Paraoxonase‑3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis

Patients with autoimmune diseases have a significantly increased risk of developing cardiovascular disease. In disease, high-density lipoprotein (HDL) particles lose their anti-inflammatory and antioxidant properties and become dysfunctional. The purpose of this study was to test the hypothesis that alterations in the HDL proteomic profile are associated with subclinical atherosclerosis and HDL dysfunction in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes. Targeted proteomics was used to quantify the relative abundance of 18 proteins in HDL from SLE patients with and without atherosclerotic plaque detectable by carotid ultrasound. Changes in the proteomic profile were compared against the in vitro ability of HDL to protect against lipid oxidation. The same proteins were quantified in HDL from patients with type 1 diabetes with or without coronary artery calcification as determined by computed tomography. In each population, paraoxonase-3 (PON3), a potent antioxidant protein, was depleted from the HDL of patients with subclinical atherosclerosis. PON3 expression in HDL was positively correlated with HDL antioxidant function. These results suggest that PON3 may be an important protein in preventing atherosclerosis and highlight the importance of antioxidant proteins in the prevention of atherosclerosis in vivo

Characteristics of the MESA-Inflammation study population by type 2 diabetes status.

<p>Data are from MESA exam 4 (2005–2007) unless otherwise noted.</p><p>*: Data are from MESA exam 5 (2010–2012).</p><p>**: Includes all participants with incident cardiovascular events (myocardial infarction, resuscitated cardiac arrest, definite or probable angina, and stroke) from baseline through the start of MESA exam 4.</p><p>Characteristics of the MESA-Inflammation study population by type 2 diabetes status.</p

Associations of lymphocyte subpopulations with prevalent type 2 diabetes.

<p>P-values are from continuous models. Model 1: Age, gender, race/ethnicity. Model 2: Age, gender, race/ethnicity, and BMI.</p><p>Associations of lymphocyte subpopulations with prevalent type 2 diabetes.</p

Associations of lymphocyte subpopulations with fasting glucose, HbA1c, and insulin among participants without type 2 diabetes.

<p>Analyses excluded participants with pharmacologically-treated type 2 diabetes. Lymphocyte subpopulations were analyzed in separate models per SD increment higher. Model 1: Age, gender, race/ethnicity. Model 2: Age, gender, race/ethnicity, and BMI.</p><p>Associations of lymphocyte subpopulations with fasting glucose, HbA1c, and insulin among participants without type 2 diabetes.</p

<b>Associations of kidney tubular biomarkers with incident macroalbuminuria and sustained low eGFR in DCCT/EDIC</b>

Objective: Tubulointerstitial injury contributes to diabetic kidney disease (DKD) progression. We tested tubular biomarker associations with DKD development in type 1 diabetes (T1D). Research Design and Methods: A case-cohort study examined associations of tubular biomarkers, measured across 7 time points spanning ~30 years, with incident macroalbuminuria (‘severely elevated albuminuria’, urinary albumin excretion rate ≥300mg/day) and sustained low eGFR (persistent eGFR<60ml/min/1.73m2) in DCCT/EDIC. Biomarkers included: KIM-1, sTNFR1 in serum/plasma; MCP-1, EGF in urine; a composite tubular secretion score reflecting secreted solute clearance. Biomarkers were assessed using single values, as mean values from consecutive time points, and as change over consecutive time points, each as time-updated exposures. Results: At baseline, mean diabetes duration was 5.9 years, with mean HbA1c 8.9%, eGFR 125ml/min/1.73m2, and AER 16mg/day. 4.8 and 3.5 cases per 1000 person-years of macroalbuminuria and low eGFR were observed, respectively. Assessed as single biomarker values, KIM-1 was associated with risk of subsequent macroalbuminuria and low eGFR (hazard ratio [HR] per 20% higher biomarker, HR=1.11 [95% CI 1.06,1.16] and HR=1.12 [95% CI 1.04,1.21], respectively); sTNFR1 was associated with subsequent macroalbuminuria (HR=1.14 [95% CI 1.03,1.25]). Mean KIM-1 and EGF to MCP-1 ratio were associated with subsequent low eGFR. In slope analyses, increases in KIM-1 and sTNFR1 were associated with subsequent macroalbuminuria (per 20% biomarker increase, HR=1.81 [95% CI 1.40,2.34] and HR=1.95 [95% CI 1.18,3.21], respectively) and low eGFR (HR=2.26 [95% CI 1.65,3.09] and HR=2.94 [95% CI 1.39,6.23], respectively). Conclusions: Serial KIM-1 and sTNFR1 are associated with incident macroalbuminuria and sustained low eGFR in T1D.</p

Associations Between Serum Potassium and Incident Diabetes, by Ethnicity (N = 5415).

<p>Associations Between Serum Potassium and Incident Diabetes, by Ethnicity (N = 5415).</p

Associations Between Serum Potassium and Fasting Glucose, by Ethnicity (N = 5415).

<p>Associations Between Serum Potassium and Fasting Glucose, by Ethnicity (N = 5415).</p

Associations Between Dietary Potassium (mg/day) and Incident Diabetes, by Ethnicity (N = 5415).

<p>Associations Between Dietary Potassium (mg/day) and Incident Diabetes, by Ethnicity (N = 5415).</p

Baseline Characteristics of Study Population (N = 5415), by Serum K (mmol/L).

<p>Baseline Characteristics of Study Population (N = 5415), by Serum K (mmol/L).</p