Cystatin C and Cardiovascular Disease A Mendelian Randomization Study

Sander W. van der Laan, Tove Fall, Aicha Soumaré, Alexander Teumer, Sanaz Sedaghat, Jens Baumert, Delilah Zabaneh, Jessica van Setten, Ivana Isgum, Tessel E. Galesloot, Johannes Arpegård, Philippe Amouyel, Stella Trompet, Melanie Waldenberger, Marcus Dörr, Patrik K. Magnusson, Vilmantas Giedraitis, Anders Larsson, Andrew P. Morris, Janine F. Felix, Alanna C. Morrison, Nora Franceschini, Joshua C. Bis, Maryam Kavousi, Christopher O'Donnell, Fotios Drenos, Vinicius Tragante, Patricia B. Munroe, Rainer Malik, Martin Dichgans, Bradford B. Worrall, Jeanette Erdmann, Christopher P. Nelson, Nilesh J. Samani, Heribert Schunkert, Jonathan Marchini, Riyaz S. Patel, Aroon D. Hingorani, Lars Lind, Nancy L. Pedersen, Jacqueline de Graaf, Lambertus A.L.M. Kiemeney, Sebastian E. Baumeister, Oscar H. Franco, Albert Hofman, André G. Uitterlinden, Wolfgang Koenig, Christa Meisinger, Annette Peters, Barbara Thorand, J. Wouter Jukema, Bjørn Odvar Eriksen, Ingrid Toft, Tom Wilsgaard, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Stéphanie Debette, Meena Kumari, Per Svensson, Pim van der Harst, Mika Kivimaki, Brendan J. Keating, Naveed Sattar, Abbas Dehghan, Alex P. Reiner, Erik Ingelsson, Hester M. den Ruijter, Paul I.W. de Bakker, Gerard Pasterkamp, Johan Ärnlöv, Michael V. Holmes, Folkert W. Asselbergs

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. The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. 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. 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. 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.