👤 Heather M Wilkins

Genetic factors are thought to play an important role in antipsychotic-induced weight gain (AIWG). This study conducted a meta-analysis of current research of the pharmacogenetic associations of adult AIWG. The analysis included papers providing comparisons of weight gain across at least two allele combinations for at least one single nucleotide polymorphism (SNP). Inclusion criteria were, patients 18 years of age or older and had received a diagnosis of severe mental illness, for which antipsychotic medication was prescribed. The association with AIWG needed to be replicated across at least two papers reporting separate sample sets. Two hundred twenty-three papers were assessed for eligibility. Of the 223 papers, 148 were excluded, leaving 75 studies to be included. Six SNPs in six different genes were identified as having significant associations ( The study identified six SNPs that predispose adult individuals to AIWG, with Show less

Apolipoprotein B (apoB) is a superior marker of residual atherosclerotic cardiovascular disease risk in patients treated with lipid-lowering therapy (LLT) compared with low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). The cost-effectiveness of LDL-C, non-HDL-C, and apoB goals has not been established. To determine the relative cost-effectiveness of intensifying LLT for primary prevention based on LDL-C, non-HDL-C, and apoB goals. This economic evaluation used a computer simulation model to evaluate the cost-effectiveness of intensifying LLT with high-intensity statins or ezetimibe according to LDL-C, non-HDL-C, or apoB goals. A cohort of 250 000 statin-eligible and atherosclerotic cardiovascular disease-free US adults was constructed from 2005 to 2016 National Health and Nutrition Examination Survey participants (N = 4149). Individuals commenced the simulation after lipid screening and received statin therapy based on 2018 American Heart Association/American College of Cardiology guidelines. Model inputs were derived from national survey data, pooled longitudinal cohort studies, and published literature. Uncertainty was explored with traditional and probabilistic sensitivity analysis. Lipid-lowering therapy was intensified if individuals did not achieve treated LDL-C level less than 100 mg/dL, non-HDL-C level less than 118 mg/dL, or apoB level less than 78.7 mg/dL. Lifetime quality-adjusted life-years (QALYs) and costs (in 2025 US dollars), discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. Strategies were considered cost-effective if they cost less than $120 000 per QALY gained. Compared with an LDL-C goal, 965 QALYs (95% uncertainty interval [UI], -3551 to 5341 QALYs) would be gained with a non-HDL-C goal, alongside a $2.1 million (95% UI, -$94.2 million to $92.0 million) reduction in costs. Compared with a non-HDL-C goal, 1324 QALYs (95% UI, -2602 to 5669 QALYs) would be gained with an apoB goal, alongside a $40.2 million (95% UI, -$43.6 million to $134 million) increase in costs, yielding an incremental cost-effectiveness ratio of $30 300 per QALY gained. At a willingness-to-pay threshold of $120 000 per QALY gained, an apoB goal was optimal in 65% of probabilistic analyses and a non-HDL-C goal was optimal in 25%. The cost of apoB testing was marginal; higher costs reflected longer life expectancy and prolonged preventive treatment. The results of this computer simulation study suggest that apoB can be used as a cost-effective marker to guide primary prevention LLT and improve population health. Show less

