HDL protein composition differs between young white European and South Asian men before and after weight gain

South Asians (SAs) in the UK are at an increased risk of cardiovascular disease (CVD), develop type 2 diabetes mellitus at a lower age and body mass index, and have a lower high-density lipoprotein cholesterol (HDL-C) concentration than their white European (EU) counterparts. The failure of HDL-C raising therapies for CVD risk reduction has turned attention to its composition and function. A previous study comparing the effect of moderate weight gain on SA and EU men found baseline and weight gain-induced ethnic differences in body composition, adipocyte function and insulin resistance (ClinicalTrials.gov registration: NCT02399423). This study investigated differences in HDL protein composition, subclass distribution and in vitro vascular functions at baseline and after weight gain in the same cohort of men. HDL protein composition was determined by nano liquid chromatography tandem mass spectrometry using label-free quantification. HDL subclass distribution was measured by native gel electrophoresis. HDL in vitro paraoxonase-1 (PON-1) activity was measured by monitoring the PON-1 mediated hydrolysis of phenylacetate. In vitro HDL anti-inflammatory function was assessed in an endothelial cell assay of adhesion molecule inhibition. SAs had higher levels of immunity- and inflammation-related proteins and a detrimental profile of lipid metabolism-related proteins at baseline and with weight gain (including lower apolipoprotein (apo) A-IV and apoF and higher apoC-III) compared with EU. HDL subclass distribution and in vitro vascular function were not different between EUs and SAs. HDL protein composition reflects systemic physiology and acts as a mechanistic marker of impaired lipid metabolism in SAs.