JACC6809_05092.pdf (1.49 MB)
Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.
journal contribution
posted on 2016-11-11, 10:05 authored by S. W. van der Laan, T. Fall, A. Soumaré, A. Teumer, S. Sedaghat, J. Baumert, D. Zabaneh, J. van Setten, I. Isgum, T. E. Galesloot, J. Arpegård, P. Amouyel, S. Trompet, M. Waldenberger, M. Dörr, P. K. Magnusson, V. Giedraitis, A. Larsson, A. P. Morris, J. F. Felix, A. C. Morrison, N. Franceschini, J. C. Bis, M. Kavousi, C. O'Donnell, F. Drenos, V. Tragante, P. B. Munroe, R. Malik, M. Dichgans, B. B. Worrall, J. Erdmann, Christopher P. Nelson, Nilesh J. Samani, H. Schunkert, J. Marchini, R. S. Patel, A. D. Hingorani, L. Lind, N. L. Pedersen, J. de Graaf, L. A. Kiemeney, S. E. Baumeister, O. H. Franco, A. Hofman, A. G. Uitterlinden, W. Koenig, C. Meisinger, A. Peters, B. Thorand, J. W. Jukema, B. O. Eriksen, I. Toft, T. Wilsgaard, N. C. Onland-Moret, Y. T. van der Schouw, S. Debette, M. Kumari, P. Svensson, P. van der Harst, M. Kivimaki, B. J. Keating, N. Sattar, A. Dehghan, A. P. Reiner, E. Ingelsson, H. M. den Ruijter, P. I. de Bakker, G. Pasterkamp, J. Ärnlöv, M. V. Holmes, F. W. AsselbergsBACKGROUND: 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.
Funding
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
History
Citation
Journal of the American College of Cardiology, 2016, 68 (9), pp. 934-945Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular SciencesVersion
- VoR (Version of Record)
Published in
Journal of the American College of CardiologyPublisher
Elsevier for American College of Cardiologyissn
0735-1097eissn
1558-3597Acceptance date
2016-05-18Available date
2016-11-11Publisher DOI
Publisher version
http://www.sciencedirect.com/science/article/pii/S0735109716344382Language
enAdministrator link
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