👤 Sheila Jeschke

When Apolipoprotein B (ApoB) is discordant with either LDL cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C), ApoB is a stronger predictor of atherosclerotic cardiovascular disease (ASCVD). It is unclear whether ApoB also provides better risk stratification when ApoB and LDL particle number (LDL-P) are discordant. Here we examine the relationship between ApoB and LDL-P in the UK Biobank to determine which biomarker provides more accurate risk prediction when ApoB and LDL-P are discordant. The UK Biobank is a prospective observational study of 500,000 adults. Analyses were restricted to 41,099 participants (mean age 57 years, 49.7% female, 95.1% white) with at least 10 years of data following enrollment, three or more recorded ICD codes, plasma lipoprotein and apolipoprotein measurements, and available baseline characteristics. Major adverse cardiovascular events (MACE) and coronary artery disease (CAD) events were plotted against LDL-P and ApoB for all participants. Concordance was defined as the linear regression line with y-intercept forced to zero. Discordant subpopulations were defined as populations 2, 4, 6, 8, 10, 20, and 30% above or below the regression line. The hazard ratio (HR) of cases to controls was determined for the discordant subpopulations and the concordant control group. A HR>1 means that the risk is greater in the discordant group than the reference group, whereas a HR<1 suggests that the cases are less common in the discordant group. Over 10 years of follow-up, 9,663 MACE and 1,754 CAD events occurred. There was no significant increase in HR for CAD events or MACE for the subpopulations with discordant LDL-P vs ApoB. In contrast, among subpopulations with discordant ApoB, the HR for both MACE and CAD events increased as discordance increased and was statistically significant at all percentage discordance cutoffs. At only 2% ApoB discordance, HRs were already elevated for both MACE (HR 1.1, P<0.0001) and CAD (HR 1.1, P<0.0001). Risk increased progressively, reaching HR 1.4 for MACE and HR 2.5 for CAD at 30% discordance. This study suggests that ApoB is a more accurate marker for cardiovascular risk than LDL-P when discordant, as marked by ApoB levels in excess of LDL-P. Notably, risk was already elevated at as little as 2% discordance, suggesting that even modest mismatches between ApoB and LDL-P may be clinically relevant. In keeping with prior data examining discordance between ApoB and LDL-C or non-HDL-C, this data reinforces the utility of ApoB in guiding lipid-lowering strategies and cardiovascular risk assessment. Show less

Skeletal pathologies are frequently observed in lysosomal storage disorders, yet the relevance of specific lysosomal enzymes in bone remodeling cell types is poorly defined. Two lysosomal enzymes, ie, cathepsin K (Ctsk) and Acp5 (also known as tartrate-resistant acid phosphatase), have long been known as molecular marker proteins of differentiated osteoclasts. However, whereas the cysteine protease Ctsk is directly involved in the degradation of bone matrix proteins, the molecular function of Acp5 in osteoclasts is still unknown. Here we show that Acp5, in concert with Acp2 (lysosomal acid phosphatase), is required for dephosphorylation of the lysosomal mannose 6-phosphate targeting signal to promote the activity of specific lysosomal enzymes. Using an unbiased approach we identified the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), mutated in mucopolysaccharidosis type VI (MPS-VI), as an osteoclast marker, whose activity depends on dephosphorylation by Acp2 and Acp5. Similar to Acp2/Acp5 Show less