The utility of emerging lipid markers-apolipoprotein B (apoB) and lipoprotein(a) (Lp[a])-for improving atherosclerotic cardiovascular disease (ASCVD) risk assessment beyond traditional lipid measures remains uncertain, particularly in young adults. To evaluate associations of traditional and emerging lipid markers with ASCVD and assess the incremental value of emerging markers beyond established risk models. This prospective cohort study included adults aged 18 years or older without cardiovascular disease from 3 US cohort studies (Coronary Artery Risk Development in Young Adults, the Framingham Heart Study Offspring, and the Multi-Ethnic Study of Atherosclerosis [MESA]). Data were analyzed from April to June 2025. Lipid markers, including low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, total-to-HDL cholesterol ratio, apoB, and Lp(a). Hazard ratios (HRs) for incident ASCVD per-SD increase in lipid marker levels, estimated using Cox proportional hazards regression models adjusted for demographic and clinical factors, and model performance metrics (Harrell concordance index [C-index], net reclassification improvement [NRI], and mean calibration) comparing models including the risk estimated by the Predicting Risk of Cardiovascular Disease Events (PREVENT) base equations against models that additionally included each lipid marker. Among 10 519 participants (mean [SD] age, 48.3 [15.7] years; 53.0% female), 1103 ASCVD events occurred during a median follow-up of 21.3 (IQR, 16.5-26.0) years. ApoB was positively associated with ASCVD events, especially in younger adults aged 18 to 39 years (adjusted HR [AHR] per-SD increase, 1.53; 95% CI, 1.30-1.79) vs those aged 40 years or older (AHR, 1.13; 95% CI, 1.06-1.20) (P < .001 for interaction). Lp(a) as a continuous variable was associated with a marginal increase in ASCVD in adults aged 40 years or older (AHR, 1.07; 95% CI, 1.00-1.16) but not in younger adults (AHR, 1.02; 95% CI, 0.87-1.19) (P = .61 for interaction). When dichotomized (>50 vs ≤50 mg/dL), Lp(a) was associated with ASCVD in adults aged 40 years or older (AHR range, 1.36; 95% CI, 1.13-1.64) but not in younger adults (AHR, 0.98; 95% CI, 0.66-1.45) (P = .42 for interaction). Adding apoB to 10-year ASCVD risk estimated by the PREVENT base equations was associated with improved risk reclassification in younger adults (continuous NRI, 0.67; 95% CI, 0.23-1.09) but not in those aged 40 years or older (continuous NRI, 0.16; 95% CI, -0.05 to 0.27). ApoB was also associated with improved 30-year risk reclassification in younger adults (continuous NRI, 0.47; 95% CI, 0.02-0.84). Dichotomized Lp(a), but not continuous Lp(a), was associated with improved 10-year NRI only in MESA (0.13; 95% CI, 0.03-0.24). In this cohort study of 10 519 adults, adding apoB to PREVENT-estimated ASCVD risks was associated with improved risk reclassification, particularly in younger adults. However, the clinical importance of these modest improvements remains uncertain. Show less

Alzheimer's disease (AD) involves proteostasis dysregulation causing protein misfolding, but whether these structural changes manifest as plasma conformational biomarkers remains unclear. We profiled plasma protein structures from 520 participants including individuals with AD, individuals with mild cognitive impairment (MCI) and healthy controls. Using mass spectrometry and machine learning, we systematically characterized the structural proteome changes associated with ApoE variations and neuropsychiatric symptoms to identify AD-specific signatures. We developed a diagnostic panel using peptides from C1QA, CLUS and ApoB representing AD-associated structural changes. This three-marker panel achieved 83.44% accuracy in three-way classification (healthy versus MCI versus AD). Binary classification yielded area under the receiver operating characteristic curves of 0.9343 for healthy versus MCI and 0.9325 for MCI versus AD. Longitudinal samples were classified with 86.0% accuracy. This multi-marker panel based on plasma protein structural alterations represents a promising diagnostic approach that may enhance early AD detection and provide insights for clinical trials, improving therapeutic outcomes. Show less

Elevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized. We sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults. In the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured Year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using LASSO regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident CHD, and hs-CRP over 27 years of follow-up. External replication was performed in the UK Biobank (n=37,996). Lp(a) was associated with CAC (OR 1.23 [1.13-1.34]; p<0.0001) and incident CHD (HR 1.23 [1.07-1.41]; p=0.004). Lp(a) correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a) proteomic score was independently associated with incident CAC (standardized beta = 0.40, p<0.0001) and hs-CRP (standardized beta = 0.11, p = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomic score was associated with CRP, incident CHD, and all-cause mortality. In young adults, Lp(a) is associated with distinct proteomic features that independently predict ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk. Show less

