Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

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• 作者：Sander W. van der Laan ; MSc^a ; ^&lowast ; ; ^{s.w.vanderlaan-2@umcutrecht.nl" class="auth_mail" title="E-mail the corresponding author} ; Tove Fall ; PhD^b ; ^&lowast ; ; Aicha Soumaré ; PhD^c ; Alexander Teumer ; PhD^d ; ^e ; Sanaz Sedaghat ; MSc^f ; Jens Baumert ; PhD^g ; Delilah Zabaneh ; PhD^h ; ⁱ ; Jessica van Setten ; PhD^a ; Ivana Isgum ; PhD^j ; Tessel E. Galesloot ; PhD^k ; Johannes Arpegå ; rd ; MD^l ; ^m ; Philippe Amouyel ; MD ; PhDⁿ ; ^o ; Stella Trompet ; PhD^p ; ^q ; Melanie Waldenberger ; PhD ; MPH^g ; ^r ; Marcus Dö ; rr ; MD^e ; ^s ; Patrik K. Magnusson ; PhD^t ; Vilmantas Giedraitis ; PhD^u ; Anders Larsson ; MD ; PhD^v ; Andrew P. Morris ; PhD^w ; ^x ; Janine F. Felix ; PhD^f ; Alanna C. Morrison ; PhD^y ; Nora Franceschini ; MD ; MPH^z ; Joshua C. Bis ; PhD^aa ; Maryam Kavousi ; MD ; PhD^f ; Christopher O'Donnell ; MD ; MPH^bb ; ^cc ; Fotios Drenos ; PhD^dd ; ^ee ; Vinicius Tragante ; PhD^ff ; Patricia B. Munroe ; PhD^gg ; Rainer Malik ; PhD^hh ; Martin Dichgans ; MD ; PhD^hh ; ⁱⁱ ; Bradford B. Worrall ; MD ; PhD^jj ; Jeanette Erdmann ; PhD^kk ; Christopher P. Nelson ; PhD^ll ; ^mm ; Nilesh J. Samani ; PhD^ll ; ^mm ; Heribert Schunkert ; MD ; PhDⁿⁿ ; ^oo ; Jonathan Marchini ; PhD^pp ; Riyaz S. Patel ; MD ; PhD^qq ; ^rr ; ^ss ; Aroon D. Hingorani ; MD ; PhD^qq ; Lars Lind ; MD ; PhD^v ; Nancy L. Pedersen ; PhD^t ; Jacqueline de Graaf ; MD ; PhD^k ; ^tt ; Lambertus A.L.M. Kiemeney ; PhD^k ; Sebastian E. Baumeister ; PhD^d ; ^uu ; Oscar H. Franco ; MD ; PhD^f ; Albert Hofman ; MD ; PhD^f ; André ; G. Uitterlinden ; PhD^vv ; Wolfgang Koenig ; MD ; PhD^e ; ⁿⁿ ; ^ww ; Christa Meisinger ; MD ; MPH^g ; Annette Peters ; PhD ; MSc^e ; ^g ; Barbara Thorand ; PhD ; MPH^g
• 关键词：coronary heart disease ; genetics ; heart failure ; ischemic stroke
• 刊名：Journal of the American College of Cardiology
• 出版年：2016
• 出版时间：30 August 2016
• 年：2016
• 卷：68
• 期：9
• 页码：934-945
• 全文大小：1633 K

文摘

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.