| 1. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 2. |
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| 3. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 4. |
- Chauhan, G., et al.
(författare)
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Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:5
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10(-8); and LINC00539/ZDHHC20, p = 5.82 x 10(-9). Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p([BI]) = 9.38 x 10(-25); p([SSBI]) = 5.23 x 10(-14) for hypertension), smoking (p([BI]) = 4.4 x 10(-10); p([SSBI]) = 1.2 x 10(-4)), diabetes (p([BI]) = 1.7 x 10(-8); p([SSBI]) = 2.8 x 10(-3)), previous cardiovascular disease (p([BI]) = 1.0 x 10(-18); p([SSBI]) = 2.3 x 10(-7)), stroke (p([BI]) = 3.9 x 10(-69); p([SSBI]) = 3.2 x 10(-24)), and MRI-defined white matter hyperintensity burden (p([BI]) = 1.43 x 10(-157); p([SSBI]) = 3.16 x 10(-106)), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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| 6. |
- 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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| 7. |
- 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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| 8. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 9. |
- Björkbacka, H, et al.
(författare)
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Plasma stem cell factor levels are associated with risk of cardiovascular disease and death
- 2017
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 282:6, s. 508-521
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Stem cell factor (SCF) is a key growth factor for several types of stem and progenitor cells. There is experimental evidence that such cells are of importance for maintaining the integrity of the cardiovascular system. We investigated the association between circulating levels of SCF and risk for development of cardiovascular events and death.METHODS: SCF was analysed by the proximity extension assay technique in plasma from 4742 subjects participating in the Malmö Diet and Cancer Study. Cardiovascular events and death were monitored through national registers with a mean follow-up time of 19.2 years.RESULTS: Subjects with high baseline levels of SCF had lower cardiovascular (n = 340) and all-cause mortality (n = 1159) as well as a lower risk of heart failure (n = 177), stroke (n = 318) and myocardial infarction (n = 452). Smoking, diabetes and high alcohol consumption were associated with lower levels of SCF. Single nucleotide polymorphisms in the gene region encoding PDX1 C-terminal inhibiting factor 1 (PCIF1) and matrix metalloproteinase-9 were associated with plasma SCF levels. The highest SCF quartile remained independently associated with a lower risk of a lower risk of cardiovascular [hazard ratio and 95% confidence interval 0.59 (0.43-0.81)] and all-cause mortality [0.68 (0.57-0.81)], heart failure [0.50 (0.31-0.80)] and stroke [0.66 (0.47-0.92)], but not with MI [0.96 (0.72-1.27)] as compared with the lowest quartile when adjusting for traditional cardiovascular risk factors in Cox proportional hazard regression models.CONCLUSIONS: This prospective population-based study demonstrates that subjects with high levels of SCF have a lower risk of cardiovascular events and death. The findings provide clinical support for a protective role of SCF in maintaining cardiovascular integrity.
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| 10. |
- Gregson, J., et al.
(författare)
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Cardiovascular Risk Factors Associated With Venous Thromboembolism
- 2019
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Ingår i: JAMA Cardiology. - : American Medical Association (AMA). - 0965-2590 .- 2380-6583 .- 2380-6591. ; 4:2, s. 163-173
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). OBJECTIVE To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. DESIGN, SETTING, AND PARTICIPANTS This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CND], 25131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). RESULTS Of the 731728 participants from the ERFC. 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. CONCLUSIONS AND RELEVANCE Older age, smoking, and adiposity were consistently associated with higher VTE risk.
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