| 1. |
- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 2. |
- Mercuri, E., et al.
(författare)
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Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study
- 2020
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Ingår i: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 9:5, s. 341-360
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype-phenotype/-ataluren benefit correlations and ataluren safety. Patients & methods: Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion: Kaplan-Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p <= 0.05). There were no DMD genotype-phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier: NCT02369731. ClinicalTrials.gov identifier: NCT02369731.
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| 3. |
- Cosmi, F., et al.
(författare)
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Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes
- 2018
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 20:5, s. 888-895
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Tidskriftsartikel (refereegranskat)abstract
- Aims Up to one-third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. Methods and results We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin [propensity score pooled hazard ratio for all-cause mortality 1.27 (1.16-1.38), for HF hospitalization 1.23 (1.13-1.33)]. In the administrative registry, insulin prescription was associated with a higher risk of all-cause death [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87-2.19] and rehospitalization for HF (OR 1.42, 95% CI 1.32-1.53). Conclusions Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose-lowering treatments for patients with HF and type 2 diabetes mellitus.
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| 4. |
- Munoz-Gil, G., et al.
(författare)
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Objective comparison of methods to decode anomalous diffusion
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Deviations from Brownian motion leading to anomalous diffusion are found in transport dynamics from quantum physics to life sciences. The characterization of anomalous diffusion from the measurement of an individual trajectory is a challenging task, which traditionally relies on calculating the trajectory mean squared displacement. However, this approach breaks down for cases of practical interest, e.g., short or noisy trajectories, heterogeneous behaviour, or non-ergodic processes. Recently, several new approaches have been proposed, mostly building on the ongoing machine-learning revolution. To perform an objective comparison of methods, we gathered the community and organized an open competition, the Anomalous Diffusion challenge (AnDi). Participating teams applied their algorithms to a commonly-defined dataset including diverse conditions. Although no single method performed best across all scenarios, machine-learning-based approaches achieved superior performance for all tasks. The discussion of the challenge results provides practical advice for users and a benchmark for developers. Deviations from Brownian motion leading to anomalous diffusion are ubiquitously found in transport dynamics but often difficult to characterize. Here the authors compare approaches for single trajectory analysis through an open competition, showing that machine learning methods outperform classical approaches.
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| 5. |
- Thorgeirsson, T. E., et al.
(författare)
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A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:5, s. 594-600
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Tidskriftsartikel (refereegranskat)abstract
- Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
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| 6. |
- Shi, C. M., et al.
(författare)
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Summer Temperature over the Tibetan Plateau Modulated by Atlantic Multidecadal Variability
- 2019
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Ingår i: Journal of Climate. - : American Meteorological Society. - 0894-8755 .- 1520-0442. ; 32:13, s. 4055-4067
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Tidskriftsartikel (refereegranskat)abstract
- Rapid warming has led to an aggregated environmental degradation over the Tibetan Plateau (TP) in the last few decades, including accelerated glacier retreat, early snowmelt, permafrost degradation, and forest fire occurrence. Attribution of this warming in recent decades has mainly been focused on anthropogenic forcing. Yet, linkages to the Atlantic multidecadal variability (AMV), an essential part of the climate system causing decadal to centennial fluctuations of temperature, remains poorly understood for the TP, especially at long time scales. Using well-replicated tree-ring width records, we reconstructed 358 years of summer minimum temperature (MinT) of the whole TP. This reconstruction matches the recent warming signal recorded since the 1980s, and captures 63% of the variance in 1950-2005 instrumental records. A teleconnection from the North Atlantic to the TP is further identified based in observations and simulations with an atmospheric general circulation model (AGCM). We propose that half of the multidecadal variability of TP summer MinT can be explained by the AMV over the past three and a half centuries. Both observations and AGCM simulations indicate that the AMV warm phase induces a zonal dipole response in sea level pressure across the Atlantic-Eurasia region, with anomalously high surface pressure and corresponding downward atmospheric motion over the TP. We propose that the descending motion during warm AMV phases causes negative rainfall and positive temperature anomalies over the TP. Our findings highlight that the AMV plays a role in the multidecadal temperature variability over the TP.
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| 7. |
- Kang, E. Y., et al.
(författare)
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Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses
- 2021
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 34:1, s. 194-206
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Tidskriftsartikel (refereegranskat)abstract
- TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (INC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
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| 8. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 9. |
- Latini, R., et al.
(författare)
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Pentraxin-3 in chronic heart failure: the CORONA and GISSI-HF trials
- 2012
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 14:9, s. 992-999
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Tidskriftsartikel (refereegranskat)abstract
- Pentraxin-3 (PTX3) is a component of the humoral arm of innate immunity which can regulate inflammatory processes. Since the role of inflammation in the progression of chronic heart failure (HF) is debated, we investigated the prognostic value of PTX3 and the effect of a statin in two large populations of patients with HF. Plasma levels of PTX3 were measured at randomization and after 3 months in 1457 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and 1233 patients enrolled in the GISSI-Heart Failure trial (GISSI-HF). The relationships between baseline PTX3 levels or their changes over time and mortality were evaluated with multivariable Cox proportional hazard models including clinical factors, high sensitivity C-reactive protein (hsCRP), and N-terminal pro brain natriuretic peptide (NT-proBNP). PTX3 concentration [median (Q1Q3) 5.34 (3.557.64) ng/mL, n 2690] was higher in females, in older patients, and those with lower body mass index. Baseline elevated PTX3 was associated with a higher risk of all-cause mortality [759 events, hazard ratio (HR) for 1 SD increase 1.20, 95 confidence interval (CI) 1.121.30, P 0.0001], cardiovascular mortality (587 events, HR 1.27, 95 CI 1.171.38, P 0.0001), or hospitalization for worsening HF (720 events, HR 1.21, 95 CI 1.121.30, P 0.0001), and marginally improved discrimination. Three-month changes in PTX3 were associated with fatal events after adjustment for hsCRP or NT-proBNP. Rosuvastatin lowered hsCRP levels but significantly raised PTX3. In two independent clinical trials that enrolled patients with chronic HF, PTX3 was consistently associated with outcomes. The opposite effects of a statin on hsCRP and PTX3 call for further investigation. NCT00336336 (GISSI-HF), NCT00206310 (CORONA).
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| 10. |
- Malik, A., et al.
(författare)
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Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction
- 2019
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 74:5, s. 617-627
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS Of the 11,900 hospitalized patients with HFrEF (EF <= 45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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