Plasma levels of fetuin-A and risk of coronary heart disease in US women: the Nurses' Health Study

Qi Sun, Monik C Jiménez, Mary K Townsend, Eric B Rimm, JoAnn E Manson, Christine M Albert, Kathryn M Rexrode, Qi Sun, Monik C Jiménez, Mary K Townsend, Eric B Rimm, JoAnn E Manson, Christine M Albert, Kathryn M Rexrode

Abstract

Background: Fetuin-A may be involved in the etiology of coronary heart disease (CHD) through opposing pathways (ie, promoting insulin resistance and inhibiting ectopic calcification). We aimed to explicitly examine whether systemic inflammation, a factor leading to elevated vascular calcification, may modify the association between fetuin-A and CHD risk.

Method and results: During 16 years of follow-up (1990-2006), we prospectively identified and confirmed 466 incident fatal or nonfatal CHD case in the Nurses' Health Study. For each case, 1 healthy control was selected using risk-set sampling from 26 245 eligible participants. Cases and controls were matched for age, smoking status, fasting status, and date of blood draw. After multivariate adjustment for lifestyle factors, body mass index, diet, and blood lipids, fetuin-A levels were not associated with CHD risk in the whole population: odds ratio (OR) (95% CI) comparing extreme quintiles of fetuin-A was 0.79 (0.44 to 1.40). However, a significant inverse association was observed among participants with higher C-reactive protein levels (Pinteraction=0.04). The OR (95% CI) comparing highest versus lowest quintiles of fetuin-A was 0.50 (0.26 to 0.97; Ptrend=0.004) when C-reactive protein levels were above population median (0.20 mg/dL), whereas among the remainder of the participants, the corresponding OR (95% CI) was 1.09 (0.58 to 2.05; Ptrend=0.75).

Conclusions: In this population of US women, fetuin-A levels were associated with lower CHD risk when C-reactive protein levels were high, but null association was observed among participants with lower C-reactive protein levels. This divergent pattern of association needs replication in future studies.

Keywords: coronary heart disease; fetuin‐A; inflammation.

© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1.
Figure 1.
Odds ratio (95% CI) of coronary heart disease for plasma fetuin‐A levels by high‐sensitivity C‐reactive protein concentrations. Multivariate logistic regression models were adjusted for the same set of covariates for model 3 in Table 3, as well as matching factors. P for interaction=0.04.
Figure 2.
Figure 2.
Dose‐response relationship between fetuin‐A levels and CHD risk stratified by plasma hsCRP levels. Study participants with the lowest and highest 1% of fetuin‐A were excluded to minimize potential impact of outliers. Multivariate logistic regression models were adjusted for the same set of covariates for model 3 in Table 3, as well as matching factors. Solid lines are ORs and dashed lines are 95% CIs. The horizontal line is the reference line, and the dotted vertical lines are cut‐off points for making quintiles. A, hsCRP levels below median (0.20 mg/dL); (B) hsCRP levels above median. CHD indicates coronary heart disease; hsCRP, high‐sensitivity C‐reactive protein; ORs, odds ratio.
Figure 3.
Figure 3.
Odds ratio (95% CI) of coronary heart disease for plasma fetuin‐A levels by other inflammatory marker concentrations. Multivariate logistic regression models were adjusted for the same set of covariates for model 3 in Table 3, as well as matching factors. The Y axis was on log scale. A, interleukin‐6 (IL‐6), n=387; (B) tumor necrosis factor, receptor 1 (TNF‐R1), n=404; (C) tumor necrosis factor, receptor 2 (TNF‐R2), n=404.
Figure 4.
Figure 4.
Odds ratio (95% CI) of coronary heart disease for plasma fetuin‐A levels by diabetes status, hemoglobin A1c levels, or body mass index at baseline. Multivariate logistic regression models were adjusted for the same set of covariates for model 3 in Table 3, as well as matching factors. The Y axis was on log scale. A, diabetes status at baseline; (B) hemoglobin A1c. (C) body mass index.
Figure 5.
Figure 5.
Odds ratio (95% CI) of coronary heart disease for joint categories of plasma fetuin‐A levels and estimated glomerular filtration rate. Multivariate logistic regression models were adjusted for the same set of covariates for model 3 in Table 3. The Y axis was on log scale.

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