👤 Barbara Sampson

Familial dysbetalipoproteinemia (FDB) is a genetic lipoprotein disorder that can develop in patients homozygous for the APOE2 genotype (ε2/ε2). It is associated with decreased clearance of remnant lipoproteins and increased atherosclerotic cardiovascular disease (ASCVD) risk disproportionate to their level of LDL-C. A goal of this study was to develop a screening test for the ε2/ε2 genotype based on routinely available lipid tests and to determine those at most risk for ASCVD. After assembly of a primary prevention cohort from the UK Biobank (n= 269,895), gene array and exome data was utilized to classify patients as being ε2/ε2 genotype positive or negative. Lipid profiles and APOB levels were extracted and the number of ASCVD events was tabulated during a 15-year follow-up period. Using a newly developed equation for estimating APOB (eAPOB) with lipid panel test results, the ratio of measured APOB to eAPOB was better than any other individual lipid test or ratio for identifying patients with the ε2/ε2 genotype (AUC: APOB/eAPOB: 0.990 (0.986-0.994), nonHDL-C/APOB: 0.961 (0.952-0.970), APOB: 0.955 (0.949-0.961), VLDL/TG: 0.788 (0.771-0.804)). The majority of ε2/ε2 patients could be identified with the APOB/eAPOB ratio even before they expressed the FDB phenotype with elevated TG and nonHDL-C. The PCE or PREVENT risk equations were the most accurate method for identifying higher risk patients (AUC: PREVENT: 0.690 (0.637-0.742), PCE: 0.697 (0.645-0.749)). The APOB/eAPOB ratio can be used to accurately identify the ε2/ε2 genotype and conventional risk equations are the best method for determining those at risk for ASCVD. Show less

Despite the growing burden of youth-onset type 2 diabetes (Y-T2D), the long-term risk for fatal/non-fatal cardiovascular disease (CVD) in Y-T2D compared to peers is unknown. The International Childhood Cardiovascular Cohort (i3C) combined-risk z-score is a novel tool for predicting 35-year risk of adult CVD events. In Y-T2D compared to peers (Lean and overweight/obesity [OW/OB]), we estimated predicted CVD events and evaluated the relationship of the i3C z-score with risk-enhancing factors. In a pooled cohort cross-sectional analysis of 1547 adolescents and young adults (AYA) aged 10-25 years [627 Lean, 803 OW/OB, 117 Y-T2D], i3C combined-risk z-scores and estimated hazard ratios (HR) were obtained from the published i3C equation using risk z-scores of systolic blood pressure, body mass index (BMI), smoking history, total cholesterol, and triglycerides. ANCOVA regression models were used: 1) to compare i3C z-scores and HR in AYA with Y-T2D, OW/OB and Lean peers, and 2) to measure associations between i3C estimated HR and risk-enhancing factors including apolipoprotein B (ApoB), total low density lipoprotein particle number (LDL-P), and high sensitivity C reactive protein (hsCRP). Models were adjusted for diagnosis group, race, study center and multiple comparisons with Bonferroni. Y-T2D had the highest i3C z-score (Y-T2D: 1.23 [1.10, 1.36] vs. OW/OB: 0.84 [0.80, 0.88] vs. Lean: -0.11 [-0.15, -0.06], mean[95%CI]) and estimated HR for predicted CVD events (Y-T2D: 4.25 [3.65-4.86] vs. OW/OB: 3.04 [2.85-3.22] vs. Lean: 0.95 [0.74-1.17], HR [95% CI]). Risk-enhancing factors increased the HR for predicted CVD risk by 0.3 for each 10 mg/dL increase in ApoB, 0.1 for each 100 nmol/L increase in LDL-P, and 0.16 for each 2 mg/L increase in hsCRP, all P < 0.001. Y-T2D had an estimated 4.5- and 1.4-times higher risk for predicted CVD events compared to Lean and OW/OB peers, respectively. Lipoprotein and inflammatory risk-enhancing factors may help stratify and guide primary prevention strategies in high-risk AYA. Show less

