |
|
|
| 2. |
-
- 2019
-
Tidskriftsartikel (refereegranskat)
|
|
| 3. |
- Mishra, A., et al.
(författare)
-
Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
-
Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
|
|
| 4. |
|
|
| 5. |
- Fresard, Laure, et al.
(författare)
-
Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
-
Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
-
Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
|
|
| 6. |
- Godambe, S. V., et al.
(författare)
-
Very High Energy Gamma-ray and Near Infrared observations of 1ES2344+514 with TACTIC and MIRO Telescopes
- 2005
-
Ingår i: 29th International Cosmic Ray Conference Pune (2005).
-
Konferensbidrag (refereegranskat)abstract
- 1ES2344+514 (z = 0.04) is one of the rst BL Lac objects to be reported as an extreme synchrotron blazar withsynchotron peak energy reaching up to 100keV and was discovered as a source of Very High Energy (VHE)gamma- rays by the Whipple group in 1995. Subsequently, it was observed by the HEGRA group in 1997/98and 2002. We have recently (Oct.- Dec. 2004) observed the 1ES2344+514 using the imaging element of theTACTIC array and have collected data for 53 hours in on/off mode. The source was also observed in nearinfrared bands J, H and K, for some nights using NICMOS-3 array mounted on 1.2m MIRO infrared telescope.Such a study is expected to provide clues to the dominance or otherwise of the Compton component. Afterdetailed analysis of the TACTIC data we have placed an upper limit of photons cmsata 3condence level on the gamma-ray ux from the source. In the near infrared band the source shows lowlevel variations without any aring activity.
|
|
| 7. |
- Godambe, S. V., et al.
(författare)
-
Very high energy γ-ray and near infrared observations of 1ES2344+514 during 2004 05
- 2007
-
Ingår i: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 34, s. 1683-1695
-
Tidskriftsartikel (refereegranskat)abstract
- We have observed the BL Lac object 1ES2344+514 (z = 0.044) in very high energy (VHE) gamma-ray and near-infrared wavelength bands with TACTIC and MIRO telescopes, respectively. The observations were made from 18th October to 9th December 2004 and 27th October 2005 to 1st January 2006. Detailed analysis of the TACTIC data indicates the absence of a statistically significant gamma-ray signal both in overall data and on a nightly basis from the source direction. We estimate an upper limit of I(≥1.5 TeV) ≤ 3.84 × 10−12 photons cm−2 s−1 at a 3σ confidence level on the integrated γ-ray flux. In addition, we have also compared TACTIC TeV light curves with those of the RXTE ASM (2–12 keV) for the contemporary period and find that there are no statistically significant increases in the signal strengths from the source in both these energy regions. During 2004 IR observations, 1ES2344+514 shows low level (0.06 magnitude) day-to-day variation in both, J and H bands. However, during the 2005 observation epoch, the source brightens up by about 0.41 magnitude from its October 2005 level J magnitude = 12.64 to J = 12.23 on December 6, 2005. It then fades by about 0.2 magnitude during 6 to 10 December, 2005. The variation is seen in both, J and H, bands simultaneously. The light travel time arguments suggest that the emission region size is of the order of 1017 cm.
|
|
| 8. |
- Godambe, S. V., et al.
(författare)
-
Very high energy γ-ray observations of Mrk 501 using the TACTIC imaging γ-ray telescope during 2005 06
- 2008
-
Ingår i: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 35:6
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper we report on the Markarian 501 results obtained during our TeV γ-ray observations from 11 March to 12 May 2005 and 28 February to 7 May 2006 for 112.5 h with the TACTIC γ-ray telescope. During 2005 observations for 45.7 h, the source was found to be in a low state and we have placed an upper limit of 4.62 × 10−12 photons cm−2 s−1 at 3σ level on the integrated TeV γ-ray flux above 1 TeV from the source direction. However, during 2006 observations for 66.8 h, detailed data analysis revealed the presence of a TeV γ-ray signal from the source with a statistical significance of 7.5σ above Eγ≥ 1 TeV. The time-averaged differential energy spectrum of the source in the energy range 1–11 TeV is found to match well with the power-law function of the form (dΦ/dE = f0E−Γ) with f0 = (1.66 ± 0.52) × 10−11 cm−2 s−1 TeV−1 and Γ = 2.80 ± 0.27.
|
|
| 9. |
- Muino, E., et al.
(författare)
-
RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis
- 2021
-
Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 10:14
-
Tidskriftsartikel (refereegranskat)abstract
- Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 x 10(-8)) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 x 10(-8)) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-beta, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.
|
|
| 10. |
- Van der Kolk, W. L., et al.
(författare)
-
Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe
- 2022
-
Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 167:1, s. 3-10
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN.Methods. We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up.Results. Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was di-agnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor >= 30 mm. Bilateral ra-diotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence.Conclusion. The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
|
|
