Cystatin C and Cardiovascular Disease A Mendelian Randomization Study
2016 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 68, no 9, 934-945 p.Article in journal (Refereed) Published
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 x 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 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora 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 x 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.
Place, publisher, year, edition, pages
2016. Vol. 68, no 9, 934-945 p.
coronary heart disease, genetics, heart failure, ischemic stroke
Cardiac and Cardiovascular Systems
IdentifiersURN: urn:nbn:se:uu:diva-303737DOI: 10.1016/j.jacc.2016.05.092ISI: 000382312900009PubMedID: 27561768OAI: oai:DiVA.org:uu-303737DiVA: diva2:973929
FunderStockholm County CouncilWellcome trust, WT098017Swedish Society of Medicine, SLS-412071NIH (National Institute of Health), HL36310Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Heart Lung Foundation, 20140422Knut and Alice Wallenberg FoundationEU, European Research Council, ERC-StG-335395Swedish Diabetes Association, 2013-024Swedish Research Council, 2012-1397; 2012-1727; 2012-2215EU, FP7, Seventh Framework Programme, HEALTH-F2-2013-601456