Association of high proprotein convertase subtilisin/kexin type 9 antibody level with poor prognosis in patients with diabetes: a prospective study

Abstract

In addition to pathogenic autoantibodies, polyclonal autoantibodies with unknown physiological roles and pathogenicity are produced in the body. Moreover, serum antibodies against the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is integral to cholesterol metabolism, have also been observed. PCSK9 was also reported to be associated with insulin secretion and diabetes mellitus (DM). Therefore, we aimed to examine the clinical significance of PCSK9 antibodies (PCSK9-Abs) levels. We measured blood PCSK9-Abs and PCSK9 protein levels in 109 healthy donors (HDs) and 274 patients with DM (type 2 DM: 89.8%) using an amplified luminescence proximity homogeneous assay-linked immunosorbent assay. Subsequently, patients with DM were followed up (mean: 4.93 years, standard deviation: 2.77 years, maximum: 9.58 years, minimum: 0.07 years) to examine associations between antibody titers and mortality, myocardial infarction, stroke onset, and cancer. The primary endpoint of this study was to examine whether PCSK9-Abs can be a prognostic marker for overall mortality among the patients with diabetes. The secondary endpoint was to examine the relationship between PCSK9-Abs and clinical parameters. Although both PCSK9-Abs and PCSK9 protein levels were significantly higher in the DM group than in the HD group (p < 0.008), PCSK9-Abs and PCSK9 protein levels showed no correlation in either group. Mortality was significantly associated with higher PCSK9-Ab levels, but unrelated to PCSK9 protein levels. After investigating for potential confounding factors, higher PCSK9-Ab levels were still associated with increased mortality among the patients with DM. PCSK9-Abs may be a novel prognostic marker for overall mortality in patients with diabetes, and further studies are warranted to verify its usefulness.

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

“…After 48 months, it was observed that Evolocumab effectively brought down LDL-C to an average of 30 mg/dL which was sustained in subsequent studies. Although a recent clinical study argued that after examining all potential confounding factors, higher levels of anti-PCSK9 autoantibodies were significantly related to the increased deaths among diabetes patients, 451 Evolocumab has been reported to significantly decrease the risk of recurring CVEs in patients with pre-existing ASCVD and/or T2D. 452 , 453 The relative risk (RR) for the main outcome reduced by 15%, with a HR of 0.85 (95% CI 0.79–0.92) over a median 2.2-year monitoring period.…”

Serum anti‑KIAA0513 antibody as a common biomarker for mortal atherosclerotic and cancerous diseases

“…In terms of biomarker species, studies have reported enzyme, antigen, and, in recent years, nucleotide markers ( 1-3 ). However, there are still some reports on antibody markers, which include heat-shock 60-kD protein 1( 4 ), replication protein A2( 5 ), programmed cell death 11( 6 ), metalloproteinase 1, chromobox homolog 1, chromobox homolog 5( 7 ), DnaJ heat shock protein family (Hsp40) member C2( 8 ), adaptor-related protein complex 3 subunit delta 1( 9 ), serpin peptidase inhibitor, clade E member 1( 10 ), death-inducer obliterator 1, cleavage and polyadenylation specificity factor 2, forkhead box J2( 11 ) and thiosulfate sulfurtransferase-like domain-containing 2( 12 ) for acute ischemic stroke (AIS); ATPase, Ca ++ transporting, plasma membrane 4( 10 ), bone morphogenetic protein 1 ( 3 , 13 ), deoxyhypusine synthase ( 14 ), SH3 domain-binding protein 5( 15 ), prolyl carboxypeptidase ( 16 ), low-density lipoprotein receptor-related protein-associated protein 1( 17 ) and additional sex combs-like 2( 18 ) for atherosclerosis; nardilysin ( 19 ) for acute cardiac syndrome; and insulin ( 20 ), glutamic acid decarboxylase ( 21 ), adiponectin ( 22 ) and growth arrest and DNA-damage-inducible gene 34 ( 23 , 24 ), and proprotein convertase subtilisin/kexin type 9( 25 ) for diabetes mellitus (DM).…”