Conventional statistical approaches are not designed to compare highly correlated variables such as low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB). Discordance analysis was designed to overcome this limitation by creating groups in which the predictions of 2 markers differ. This systematic review compiled all discordance studies that compare the predictive powers of LDL-C and non-HDL-C vs LDL particle number (LDL P) or apoB as markers of atherosclerotic disease risk to determine which is the most accurate marker of cardiovascular risk. A PubMed search completed September 30, 2024, identified 15 studies involving 593,354 participants. These studies encompassed diverse populations, and included patients with and without statin therapy. Several variations of discordance analysis were used including median-based, percentile-based, residual-based, and variance-based approaches. ApoB outperformed LDL-C in 9 of 9 studies whereas LDL P was superior to LDL-C in 2 of 3 comparisons. In 1 study, non-HDL-C was superior to apoB, in 1 study apoB and non-HDL-C were equivalent, whereas in 7 studies, apoB, overall, was a significantly more accurate marker of atherosclerotic cardiovascular disease risk than non-HDL-C. Discordance analysis provides robust evidence that apoB is a more accurate marker of cardiovascular risk than either LDL-C or non-HDL-C, notwithstanding these variables are highly intercorrelated. Thus, neither LDL-C nor non-HDL-C are adequate clinical surrogates for apoB. Accordingly, apoB should be the primary measure in clinical care to estimate the cardiovascular risk attributable to the apoB lipoproteins and the adequacy of lipid-lowering therapy to reduce this risk. Show less

Atherogenic lipoprotein exposure during young adulthood increases the risk of atherosclerotic cardiovascular disease (ASCVD) later in life. The relationships between cumulative and usual yearly apolipoprotein B (apoB), low-density lipoprotein particle (LDL-P), and triglyceride-rich lipoprotein particle (TRL-P) exposure in early adult life and incident ASCVD was quantified. Follow-up data of young adults aged 18 to <40 years from the longitudinal population-based Coronary Artery Risk Development in Young Adults (CARDIA) cohort were used. Cumulative early adult exposure of apoB, LDL-P, and TRL-P were defined over a 22-year exposure period (18 to <40 years). 'Usual' exposure to atherogenic lipid particles was calculated by dividing the cumulative exposure to apoB, LDL-P, and TRL-P by 22 years, and the hazard ratio was calculated between a 1 SD higher cumulative lipoprotein exposure with incident ASCVD after age 40 using adjusted Cox regression models. Among 4366 CARDIA participants, there were 241 ASCVD events after age 40 (mean follow-up of 19.3 years). A 1 SD higher cumulative exposure to apoB, LDL-P, and TRL-P was associated with unadjusted HRs of 1.53 [95% confidence interval (CI) 1.36-1.72], 1.54 (95% CI 1.36-1.75), and 1.48 (95% CI 1.30-1.68) for incident ASCVD after age 40, respectively. Adjustment for covariates yielded HRs for each measure of approximately 1.30. The hazard ratio for ASCVD increased after a usual apoB exposure of approximately 75 mg/dL/year from age 18 to <40. Cumulative exposure to atherogenic lipid particles in young adulthood increases the risk for incident ASCVD later in life. Apolipoprotein B concentration <75 mg/dL may represent a goal to maintain low risk in young adults. Show less

Alzheimer's disease (AD) pathology is complex and involves mitochondrial dysfunction. There are emerging therapies targeting mitochondrial function in clinical trials for AD. This highlights the need for biomarkers that measure mitochondrial function. We determined the utility of a novel blood-based mitochondrial biomarker, the mitochondrial functional index (MFI), in the context of AD in a pilot study. In vitro and in vivo models of AD had a reduced MFI. MFI was lower in human AD subjects and APOE 𝜀4 carriers. Receiver operating characteristic analysis showed MFI had a higher area under the curve than other plasma biomarkers. The MFI biomarker correlated with the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale. This study highlights the potential utility of MFI as a functional blood-based mitochondrial biomarker to interrogate energy metabolism. Ongoing studies are examining the relationship of MFI with brain energy metabolism outcomes. The MFI biomarker is reduced in cell and animal models of AD. The MFI biomarker is reduced in human AD subjects and APOE ε4 carriers. The MFI biomarker can discriminate between subjects with normal cognition and AD with better performance than other plasma biomarkers. The MFI biomarker correlates with cognitive scores. Show less

