👤 Sara Haidermota

Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood. To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024. LDL-C level, LDL-C PRS, FH, or pLOF variant status. Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks. Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS. In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted. Show less

Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for coronary artery disease (CAD). Data on long-term outcomes following invasive coronary angiography (ICA) in those with elevated Lp(a) are limited. This study examined the association of Lp(a) levels with clinical outcomes after index ICA, accounting for baseline atherosclerotic plaque burden. Data were from participants with Lp(a) measurement who underwent index ICA between 2000 and 2023. Lp(a) levels were categorized as normal (<75 nmol/L), intermediate (75- < 125 nmol/L), high (125- < 175 nmol/L), and very high (≥175 nmol/L). Angiographic characteristics (severity, burden), CAD presentation (stable, acute), and subsequent clinical outcomes [acute myocardial infarction (AMI), revascularization, in-stent restenosis (ISR), and all-cause mortality] were assessed. Among 5118 participants, 973 (19.0%) had very high Lp(a). Compared with normal Lp(a), very high Lp(a) was associated with severe obstructive CAD {adjusted odds ratio (aOR), 1.51 [95% confidence interval (CI), 1.17-1.96]}, left main disease [aOR, 1.67 (95% CI, 1.22-2.29)], and a 14.04-point higher Gensini score (95% CI, 9.57-18.52). During a median (interquartile range) follow-up of 16.87 (6.38-18.99) years, participants with very high vs. normal Lp(a) had higher risk of AMI [adjusted hazard ratio (aHR), 1.20 (95% CI, 1.05-1.37)], revascularization [aHR, 1.32 (95% CI, 1.13-1.56)], ISR [aHR, 1.28 (95% CI, 1.04-1.56)], and mortality [aHR, 1.19 (95% CI, 1.05-1.34)]. Among 798 individuals undergoing coronary artery bypass grafting surgery after index ICA, those with very high vs. other Lp(a) were more likely to require subsequent percutaneous coronary intervention [aHR, 2.20 (95% CI, 1.06-4.58)]. Elevated Lp(a) levels are associated with increased burden of coronary atherosclerosis and significant residual risk for adverse outcomes following ICA, highlighting a need for targeted risk-reduction strategies. Show less

The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) in the development and progression of coronary disease is known, but their influence on extracoronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extracoronary vascular disease and incident major adverse limb events (MALEs). Four hundred forty-six participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extracoronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (odds ratio: 2.14, 95% confidence interval: 1.03, 4.44), and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extracoronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extracoronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries. Show less