Using proximity extension proteomics assay to discover novel biomarkers associated with circulating leptin levels in patients with type 2 diabetes

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. Abbreviations ADM Adrenomedullin A-FABP Adipocyte fatty acid binding protein BMI Body mass index CARDIPP Cardiovascular risk factors in patients with diabetes-a prospective study in primary care CHD Coronary heart disease CRP C-reactive protein CVD Cardiovascular disease HDL High density lipoprotein HR Hazard ratio LDL Low density lipoprotein LOD Limit of detection MACE Major adverse cardiac events PCR Polymerase chain reaction

Examination of the Complex Molecular Landscape in Obesity and Type 2 Diabetes

“…By leveraging advanced analytics and pathway enrichment analyses, we elucidate the functional implications of differential protein expression patterns and uncover unique mechanisms underlying disease development and progression. Our results align with previous studies utilizing PEA technology, which has been instrumental in uncovering associations between cardiovascular proteins and metabolic diseases [8,9].…”

“…PEA has become a widely used method in proteomics research of cardiovascular and metabolic diseases. For instance, Vavruch et al used PEA technology to find association between the level of 92 cardiovascular proteins and the amount of leptin to obtain better understanding of how leptin is linked to cardiovascular disease in patients with T2D [8]. In another study, Kozakova et al assessed the connection between matrix-metalloproteinases, interleukins, lipids, and various cardiovascular parameters in both T2D and non-T2D cohorts [9].…”

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects

“…to explore if physical exercise changes immune marker profiles in plasma and CSF. Accordingly, we analyzed samples with an inflammation panel that has been used in many previous studies 52 – 55 .…”

Determination of the Plasma Concentration of the Protein Product of the Ob Gene and Lipid Profile in Bosnian Type 2 Diabetic Individuals

“…Considering these and results of the others, elevated plasma leptin concentrations together with impaired lipids metabolism in obese uncontrolled T2D patients could be a potential target for further treatment [20,[23][24][25].…”