A significant gap in the knowledge of zinc homeostasis exists for breast cancer cells. In this study, we investigated the transcriptomic response of the luminal breast cancer cells (MCF-7) to the exposure of extracellular zinc using next-generation RNA sequencing. The dataset was collected for three time points (T0, T30, and T120) in the time course of zinc treatment, which revealed the dramatic increase, up to 869-fold, of the gene expression for metallothioneins (MT1B, MT1F, MT1X, and MT2A) and the zinc exporter ZnT1 (SLC30A1) at T30, continuingly through to T120. The similar dynamic expression pattern was found for the autophagy-related gene (VMP1) and numerous genes for zinc finger proteins (e.g. RNF165, ZNF365, ZBTB2, SNAI1, ZNF442, ZNF547, ZNF563, and ZNF296). These findings point to the all-hands-on-deck strategy adopted by the cancer cells for maintaining zinc homeostasis. The stress responsive genes encoding heat shock proteins (HSPA1A, HSPA1B, HSPA1L, HSPA4L, HSPA6, HSPA8, HSPH1, HSP90AA1, and HSP90AB1) and the MTF-1 biomarker genes (AKR1C2, CLU, ATF3, GDF15, HMOX1, MAP1A, MAFG, SESN2, and UBC) were also differentially up-regulated at T120, suggesting a role of heat shock proteins and the MTF-1 related stress proteins in dealing with zinc exposure. It is for the first time that the gene encoding Polo-like kinase 2 (PLK2) was found to be involved in zinc-related response. The top differentially expressed genes were validated by qRT-PCR and further extended to the basal type breast cancer cells (MDA-MB-231). It was found that the expression level of SLC30A1 in MDA-MB-231 was higher than MCF-7 in response to zinc exposure. Taken together, the findings contribute to our knowledge and understanding of zinc homeostasis in breast cancer cells. Show less

Histone H3 trimethylation of lysine 9 (H3K9me3) and proteins of the heterochromatin protein 1 (HP1) family are hallmarks of heterochromatin, a state of compacted DNA essential for genome stability and long-term transcriptional silencing. The mechanisms by which H3K9me3 and HP1 contribute to chromatin condensation have been speculative and controversial. Here we demonstrate that human HP1β is a prototypic HP1 protein exemplifying most basal chromatin binding and effects. These are caused by dimeric and dynamic interaction with highly enriched H3K9me3 and are modulated by various electrostatic interfaces. HP1β bridges condensed chromatin, which we postulate stabilizes the compacted state. In agreement, HP1β genome-wide localization follows H3K9me3-enrichment and artificial bridging of chromatin fibres is sufficient for maintaining cellular heterochromatic conformation. Overall, our findings define a fundamental mechanism for chromatin higher order structural changes caused by HP1 proteins, which might contribute to the plastic nature of condensed chromatin. Show less

MAPK signaling pathways function as critical regulators of cellular differentiation, proliferation, stress responsiveness, and apoptosis. One branch of the MAPK signaling pathway that culminates in ERK1/2 activation is hypothesized to regulate the growth and adaptation of the heart to both physiologic and pathologic stimuli, given its known activation in response to virtually every stress- and agonist-induced hypertrophic stimulus examined to date. Here we investigated the requirement of ERK1/2 signaling in mediating the cardiac hypertrophic growth response in Erk1(-/-) and Erk2(+/-) mice, as well as in transgenic mice with inducible expression of an ERK1/2-inactivating phosphatase in the heart, dual-specificity phosphatase 6. Although inducible expression of dual-specificity phosphatase 6 in the heart eliminated ERK1/2 phosphorylation at baseline and after stimulation without affecting any other MAPK, it did not diminish the hypertrophic response to pressure overload stimulation, neuroendocrine agonist infusion, or exercise. Similarly, Erk1(-/-) and Erk2(+/-) mice showed no reduction in pathologic or physiologic stimulus-induced cardiac growth in vivo. However, blockade or deletion of cardiac ERK1/2 did predispose the heart to decompensation and failure after long-term pressure overload in conjunction with an increase in myocyte TUNEL. Thus, ERK1/2 signaling is not required for mediating physiologic or pathologic cardiac hypertrophy in vivo, although it does play a protective role in response to pathologic stimuli. Show less