| 1. |
- Teslovich, Tanya M., et al.
(författare)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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| 2. |
- Patel, Riyaz S., et al.
(författare)
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Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Voight, Benjamin F, et al.
(författare)
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Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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| 4. |
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| 5. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)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.
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| 6. |
- de Zee, Mark, et al.
(författare)
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A generic detailed rigid-body lumbar spine model
- 2007
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Ingår i: Journal of Biomechanics. - : Elsevier BV. - 1873-2380 .- 0021-9290. ; 40:6, s. 1219-1227
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this work is to present a musculo-skeletal model of the lumbar spine, which can be shared and lends itself to investigation in many locations by different researchers. This has the potential for greater reproducibility and subsequent improvement of its quality from the combined effort of different research groups. The model is defined in a text-based, declarative, object-oriented language in the AnyBody Modelling System software. Text-based models will facilitate sharing of the models between different research groups. The necessary data for the model has been taken from the literature. The work resulted in a detailed lumbar spine model with seven rigid segments with 18 degrees-of-freedom and 154 muscles. The model is able to produce a maximum extension moment of 238 Nm around L5/S1. Moreover, a comparison was made with in vivo intradiscal pressure measurements of the L4-5 disc available from the literature. The model is based on inverse dynamics, where the redundancy problem is solved using optimization in order to compute the individual muscle forces and joint reactions. With the presented model it is possible to investigate a range of research questions, because the model is relatively easy to share and modify due to the use of a well-defined and self-contained scripting language. Validation is though still necessary for specific cases. (c) 2006 Elsevier Ltd. All rights reserved.
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| 7. |
- Hansen, Lone, et al.
(författare)
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Anatomy and biomechanics of the back muscles in the lumbar spine with reference to biomechanical modeling
- 2006
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Ingår i: Spine. - 0362-2436. ; 31:17, s. 1888-1899
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Forskningsöversikt (refereegranskat)abstract
- Study Design. This article describes the development of a musculoskeletal model of the human lumbar spine with focus on back muscles. It includes data from literature in a structured form. Objective. To review the anatomy and biomechanics of the back muscles related to the lumbar spine with relevance for biomechanical modeling. Summary of Background Data. To reduce complexity, muscle units have been incorporated in an abridged manner, reducing their actions more or less to a single force equivalent. In early models of the lumbar spine, this may have been a necessary step to reduce complexity and, thereby, calculation time. The muscles of the spine are well described in the literature, but mainly qualitatively. Most of the literature provides a description of the structures without precise data of fiber length, muscle length, cross-sectional areas, moment arms, forces, etc. The predicted output of musculoskeletal models is very much dependent on the input parameters. The information needed to improve models consists of better approximations of the attachments to the vertebrae, and more precise data. Method. Review of literature. Results. The predicted output of musculoskeletal models is very much dependent on the input parameters. Moderate changes in the assumed muscle line-of-action (i.e., moment arm) could substantially alter the magnitudes of predicted muscle and spinal forces, while the choice of optimization formulation is less sensitive. Conclusions. Input parameters, moment arms, as well as physiologic cross-sectional areas have a profound effect on the predicted muscle forces. Therefore, it is important to choose the values for moment arm and physiologic cross-sectional area carefully because they are essential input parameters to biomechanical models.
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| 8. |
- Klitgaard, Kent K, et al.
(författare)
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Characterization of Leg Push Forces and Their Relationship to Velocity in On-Water Sprint Kayaking.
- 2021
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Ingår i: Sensors. - : MDPI. - 1424-8220. ; 21:20
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this work was to describe the leg-muscle-generated push force characteristics in sprint kayak paddlers for females and males on water. Additionally, the relationship between leg pushing force characteristics and velocity was investigated. Twenty-eight paddlers participated in the study. The participants had five minutes of self-chosen warm-up and were asked to paddle at three different velocities, including maximal effort. Left- and right-side leg extension force were collected together with velocity. Linear regression analyses were performed with leg extension force characteristics as independent variables and velocity as the dependent variable. A second linear regression analysis investigated the effect of paddling velocity on different leg extension force characteristics with an explanatory model. The results showed that the leg pushing force elicits a sinus-like pattern, increasing and decreasing throughout the stroke cycle. Impulse over 10 s showed the highest correlation to maximum velocity (r = 0.827, p < 0.01), while a strong co-correlation was observed between the impulse per stroke cycle and mean force (r = 0.910, p < 0.01). The explanatory model results revealed that an increase in paddling velocity is, among other factors, driven by increased leg force. Maximal velocity could predict 68% of the paddlers' velocity within 1 km/h with peak leg force, impulse over 10 s, and stroke rate (p-value < 0.001, adjusted R-squared = 0.8). Sprint kayak paddlers elicit a strong positive relationship between leg pushing forces and velocity. The results confirm that sprint kayakers' cyclic leg movement is a key part of the kayaking technique.
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| 9. |
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| 10. |
- Schillemans, Tessa, et al.
(författare)
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Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease : An Individual-Level Meta-Analysis
- 2022
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Ingår i: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD.Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed.Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged >= 65, 2) individuals with renal impairment, and 3) antiplatelet users.Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.
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