Gang Liu1, Ming Ding1, Stephanie E Chiuve1, Eric B Rimm1, Paul W Franks1, James B Meigs1, Frank B Hu1, Qi Sun2. 1. From the Department of Nutrition (G.L., M.D., S.E.C., E.B.R., P.W.F., F.B.H., Q.S.) and Department of Epidemiology (E.B.R., F.B.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Division of Preventive Medicine (S.E.C.) and Channing Division of Network Medicine (E.B.R., F.B.H., Q.S.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden (P.W.F.); Skåne University Hospital Malmö, Sweden (P.W.F.); Department of Public Health and Clinical Medicine, Faculty of Medicine, Umeå University, Sweden (P.W.F.); Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (J.B.M.); and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.B.M.). 2. From the Department of Nutrition (G.L., M.D., S.E.C., E.B.R., P.W.F., F.B.H., Q.S.) and Department of Epidemiology (E.B.R., F.B.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Division of Preventive Medicine (S.E.C.) and Channing Division of Network Medicine (E.B.R., F.B.H., Q.S.), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden (P.W.F.); Skåne University Hospital Malmö, Sweden (P.W.F.); Department of Public Health and Clinical Medicine, Faculty of Medicine, Umeå University, Sweden (P.W.F.); Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (J.B.M.); and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.B.M.). qisun@hsph.harvard.edu.
Abstract
OBJECTIVE: To examine select adipokines, including fatty acid-binding protein 4, retinol-binding protein 4, and high-molecular-weight (HMW) adiponectin in relation to cardiovascular disease (CVD) mortality among patients with type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, and HMW adiponectin were measured in 950 men with type 2 diabetes mellitus 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 fatty acid-binding protein 4 were significantly associated with a higher CVD mortality: comparing extreme tertiles, the hazard ratio and 95% confidence interval of CVD mortality was 1.78 (1.22-2.59; P trend=0.001). A positive association was also observed for HMW adiponectin: the hazard ratio (95% confidence interval) was 2.07 (1.42-3.06; P trend=0.0002), comparing extreme tertiles, whereas higher retinol-binding protein 4 levels were nonsignificantly associated with a decreased CVD mortality with an hazard ratio (95% confidence interval) of 0.73 (0.50-1.07; P trend=0.09). A Mendelian randomization analysis suggested that the causal relationships of HMW adiponectin and retinol-binding protein 4 would be directionally opposite to those observed based on the biomarkers, although none of the Mendelian randomization associations achieved statistical significance. CONCLUSIONS: These data suggest that higher levels of fatty acid-binding protein 4 and HMW adiponectin are associated with elevated CVD mortality among men with type 2 diabetes mellitus. Biological mechanisms underlying these observations deserve elucidation, but the associations of HMW adiponectin may partially reflect altered adipose tissue functionality among patients with type 2 diabetes mellitus.
OBJECTIVE: To examine select adipokines, including fatty acid-binding protein 4, retinol-binding protein 4, and high-molecular-weight (HMW) adiponectin in relation to cardiovascular disease (CVD) mortality among patients with type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of fatty acid-binding protein 4, retinol-binding protein 4, and HMW adiponectin were measured in 950 men with type 2 diabetes mellitus 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 fatty acid-binding protein 4 were significantly associated with a higher CVD mortality: comparing extreme tertiles, the hazard ratio and 95% confidence interval of CVD mortality was 1.78 (1.22-2.59; P trend=0.001). A positive association was also observed for HMW adiponectin: the hazard ratio (95% confidence interval) was 2.07 (1.42-3.06; P trend=0.0002), comparing extreme tertiles, whereas higher retinol-binding protein 4 levels were nonsignificantly associated with a decreased CVD mortality with an hazard ratio (95% confidence interval) of 0.73 (0.50-1.07; P trend=0.09). A Mendelian randomization analysis suggested that the causal relationships of HMW adiponectin and retinol-binding protein 4 would be directionally opposite to those observed based on the biomarkers, although none of the Mendelian randomization associations achieved statistical significance. CONCLUSIONS: These data suggest that higher levels of fatty acid-binding protein 4 and HMW adiponectin are associated with elevated CVD mortality among men with type 2 diabetes mellitus. Biological mechanisms underlying these observations deserve elucidation, but the associations of HMW adiponectin may partially reflect altered adipose tissue functionality among patients with type 2 diabetes mellitus.
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