Suchergebnisse

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.118.002115 ; BACKGROUND: Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms. METHODS: We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression. RESULTS: A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10-6 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood. CONCLUSIONS: Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics. ; Dr van der Laan is funded through grants from the Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation (CVON 2011/B019 and CVON 2017-20: Generating the best evidence-based pharmaceutical targets for atherosclerosis [GENIUS I&II]) and the Interuniversity Cardiology Institute of the Netherlands (ICIN, 09.001). Drs van der Laan and Haitjema are both funded through the FP7 EU project CVgenes@target (HEALTH-F2-2013–601456). Dr Siemelink is funded by the European Union (BiomarCaRE, grant number: HEALTH-2011–278913), and the technology foundation Stichting voor de Technische Wetenschappen through the Danone partnership program (Project 11679). The UCL Hospitals NIHR Biomedical Research Centre and the Dutch Heart Foundation (Junior Staff Member 2014T001) supported by Dr Asselbergs. The BiKE study was conducted with support from the Swedish Heart and Lung Foundation, the Swedish Research Council (K2009-65X-2233-01-3, K2013-65X-06816-30-4, and 349-2007-8703), Uppdrag Besegra Stroke (P581/2011–123), the Strategic Cardiovascular Programs of Karolinska Institutet and Stockholm County Council, the Stockholm County Council (ALF2011-0260 and ALF-2011-0279), the Foundation for Strategic Research and the European Commission (CarTarDis). ; Peer-reviewed ; Publisher Version

BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. ; The individual study sponsor(s) had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Dr. Isgum is supported by research grants from Pie Medical Imaging, 3Mensio Medical Imaging B.V., the NWO and Foundation for Technological Sciences under Project 12726, The Netherlands Organization for Health Research and Development, and the Dutch Cancer Society. Dr. Arpegård has received funding through the Stockholm County Council (combined clinical residency and PhD training program). Dr. Amouyel has received personal fees from Servier, Hoffman Laroche, Total, Genoscreen, Alzprotect, Fondation Plan Alzheimer, and Takeda outside of the submitted work; and has shares in Genoscreen. Dr. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science under grant number WT098017. Dr. Worrall has received compensation for his role as deputy editor of the Journal of Neurology; and has received National Institutes of Health funding through the National Institute of Neurological Disorders and Stroke (U-01 NS069208) and National Human Genome Research Institute (U-01 HG005160). Dr. Samani is supported by the British Heart Foundation (BHF); and is a National Institute for Health Research Senior Investigator. Dr. Nelson is supported by the BHF. Dr. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA; Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Patel is supported by a BHF Intermediate Fellowship. Dr. Koenig has received funds through NGFNplus, project number 01GS0834; has received research grants from Abbott, Roche Diagnostics, Beckmann, and Singulex; has received honorarium for lectures from AstraZeneca, Novartis, Merck Sharp & Dohme, Amgen, and Actavis; and has served as a consultant for Novartis, Pfizer, The Medicines Company, Amgen, AstraZeneca, Merck Sharp & Dohme, and GlaxoSmithKline. Dr. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Dr. Svensson has received a grant from the Swedish Society of Medicine (SLS-412071). Dr. Kivimaki has received funding through the Medical Research Council (K013351), Economic and Social Research Council, and National Institutes of Health (HL36310). Dr. Dehghan is supported by a Netherlands Organization for Scientific Research (NWO) grant (VENI, 916.12.154) and the EUR Fellowship; and has received consultancy and research support from Metagenics Inc. (outside the scope of this work). Dr. Ingelsson is supported by grants from Göran Gustafsson Foundation, Swedish Heart-Lung Foundation (20140422), Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse), European Research Council (ERC-StG-335395), Swedish Diabetes Foundation (Diabetesfonden; grant no. 2013-024), and the Swedish Research Council (VR; grant no. 2012-1397). Dr. de Bakker is an employee of Vertex Pharmaceuticals. Dr. Ärnlöv was funded by the Swedish Research Council (2012-1727, 2012-2215), Swedish Heart-Lung Foundation, Thuréus Foundation, the Marianne and Marcus Wallenberg Foundation, Dalarna University, and Uppsala University. Dr. Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals National Institute for Health Research Biomedical Research Centre. The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. ; Peer-reviewed ; Publisher Version