Abstract
We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to p < 0.0017) were replicated in patients with T2DM in an independent cohort. We also investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). One protein, adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Multiplicative interaction analyses in the two cohorts suggest a stronger association between A-FABP and leptin in men than in women. In longitudinal analyses, the association between leptin and MACE was slightly attenuated after adding A-FABP to the multivariate model. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, particularly in men.Trial registration: ClinicalTrials.gov identifier NCT 01049737.
Highlights
We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM)
We investigated to what degree the proteins that were cross-sectionally associated with leptin mediated the longitudinal association between leptin and major cardiovascular events (MACE) incidence, using multivariable Cox regression adjusted for age, sex, body mass index (BMI), systolic blood pressure, GFR, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol with and without the protein
In the discovery analysis in CARDIPP, two proteins were significantly positively associated with to leptin at the 5% false detection rate threshold: adipocyte fatty acid binding protein (A-FABP) (regression coefficient 0.118, 95% CI (0.064, 0.173) p = 0.000024) and adrenomedullin (ADM) (regression coefficient 0.119, 95% CI (0.07, 0.168), p = 0.000002) The associations between all 88 proteins and leptin are shown in Supplementary Table 1
Summary
We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). We investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). Adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, in men. We aimed to discover and replicate the association between plasma leptin and 88 proteins from a multiplex proteomics assay in two independent cohorts of type 2 diabetes patients. We aimed to explore if these proteins mediate the association between plasma leptin and future cardiovascular events
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