Cystatin C and Cardiovascular Disease

Abstract

BACKGROUNDEpidemiological 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.OBJECTIVESThe aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.METHODSWe 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.RESULTSCystatin 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.CONCLUSIONSMendelian 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.

Factors associated with high brachial–ankle pulse wave velocity in non-hypertensive and appropriately treated hypertensive patients with atherosclerotic risk factors

“…Further, those indices have no causality with regard to atherosclerotic events. 62 , 63 Therefore, it might be inappropriate to undertake statistical analysis upon eGFR and cystatin C as independent determinants for baPWV, because we hypothesize that baPWV is a prognostic predictor. Fourth, we excluded some patients as possible ASO patients using not only borderline ABI (≤0.99) but also by using high %MAP (≥45) and UT (≥180).…”

“…It is not the case that chronic kidney disease, or end-stage renal failure alone can predict a poorer prognosis. 2 , 61 Nevertheless, recent Mendelian randomization studies have, at least, cast doubt on the causative relationship between cardiovascular prognosis and eGFR or cystatin C. Specifically, causative factors related to eGFR and CAD 62 and on the association between serum cystatin C and cardiovascular events 63 are evaluated. In other words, these studies potentially suggest that the surrogate indices of renal function, such as eGFR and serum cystatin C, are only mediating factors of prognosis.…”

Cardiovascular Risk in Type 1 Diabetes Mellitus

“…Cystatin C is well established in the assessment of renal function and nephropathy in T1DM, but recent interest has centred on its potential value in cardiovascular risk assessment [ 60 ]. Epidemiological studies show a strong association between circulating cystatin C and the development of CVD independent of renal function [ 61 ]. Serum uromodulin appears to have renal protective properties; higher levels also appear to be associated with reduced coronary artery calcification [ 62 ].…”

Multi-Imaging Investigation to Evaluate the Relationship between Serum Cystatin C and Features of Atherosclerosis in Non-ST-Segment Elevation Acute Coronary Syndrome

“…At least partially, some studies have recently shed light on this topic. First, based on the fact that several single nucleotide polymorphisms are associated with circulating cystatin C level [22,23], prospective observational studies [24,25] and mendelian randomization studies [10,11] have shown that high levels of cystatin C are not causally related to the incidence of coronary artery disease, ischemic stroke, and heart failure. In particular, mendelian randomization studies rely on a very large sample size and on the fact that genetic information, randomly distributed from parents to offspring, are not influenced by either disease status (reverse causality) or potential confounders.…”

“…On the other hand, since elastolytic cysteine proteases and their inhibitors are involved in the pathogenesis of atherosclerosis, it has also been suggested that cystatin C levels may be directly linked to the development and progression of atherosclerosis [8,9]. However, mendelian randomization studies [10,11] have shown that the association between cystatin C and cardiovascular disease is not causal. Nonetheless, its role as a marker of atherosclerosis (reverse causality) is still controversial.…”