Albuminuria, the HDL Proteome, and Prevalent Coronary Artery Calcium in Type 1 Diabetes

Patients with type 1 diabetes (T1D) are at high risk of atherosclerotic cardiovascular disease (CVD). Albuminuria is strongly associated with CVD risk and fully accounts for the excess overall mortality risk in some T1D cohorts. One important contributor might be alterations of the HDL proteome. In the current study, we tested the hypotheses that albuminuria is associated with alterations in the HDL proteome in T1D, and that these alterations are associated with prevalent CVD. We performed a cross-sectional study of 191 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) participants selected according to levels of urine albumin excretion (67 persistent normoalbuminuria, 64 persistent microalbuminuria, and 60 persistent macroalbuminuria). We used targeted proteomics and isotope dilution tandem-mass spectrometry to quantify the concentration of 47 proteins in HDL. Adjusting for age, sex, DCCT treatment group, duration of diabetes, lipid-lowering medications, renin-angiotensin system inhibitors, smoking, BMI, and HbA1c, and after accounting for multiple comparisons, six proteins in HDL were significantly associated with albuminuria (2 increased and 4 decreased). For example, compared to normoalbuminuria, macroalbuminuria was associated with 57% and 177% higher AMBP ( P =0.0003) and PTGDS ( P =0.0006), respectively, and 28% and 27% lower PON1 ( P =0.002) and PON3 ( P =0.008), respectively. Furthermore, PON1 and PON3 in HDL were strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (0.43-0.92, 95% CI, P =0.02) for PON1 and 0.59 (0.40-0.87, 95% CI, P =0.008) for PON3. Our observations indicate that the HDL proteome is remodeled in albuminuric patients with T1D, and that these alterations in HDL’s protein cargo may mediate, in part, the relationship of albuminuria with CVD. Because PON1 and PON3 are anti-atherogenic in hypercholesterolemic mice, our data suggest that low levels of PON1 and PON3 in HDL increase the risk of atherosclerosis in diabetic humans. In future studies, it will be important to determine whether reductions of PON1 and PON3 in HDL predict the risk of future CVD in subjects with T1D.