A key step in primary prevention is the assessment of atherosclerotic cardiovascular disease (ASCVD) risk. Risk enhancer tests are additional tools used to further improve ASCVD risk assessment over conventional risk markers. Our objective was to determine whether estimated small, dense low-density lipoprotein cholesterol (E-sdLDL-C) can improve risk assessment and serve as a new risk enhancer test. We used a prospective cohort analysis of participants in the UK Biobank study with a median (interquartile range) follow-up of 10 (6.7-12.3) years. We included 271 760 individuals who were not on lipid-lowering medication at baseline and did not have incident ASCVD. The primary study outcome was the incidence of all-cause ASCVD. E-sdLDL-C was strongly associated with ASCVD events with a hazard ratio (HR) of 1.23 (95% CI, 1.22-1.24). After multivariable adjustment for age, sex, systolic blood pressure, hypertension, type 2 diabetes, and blood pressure medications, E-sdLDL-C and ApoB (apolipoprotein B) remained the most significant lipid risk factors (HR, 1.18 [95% CI, 1.16-1.19] and 1.17 [95% CI, 1.16-1.18] per SD, respectively). After further adjustment for ApoB, the association between low-density lipoprotein cholesterol (LDL-C) with all-cause ASCVD was completely reversed with an HR of 0.84 (95% CI, 0.81-0.86), but E-sdLDL-C continued to have a significant positive association with an HR of 1.11 (95% CI, 1.08-1.13). When E-sdLDL-C was discordantly higher than either LDL-C or ApoB, the risk for ASCVD was higher (LDL-C, 31% higher; ApoB, 17% higher). When elevated E-sdLDL-C is coupled with other risk enhancer tests, there is a greater risk for developing ASCVD. In a UK Biobank cohort for primary prevention, the risk of all-cause ASCVD was better captured by E-sdLDL-C than LDL-C. It was also more predictive than LDL-C and ApoB when discordant with these 2 measures. E-sdLDL-C, which can be freely and automatically calculated from a standard lipid panel, can potentially improve ASCVD risk assessment without additional laboratory testing. Show less

The triglyceride (TG) content of low-density lipoprotein (LDL-TG) has been shown to be more predictive of atherosclerotic cardiovascular disease (ASCVD) events than the cholesterol content of LDL (LDL-C). The goal of our study was to develop an equation for estimating LDL-TG ( Using least-square regression analysis, the following Like LDL-C, LDL-TG can also be calculated from the results of the standard lipid panel. Compared to estimated LDL-C, Show less

Few reports describe the yield of postmortem genetic testing from medical examiners' offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort. To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States' largest medical examiner office. Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated. The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel. Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members. Show less

Currently, no standardized system exists for evaluating and testing at-risk family members of decedents with abnormal post-mortem genetic testing in cases of sudden unexpected death (SUD). The goal of this study was to evaluate the outcomes of referrals made by an urban medical examiner's office to a multi-disciplinary cardiogenetics clinic. Relatives of decedents with pathogenic/likely pathogenic (P/LP) variants or variants of unknown significance (VUS) in genes known to be associated with cardiomyopathies and/or arrhythmias were identified by the New York City Office of Chief Medical Examiner and referred to the Cardiogenetics Clinic at Montefiore Medical Center. Familial referrals of 15 decedents (median 15 years, range 2 days to 57 years) were evaluated. Variants in 13 genes were identified among decedents (9 arrhythmia, 5 cardiomyopathy). P/LP variants were identified in both arrhythmia (RYR2, SCN5A) and cardiomyopathy syndrome (MYBPC3 (2), MYH7) genes. Thirty-two family members were referred, and 14 variants were detected. One pathogenic (MYBPC3) and two likely pathogenic (RYR2, MYH7) mutations were identified. Referral of at-risk family members of decedents who experienced SUD based on informative post-mortem genetic testing for cardiac and genetic evaluation is warranted, as family studies help to reclassify variants and prevent additional sudden death. Show less

Elevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is a potential alternative to other ANGPTL3-inhibiting therapies. Show less

The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis. Show less

Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents. All variants were previously submitted to ClinVar without phenotype details. Two PTVs were located in the cardiac-specific myosin S2-binding (M) motif at the N-terminus of the MYBPC3-encoded cMyBP-C protein, and two PTVs were in the non-cardiac-specific C-terminus of the protein. The carriers of two cardiac-specific M-motif PTVs died at age 38 years; their heart weight (HW, g) and body mass index (BMI, kg/m Show less

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)). Show less

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. Show less