| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Best, Myron G., et al.
(författare)
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Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor-Educated Platelets
- 2017
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Ingår i: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 32:2, s. 238-252
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
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| 3. |
- Mahmoodi, Bakhtawar K., et al.
(författare)
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Association of Factor V Leiden With Subsequent Atherothrombotic Events A GENIUS-CHD Study of Individual Participant Data
- 2020
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 142:6, s. 546-555
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16];I-2=28%;P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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| 4. |
- 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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| 5. |
- Eikendal, Anouk L M, et al.
(författare)
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Common Carotid Intima-Media Thickness Relates to Cardiovascular Events in Adults Aged
- 2015
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Ingår i: Hypertension. - 1524-4563. ; 65:4, s. 707-707
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Tidskriftsartikel (refereegranskat)abstract
- Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavor-able risk factor burden.
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| 6. |
- Gijsberts, Crystel M, et al.
(författare)
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Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.
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| 7. |
- 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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| 8. |
- Zewinger, Stephen, et al.
(författare)
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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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| 9. |
- Meeuwsen, John A.L., et al.
(författare)
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High levels of (un)switched memory B cells are associated with better outcome in patients with advanced atherosclerotic disease
- 2017
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 6:9
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Tidskriftsartikel (refereegranskat)abstract
- Background--Atherosclerosis is an inflammatory lipid disorder and the main underlying pathology of acute ischemic events. Despite a vast amount of data from murine atherosclerosis models, evidence of B-cell involvement in human atherosclerotic disease is limited. We therefore investigated the association of circulating B-cell subtypes with the occurrence of secondary cardiovascular events in advanced atherosclerotic disease. Methods and Results--This cohort study consists of 168 patients who were included in the Athero-Express biobank between 2009 and 2011. Before surgery, peripheral blood mononuclear cells were isolated and stored in liquid nitrogen. After gentle thawing of the peripheral blood mononuclear cells, different B-cell subtypes including naïve, (un)switched memory, and CD27+CD43+ B1-like B cells, were analyzed by flow cytometry. Univariable and multivariable Cox proportional hazard models were used to analyze associations between B-cell subtypes, circulating antibodies and secondary cardiovascular manifestations during the 3-year follow-up period. Mean age was 70.1±9.6 years, males represented 62.8% of the population, and 54 patients had secondary manifestations during follow-up. High numbers of unswitched memory cells were protective against secondary outcome (hazard ratio, 0.30 [95% CI, 0.13-0.69]; P < 0.01). Similar results were obtained for the switched memory cells that also showed to be protective against secondary outcome (hazard ratio, 0.33 [95% CI, 0.14-0.77]; P = 0.01). Conclusions--A high number of (un)switched memory B cells is associated with better outcome following carotid artery endarterectomy. These findings suggest a potential role for B-cell subsets in prediction and prevention of secondary cardiovascular events in patients with atherosclerosis.
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