Cystatin C and Cardiovascular Disease A Mendelian Randomization Study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2016-08-30
Date Acceptance
2016-05-18
Citation
Journal of the American College of Cardiology, 2016, 68 (9), pp.934-945
ISSN
0735-1097
Publisher
Elsevier
Start Page
934
End Page
945
Journal / Book Title
Journal of the American College of Cardiology
Volume
68
Issue
9
Copyright Statement
© 2016 THE AUTHORS. PUBLISHED BY ELSEVIER INC. ON BEHALF OF THE AMERICAN
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY-NC-ND LICENSE ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) .
COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY-NC-ND LICENSE ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) .
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
coronary heart disease
genetics
heart failure
ischemic stroke
CHRONIC KIDNEY-DISEASE
GENOME-WIDE ASSOCIATION
CORONARY-ARTERY-DISEASE
INCIDENT HEART-FAILURE
BODY-MASS INDEX
SUSCEPTIBILITY LOCI
CHARGE CONSORTIUM
COMMON VARIANTS
ISCHEMIC-STROKE
RISK
Publication Status
Published