The Association of Fetuin-A With Cardiovascular Disease Mortality in Older Community-Dwelling Adults: The Rancho Bernardo Study

Study Questions:

Fetuin-A is a circulating inhibitor of calcium deposition in the vasculature, and of insulin action in muscle and fat, and may be involved in the pathogenesis of cardiovascular disease (CVD). What is the association of fetuin-A levels with CVD mortality?


A population-based (residents living in Rancho Bernardo, CA) prospective study was conducted in 633 men and 1,025 women 50 years or older who had fetuin-A levels and CVD risk factors evaluated from 1992 to 1996, and were followed for vital status through 2010. Primary outcome was CVD mortality.


Mean age was 72 years, body mass index was 25.4 kg/m2, blood pressure was 137/76 mm Hg, 39% of women used oral estrogens, 18% of participants met criteria for the metabolic syndrome, 14% had diabetes, and 20% had prevalent CVD. Plasma fetuin-A (g/L ± standard deviation) was highest in women using oral estrogens (0.55 ± 0.12), intermediate for women not using oral estrogens (0.51 ± 0.10), and lowest for men (0.50 ± 0.10), p < 0.001. Lower fetuin-A levels were associated with older age, but with lower levels of other CVD risk factors including adiposity, blood pressure, lipids, triglycerides, and insulin resistance (all p < 0.01). During the median 12-year follow-up, 273 deaths were attributed to CVD. The association of fetuin-A with CVD mortality differed by diabetes status (p for interaction = 0.003). Adjusting for age, sex, oral estrogens, and lifestyle, the hazard ratio for CVD mortality comparing the lowest fetuin-A quartile with all higher values was 1.76 (95% confidence interval [CI], 1.34-2.31; p < 0.001) for participants without diabetes and 0.43 (95% CI, 0.19-0.98; p = 0.046) for participants with diabetes.


Low fetuin-A levels predicted greater risk for CVD mortality in older adults without diabetes, but were associated with reduced risk of CVD death in those with diabetes. Fetuin-A may provide novel insight into mechanisms, leading to CVD death in those with versus without diabetes.


Higher fetuin-A levels are associated with lower coronary calcium scores and low fetuin-A with an increased CVD risk in individuals without diabetes; findings that conflict with the relationship between lower levels and lower blood pressure, better lipids, lower adiposity, and reduced likelihood of metabolic syndrome. The relationship between fetuin-A concentrations and incident CVD requires studies in an unselected representation of the general population.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia, Lipid Metabolism

Keywords: Insulin, Lipids, Blood Pressure, Risk Factors, Insulin Resistance, Metabolic Syndrome X, Body Mass Index, Biological Markers, Estrogens, Adiposity, Cardiovascular Diseases, Fetuins, Triglycerides, Diabetes Mellitus

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