Plasma Levels of Fatty Acid–Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes

Abstract

Objective To examine select adipokines, including fatty acid-binding protein 4 (FABP4), retinol-binding protein 4 (RBP4), and high-molecular weight (HMW) adiponectin in relation to cardiovascular disease (CVD) mortality among patients with type 2 diabetes (T2D). Approach and Results Plasma levels of FABP4, RBP4, and HMW adiponectin were measured in 950 men with T2D in the Health Professionals Follow-up Study. After an average of 22 years of follow up (1993–2015), 580 deaths occurred, of whom 220 died of CVD. After multivariate adjustment for covariates, higher levels of FABP4 were significantly associated with a higher CVD mortality: comparing extreme tertiles, the hazard ratio (HR) and 95% confidence interval (CI) of CVD mortality was 1.78 (1.22, 2.59; P trend=0.001). A positive association was also observed for HMW adiponectin: the HR (95% CI) was 2.07 (1.42, 3.06; P trend=0.0002), comparing extreme tertiles, whereas higher RBP4 levels were non-significantly associated with a decreased CVD mortality with an HR (95% CI) of 0.73 (0.50, 1.07; P trend=0.09). A Mendelian randomization (MR) analysis suggested that the causal relationships of HMW adiponectin and RBP4 would be directionally opposite to those observed based on the biomarkers, although none of the MR associations achieved statistical significance. Conclusions These data suggest that higher levels of FABP4 and HMW adiponectin are associated with elevated CVD mortality among men with T2D. Biological mechanisms underlying these observations deserve elucidation, but the associations of HMW adiponectin may partially reflect altered adipose tissue functionality among T2D patients.

Letter by Menzaghi et al Regarding Article, “Plasma Levels of Fatty Acid–Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes: A 22-Year Prospective Study”

“…1 These data resemble those we have previously reported 2 in men with type 2 diabetes mellitus, comprising a large subset of the same HPSF and additional Italian individuals. 2 To address whether such association is sustained by a causeeffect relationship, a genetic risk score (GRS) built on 19 single nucleotide polymorphisms previously associated with adiponectin levels (Mendelian randomization) was used.…”

“…1 If this is the case, ignoring time to event could have altered the results and contributed to the discrepancy with our study.…”

“…In addition, whereas our participants were all Whites, 4 those of HPFS were not. 1 Because genetic background of serum adiponectin is heterogeneous across ethnicities, 6 such difference too may have contributed to discrepancy between the 2 studies.…”

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

“…2). Recently, FABP4 plasma levels have been associated with elevated CVD mortality in men with type 2 diabetes mellitus (Liu et al 2016). Decreased FABP4 expression as a consequence of a genetic variant of the FABP4 promoter (T-87C) results in reduced serum triglycerides and a lower risk of CVD (Tuncman et al 2006).…”

Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

“…These results suggested a role for sIL-2Rα in atherosclerosis and generated hypotheses for studies of multiple-associated SNPs near chromosome 10p15-14. 9 Liu et al 10 used Mendelian randomization to test whether plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, and high molecular weight adiponectin were directly causal for cardiovascular mortality in 950 patients with type 2 diabetes mellitus and found no statistically significant associations. It is important to note that although this particular study did not show a significant association, the study design should be taken into consideration before permanently classifying something as causative or not.…”