AIM:A high polygenic score for coronary artery disease (PRSCAD) has been demonstrated to be a strong and independent predictor of atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). The objective was to investigate if the addition of a PRSCAD to the FH-Risk-Score enhances ASCVD risk prediction compared to the clinical score alone. METHODS:Data from 3 independent cohorts of patients with FH have been analysed in this longitudinal study (n=1438). The FH-Risk-Score equation was used to calculate the baseline 10-year ASCVD risk. A high PRSCAD was defined as a score > 75th percentile. The performance of the Combined score was assessed using measures of discrimination (C statistics), calibration (predicted risk vs. observed risk), and reclassification (using a 10-year risk cutoff of 20%). RESULTS:Overall, the event rate was nearly doubled in individuals having a high PRSCAD (15% vs. 9%, HR 1.77, 95% CI 1.20-2.61, P=0.004). This association was stronger in those with a genetic confirmation of FH (17% vs. 8%, HR 2.34, 95% CI 1.50-3.67, P=0.0002). The Combined score was associated with a marginally non-significant higher C-index than the FH-Risk-Score alone (0.746 to 0.750, P=0.60). The difference in C-index was significant in patients with a genetic confirmation of FH in the moderate FH-Risk-Score group (0.617 to 0.717, P=0.05). CONCLUSION:Overall, the addition of polygenic information using PRSCAD percentiles to the FH-Risk-Score estimate did not significantly enhance ASCVD risk prediction in patients with FH. Replication efforts with larger number of individuals and incident cases are warranted.

BACKGROUND:Prior work suggests modifiable cardiovascular risk factors (CRFs) account for 80% to 90% of the risk for incident myocardial infarction. The contributions of genetic and other novel CRFs have not been simultaneously assessed in contemporary data sets. METHODS:In the United Kingdom Biobank, CRFs were identified and Cox proportional hazards models with traditional CRFs (hypertension, diabetes, dyslipidemia, waist-to-hip ratio, diet, exercise, alcohol, and socioeconomic deprivation) and contemporary/genetic CRFs (Lp(a) [lipoprotein(a)], hsCRP [high-sensitivity C-reactive protein], familial hypercholesterolemia variants, and polygenic risk score for coronary artery disease) were constructed for coronary artery disease. Coronary artery disease was defined as a first-time myocardial infarction diagnosis or coronary revascularization. R2 was calculated for each model, and the percent contribution of each individual CRF was calculated by the R2 percent decrease after its removal. RESULTS:Among 299 707 individuals, the mean (SD) age was 56.2 (8.1) years, and 166 533 (55.6%) were women. Over a median (interquartile range) follow-up of 11.0 (9.6-12.5) years, 17 409 (5.8%) of participants developed myocardial infarction. R2 increased from the base model (R2, 0.021 [0.020-0.022]), to the clinical model (R2, 0.045 [0.043-0.046]), to the contemporary/genetic model (R2, 0.053 [0.052-0.055]). The most powerful individual CRFs were hypertension (R2 loss, 15.2% [14.5-17.1]) and polygenic risk score for coronary artery disease (R2 loss, 12.4% [10.8-13.3]), followed by dyslipidemia (R2 loss, 3.4% [2.6-3.5]), diabetes (R2 loss, 2.2% [1.5-2.0]), hsCRP (R2 loss, 1.8% [1.5-2.0]), and Lp(a) (R2 loss, 1.5% [1.2-1.8]). CONCLUSIONS:Novel CRFs like polygenic risk score for coronary artery disease, hsCRP, and Lp(a) have similar importance, comparable to traditional CRFs such as hypertension, dyslipidemia, and diabetes, for incident myocardial infarction, highlighting important identifiable residual risk factors.

BACKGROUND:Patients with familial hypercholesterolemia (FH) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is heterogeneous, and the contribution of several clinical risk factors has been well demonstrated in this population. The proportion of the risk conferred by the accumulation of common small effect variants in coronary artery disease (CAD) susceptibility genes remains to be determined. OBJECTIVE:The objective was to determine if a weighted polygenic risk score (PRS) for CAD (PRSCAD) is associated with ASCVD risk in patients with heterozygous FH (HeFH). METHODS:This study included 1886 participants with HeFH from 3 independent cohorts: the FH Canada national registry, the UK Biobank, and the Montreal Clinical Research Institute FH cohort. The lifelong ASCVD risk was compared between groups using Kaplan-Meier estimates and Cox proportional hazards regression models. RESULTS:The group with a high PRSCAD (>75th percentile) had a ∼2-fold increased risk of ASCVD compared to those with a lower PRSCAD (≤75th percentile) (hazard ratio 1.92 (1.55-2.37), P < .0001). The effect of the PRSCAD on ASCVD risk remained significant after correction for clinical risk factors (P = .0002). This association was similar between women and men (P interaction = .68), between genetic and clinical FH (P interaction = .48), between cohorts (P interaction = .39), and between the type of PRS (P interaction = .81). CONCLUSION:We demonstrated in the largest study to date that the use of a PRSCAD allowed us to further refine risk stratification in HeFH. Further studies are needed to evaluate the clinical value of adding the PRSCAD to current risk prediction tools.

