Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study

UMMS Affiliation

Meyers Primary Care Institute; Department of Medicine, Division of Cardiovascular Medicine

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Document Type



Adiposity; Adult; Biological Markers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Fatty Acid-Binding Proteins; Female; Humans; Insulin Resistance; Male; Massachusetts; Metabolic Syndrome X; Middle Aged; Multivariate Analysis; Retinol-Binding Proteins, Plasma; Risk Factors; Sex Characteristics; Sex Distribution; alpha-2-HS-Glycoprotein


Cardiology | Cardiovascular Diseases | Endocrine System Diseases | Endocrinology, Diabetes, and Metabolism | Nutritional and Metabolic Diseases


CONTEXT: Fetuin-A, retinol-binding protein 4 (RBP4), and fatty-acid binding protein 4 (FABP4) are novel biomarkers that may link adiposity to insulin resistance and the metabolic syndrome (MetSyn).

OBJECTIVE: The aim of this study was to investigate the correlates of these three adiposity biomarkers in a large community-based sample.

DESIGN, SETTING, PARTICIPANTS, AND OUTCOMES: Serum concentrations of fetuin-A, RBP4, and FABP4 were assayed in 3658 participants of the Third Generation Framingham Heart Study cohort (mean age 40 yr, 54% women). We used multivariable regression to cross-sectionally relate biomarkers to insulin resistance, cardiovascular risk factors, and the MetSyn. The genetic contribution to inter-individual variation in biomarker levels was assessed using variance-components analysis.

RESULTS: All three biomarkers exhibited sexual dimorphisms (levels higher in women for fetuin-A and FABP4 but greater in men for RBP4) and were associated positively with insulin resistance assessed using the homeostasis model, with high-sensitivity C-reactive protein, and with prevalent MetSyn (P<0.01 for all). The biomarkers showed distinct patterns of association with metabolic risk factors. RBP4 levels were correlated with body mass index only in unadjusted but not in adjusted models. None of the biomarkers were associated with prevalent diabetes in multivariable models. Circulating fetuin-A, RBP4, and FABP4 levels showed modest heritability, ranging from 15-44% (all P<0.0001).

CONCLUSIONS: In our large young- to middle-aged community-based sample, we observed that circulating levels of fetuin-A, RBP4, and FABP4 are associated with insulin resistance and with distinct components of MetSyn consistent with the multifactorial pathogenesis of metabolic dysregulation.

DOI of Published Version



J Clin Endocrinol Metab. 2012 Oct;97(10):E1943-7. doi: 10.1210/jc.2012-1458. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of clinical endocrinology and metabolism

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