| 1. |
- Scott, Robert A., et al.
(author)
-
An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
-
Journal article (peer-reviewed)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
|
|
| 2. |
- Gaulton, Kyle J, et al.
(author)
-
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
-
Journal article (peer-reviewed)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
|
|
| 3. |
- Patel, Riyaz S., et al.
(author)
-
Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
-
In: Circulation. - 2574-8300. ; 12:4
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
|
|
| 4. |
- Patel, Riyaz S., et al.
(author)
-
Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
-
In: Circulation. - 2574-8300. ; 12:4
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
|
|
| 5. |
- Benatar, Michael, et al.
(author)
-
Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
-
In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
-
Journal article (peer-reviewed)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
|
|
| 6. |
- Almgren, M, et al.
(author)
-
The Richmond Agitation-Sedation Scale: translation and reliability testing in a Swedish intensive care unit.
- 2010
-
In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 54, s. 729-735
-
Journal article (peer-reviewed)abstract
- Background: Awareness about adequate sedation in mechanically ventilated patients has increased in recent years. The use of a sedation scale to continually evaluate the patient's response to sedation may promote earlier extubation and may subsequently have a positive effect on the length of stay in the intensive care unit (ICU). The Richmond Agitation-Sedation Scale (RASS) provides 10 well-defined levels divided into two different segments, including criteria for levels of sedation and agitation. Previous studies of the RASS have shown it to have strong reliability and validity. The aim of this study was to translate the RASS into Swedish and to test the inter-rater reliability of the scale in a Swedish ICU. Methods: A translation of the RASS from English into Swedish was carried out, including back-translation, critical review and pilot testing. The inter-rater reliability testing was conducted in a general ICU at a university hospital in the south of Sweden, including 15 patients mechanically ventilated and sedated. Forty in-pair assessments using the Swedish version of the RASS were performed and the inter-rater reliability was tested using weighted kappa statistics (linear weighting). Result: The translation of the RASS was successful and the Swedish version was found to be satisfactory and applicable in the ICU. When tested for inter-rater reliability, the weighed kappa value was 0.86. Conclusion: This study indicates that the Swedish version of the RASS is applicable with good inter-rater reliability, suggesting that the RASS can be useful for sedation assessment of patients mechanically ventilated in Swedish general ICUs.
|
|
| 7. |
|
|
| 8. |
- Almgren, Karin M., et al.
(author)
-
Characterization of interfacial stress transfer ability by dynamic mechanical analysis of cellulose fiber based composite materials
- 2010
-
In: Composite interfaces (Print). - 0927-6440 .- 1568-5543. ; 17:9, s. 845-861
-
Journal article (peer-reviewed)abstract
- The stress transfer ability at the fiber-matrix interface of wood fiber composites is known to affect the mechanical properties of the composite. The evaluation of interface properties at the level of individual fibers is however difficult due to the small dimensions and variability of the fibers. The dynamical mechanical properties of composite and constituents, in this case wood fibers and polylactide matrix, was here used together with micromechanical modeling to quantify the stress transfer efficiency at the fiber-matrix interface. To illustrate the methodology, a parameter quantifying the degree of imperfection at the interface was identified by inverse modeling using a micromechanical viscoelastic general self-consistent model with an imperfect interface together with laminate analogy on the composite level. The effect of moisture was assessed by comparison with experimental data from dynamic mechanical analysis in dry and moist state. For the wood fiber reinforced polylactide, the model shows that moisture absorption led to softening and mechanical dissipation in the hydrophilic wood fibers and biothermoplastic matrix, rather than loss of interfacial stress transfer ability.
|
|
| 9. |
- Almgren, Karin M., et al.
(author)
-
Contribution of wood fiber hygroexpansion to moisture induced thickness swelling of composite plates
- 2010
-
In: Polymer Composites. - : Wiley. - 0272-8397 .- 1548-0569. ; 31:5, s. 762-771
-
Journal article (peer-reviewed)abstract
- One of the main drawbacks of wood fiber-based composite materials is their propensity to swell due to moisture uptake. Because the wood fibers are usually the main contributor to hygroexpansion, it is of interest to quantify the hygroexpansion coefficient of wood fibers, to compare and rank different types of fibers. This investigation outlines an inverse method to estimate the transverse hygroexpansion coefficient of wood fibers based on measurements of moisture induced thickness swelling of composite plates. The model is based on composite micromechanics and laminate theory. Thickness swelling has been measured on polylactide matrix composites with either bleached reference fibers or crosslinked fibers. The crosslinking modification reduced the transverse hygroexpansion of the composites and the transverse coefficient of hygroexpansion of the fibers was reduced from 0.28 strain per relative humidity for reference fibers to 0.12 for cross-linked fibers
|
|
| 10. |
- Almgren, Karin M., et al.
(author)
-
Effects of Moisture on Dynamic Mechanical Properties of Wood Fiber Composites Studied by Dynamic FT-IR Spectroscopy
- 2008
-
In: Journal of reinforced plastics and composites (Print). - : SAGE Publications. - 0731-6844 .- 1530-7964. ; 27:16-17, s. 1709-1721
-
Journal article (peer-reviewed)abstract
- Wood fiber reinforced polylactide is a biodegradable composite where both fibers and matrix are from renewable resources. In the development of such new materials, information on mechanical behavior on the macroscopic and the molecular level is useful. In this study, dynamic Fourier transform infrared (FT-IR) spectroscopy is used to measure losses at the molecular level during cyclic tensile loading for bonds that are characteristic of the cellulosic fibers and the polylactid matrix. This molecular behavior is compared with measured macroscopic hysteresis losses for different moisture levels. The results show that moisture ingress will transfer the load from the fibers to the matrix, and that a more efficient fiber-matrix interface would diminish mechanical losses. Although the dynamic FT-IR spectroscopy method is still qualitative, this investigation shows that it can provide information on the stress transfer of the constituents in wood fiber reinforced plastics.
|
|
