Abstract
Apolipoproteins function as structural components of lipoprotein particles, cofactors for enzymes, and ligands for cell-surface receptors. Most of the apoliporoteins exhibit proteoforms, arising from single nucleotide polymorphisms (SNPs) and post-translational modifications such as glycosylation, oxidation, and sequence truncations. Reviewed here are recent studies correlating apolipoproteins proteoforms with the specific clinical measures of lipid metabolism and cardiometabolic risk. Targeted mass spectrometric immunoassays toward apolipoproteins A-I, A-II, and C-III were applied on large cross-sectional and longitudinal clinical cohorts. Several correlations were observed, including greater apolipoprotein A-I and A-II oxidation in patients with diabetes and cardiovascular disease, and a divergent apoC-III proteoforms association with plasma triglycerides, indicating significant differences in the metabolism of the individual apoC-III proteoforms. These are the first studies of their kind, correlating specific proteoforms with clinical measures in order to determine their utility as potential clinical biomarkers for disease diagnosis, risk stratification, and therapy decisions. Such studies provide the impetus for the further development and clinical translation of MS-based protein tests.
Highlights
Protein biomarkers are critical for the early detection of disease, prognosis, and therapy monitoring
We have investigated clinical proteoforms correlations for several protein biomarkers, utilizing multiple clinical cohorts across the type 2 diabetes (T2D) continuum
Apolipoprotein A-I is a major protein component of high-density lipoproteins (HDL) particles in plasma that has been implicated as a biomarker for cardiovascular disease [52]
Summary
Protein biomarkers are critical for the early detection of disease, prognosis, and therapy monitoring. Only a few of the putative protein biomarkers have been taken through verification and validation steps [1,2,3,4,5], contributing to the notion that MS is a great protein biomarker discovery tool, but a difficult one to translate into clinical practice Further supporting this argument is the fact that, thirty years after the development of electrospray (ESI) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS, there are only about a dozen MS protein tests in clinical use today [6]. There are some hybrid methods combining immunoaffinity protein isolation with MS detection that are well-suited for studying proteoforms One such method is known as mass spectrometric immunoassay (MSIA) [16]. Recent studies have raised the prospects of apolipoprotein profiling for cardiovascular disease (CVD) [38] and a role for apolipoprotein C-III in CVD risk lowering has been suggested [39]
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