Autoantibodies to Apolipoprotein A-1 as Independent Predictors of Cardiovascular Mortality in Renal Transplant Recipients

Abstract

Renal transplant recipients (RTRs) are known to have a high cardio-vascular disease (CVD) burden only partly explained by traditional CVD risk factors. The aim of this paper was therefore to determine: i) the prognostic value of autoantibodies against apoA-1 (anti-apoA-1 IgG) for incidence of CVD mortality, all-cause mortality and graft failure in RTR. Four hundred and sixty two (462) prospectively included RTRs were followed for 7.0 years. Baseline anti-apoA-1 IgG were determined and associations with incidence of CVD mortality (n = 48), all-cause mortality (n = 92) and graft failure (n = 39) were tested. Kaplan–Meier analyses demonstrated significant associations between tertiles of anti-apoA-1 IgG and CVD mortality (log rank test: p = 0.048). Adjusted Cox regression analysis showed a 54% increase in risk for CVD mortality for each anti-apoA-1 IgG levels standard deviation increase (hazard ratio [HR]: 1.54, 95% Confidence Interval [95%CI]: 1.14–2.05, p = 0.005), and a 33% increase for all-cause mortality (HR: 1.33; 95%CI: 1.06–1.67, p = 0.01), independent of CVD risk factors, renal function and HDL function. The association with all-cause mortality disappeared after excluding cases of CVD specific mortality. The sensitivity, specificity, positive predictive value, and negative predictive value of anti-apoA-1 positivity for CVD mortality were 18.0%, 89.3%, 17.0%, and 90.0%, respectively. HDL functionality was not associated with anti-apoA-1 IgG levels. This prospective study demonstrates that in RTR, anti-apoA-1 IgG are independent predictors of CVD mortality and are not associated with HDL functionality.

Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

“…Among autoantibodies of interest in CVD, the interest in antibodies against apolipoprotein A-1 (anti-ApoA-1 IgG) appears to be gaining momentum. Indeed, three recent studies derived from a large multicenter general population cohort demonstrated that anti-ApoA-1 IgGs were an independent cardiovascular (CV) risk factor predictive of poor prognosis [3][4][5] similarly to what had been reported previously and more recently in high CV risk populations [6][7][8][9][10][11]. In parallel, translational studies pointed to these autoantibodies as mediators of atherogenesis, promoting atherosclerosis, myocardial necrosis, and mice death through toll-like receptors (TLR) 2,4 and CD14 signaling [12][13][14].…”

Prognostic and therapeutic considerations of antibodies against c‐ter apolipoprotein A‐1 in the general population

“…Multivariate HRs were calculated after adjusting for age, gender, hypertension, diabetes, smoking, BMI, eGFR, HDL and LDL cholesterol, baseline CVD, and ADs. Humoral autoimmunity against apoA1 being known to be relevant for CVD, 2,3,5,8,10,11 sensitivity analyses were performed in primary and secondary prevention subgroups. Secondary prevention individuals were defined by the anamnestic presence of any CAD, any stroke or peripheral artery disease.…”

“…Routine analyses consisted of standard lipid profile, serum creatinine, glucose, homocysteine, uric acid, US-CRP, interleukin (IL)-1b, IL-6 and TNF-a measures that were performed according to routine methods as previously reported. 31,32 Anti-apoA1 and anti-cter apoA1 IgGs were measured following our validated anti-apoA1 IgG protocol reported above, [2][3][4][5]7,8,10,11,13,14,16,17,33 except that the F3L1 apoA1 analogue (1 µg per well) was used as coating antigen instead of fully delipidated and native apoA1. 20 The seropositivity cut-off for anti-cter apoA1 IgGs was prospectively set at an optical density (405 nm) value of 0.5, Figure 3.…”

“…1 Autoantibodies of the IgG subclass against apolipoprotein A1 (anti-apoA1 IgG), the major apolipoprotein of HDL, have been shown to be an independent CV risk factor in the general population, as well as predictors of poor CV outcomes and overall mortality in most populations reported so far. [2][3][4][5][6][7][8][9][10][11] Translational investigations showed that anti-apoA1 IgGs efficiently promote sterile inflammation, facilitate foam cell formation in vitro, and enhance the development of atherosclerosis and atherothrombosis in mice through specific innate immune receptors complexes and related signalling pathways. [12][13][14][15][16][17][18] In humans, the polyclonal anti-apoA1 IgG response has been shown to be preferentially oriented against the last alpha helix of the C-terminal part of apoA1 (amino acids: 241-266).…”

“…During the last decade, evidence has accumulated that autoantibodies against high‐density lipoproteins (HDLs) and their components impact multiple pro‐atherogenic processes, facilitating atherogenesis and the occurrence of cardiovascular (CV) diseases 1 . Autoantibodies of the IgG subclass against apolipoprotein A1 (anti‐apoA1 IgG), the major apolipoprotein of HDL, have been shown to be an independent CV risk factor in the general population, as well as predictors of poor CV outcomes and overall mortality in most populations reported so far 2–11 . Translational investigations showed that anti‐apoA1 IgGs efficiently promote sterile inflammation, facilitate foam cell formation in vitro, and enhance the development of atherosclerosis and atherothrombosis in mice through specific innate immune receptors complexes and related signalling pathways 12–18 .…”