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.
Gang Liu, Ming Ding, Stephanie E Chiuve, Eric B Rimm, Paul W Franks, James B Meigs, Frank B Hu, Qi Sun
Author Information
Gang Liu: 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.).
Ming Ding: 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.).
Stephanie E Chiuve: 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.).
Eric B Rimm: 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.).
Paul W Franks: 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.).
James B Meigs: 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.).
Frank B Hu: 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.).
Qi Sun: 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.
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.