Sepsis is the dysregulated immune response to an infection and is a leading cause of mortality. Low levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of death from sepsis, and increasing levels of HDL by inhibition of cholesteryl ester transfer protein (CETP) has been shown to decrease mortality in mouse models of sepsis. The objective of this study was to investigate the cellular mechanisms by which CETP inhibition and HDL lead to improved survival during sepsis. We found that HDL inhibits lipopolysaccharide (LPS)-induced activation of IL-1β in a mouse model of sepsis. The activation of IL-1β was dependent on the activity of scavenger receptor class B type 1 (SR-B1), and knockdown of SR-B1 significantly attenuated LPS-induced production of IL-1β in macrophages. Additionally, we found that LPS-induced SR-B1 internalization occurs through the endosome-lysosome pathway, which is also likely responsible for LPS degradation in the macrophages. Furthermore, we revealed that raising HDL by CETP inhibition markedly enhanced HDL-mediated anti-inflammatory effects in response to LPS stimulation, and these effects were not due to CETP itself but rather were HDL-dependent. Finally, we show that pharmacological inhibition of CETP significantly improved endotoxemia-induced mortality by inhibiting IL-1β production in the liver and circulation after LPS injection. Pathologically, CETP inhibition attenuated LPS-induced diffuse alveolar damage and hepatocyte necrosis, which may contribute to the improved mortality in mice treated with the CETP inhibitor anacetrapib. Taken together, our findings uncover a cellular mechanism by which HDL attenuates LPS-induced pro-inflammatory response via SR-B1-mediated LPS degradation.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high -density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae -induced sepsis in APOE*3-Leiden. CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune -mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

Background Dysbetalipoproteinemia (DBL) is a disorder of remnant cholesterol metabolism associated with a severe risk of atherosclerotic cardiovascular disease (ASCVD). Objective The objective of this study was to investigate the univariate and multivariate predictors of ASCVD in individuals with DBL. Methods Data from 2699 individuals with epsilon 2/epsilon 2 genotypes from the UK Biobank were included in this study. DBL was defined as having an epsilon 2 epsilon 2 genotype with evidence of dyslipidemia, defined as total cholesterol >= 200 mg/dL (5.2 mmol/L) and triglyceride >= 175 mg/dL (2.0 mmol/L) or lipid-lowering therapy use (n = 964). Results Age, hypertension, waist circumference, and a polygenic risk score for coronary artery disease (PRSCAD) were independent predictors of ASCVD among individuals with DBL. Cumulative ASCVD-free survival was lower in the epsilon 2/epsilon 2 DBL group (84%) compared to the epsilon 2/epsilon 2 non-DBL group (94%) (P < .0001) and for DBL individuals with a PRSCAD >= median (79%) compared to those with a PRSCAD < median (89%) (P = .001). Conclusion We show in a large prospective cohort that a PRSCAD predicts the ASCVD risk among individuals with DBL. The findings of the present study highlight the need for better risk stratification in epsilon 2/epsilon 2 carriers to identify high-risk individuals who would need aggressive cardiovascular management despite their low apolipoprotein B value.

Context: Dysbetalipoproteinemia (DBL) is a multifactorial disorder that disrupts the normal metabolism of remnant lipoproteins, causing increased risk of cardiovascular disease. However, establishing a proper diagnosis is difficult, and the true prevalence of the disease in the general population remains unknown. Objective: The objectives were to study the prevalence of the disease and to validate the performance of different clinical diagnostic criteria in a large population-based cohort. Methods: This study included 453 437 participants from the UK Biobank. DBL was established in participants having an epsilon 2 epsilon 2 genotype with mixed dyslipidemia or lipid-lowering therapy use (n = 964). The different diagnostic criteria for DBL were applied in individuals without lipid-lowering medication (n = 370 039, n = 534 DBL), to compare their performance. Results: Overall, 0.6% of participants had an epsilon 2 epsilon 2 genotype, of which 36% were classified as DBL, for a disease prevalence of 0.2% (1:469). The prevalence of DBL was similar between the different genetic ancestries (<= 0.2%). Several diagnostic criteria showed good sensitivity for the diagnosis of DBL (>90%), but they suffered from a very low positive predictive value (0.6-15.4%). Conclusion: This study reported for the first time the prevalence of DBL in the UK Biobank according to genetic ancestry. Furthermore, we provided the first external validation of different diagnostic criteria for DBL in a large population-based cohort and highlighted the fact that these criteria should not be used to diagnose DBL alone but should rather be used as a first screening step to determine which individuals may benefit from genetic testing to confirm the diagnosis.

BACKGROUND:Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS:We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS:Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS:Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

BACKGROUND:Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort.METHODS:Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data.RESULTS:Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2x10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6x10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia.CONCLUSIONS:Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

BACKGROUND:Familial hypercholesterolemia (FH) is a genetic condition causing premature atherosclerotic cardiovascular disease (ASCVD). It is well established that patients with FH should be treated with statin therapy. However, there exists discordance concerning low-density lipoprotein cholesterol-lowering goals in the management of these patients between different guidelines worldwide. The objective was to compare the 10-year ASCVD risk of different subgroups of patients with and without FH including those with diabetes or a history of ASCVD and patients with FH within different FH-Risk-Score categories. METHODS:This multinational observational study used data from 3 different prospective cohorts. A total of 3383 FH and 6917 non-FH controls matched for age and sex were included (104 363 person-years of follow-up). The 10-year incident ASCVD risk was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models. RESULTS:FH patients with a high (score >20%) FH-Risk-Score (hazard ratio, 8.45 [95% CI, 6.69-10.67]; P<0.0001), FH patients with diabetes (hazard ratio, 7.67 [95% CI, 4.82-12.21]; P<0.0001), and non-FH patients with ASCVD (hazard ratio, 6.78 [95% CI, 5.45-8.42]; P<0.0001) had a significantly higher incident ASCVD risk over 10 years than the reference group (non-FH without ASCVD or diabetes). The observed 10-year risks in these groups were 32.1%, 30.8%, 30.0%, and 5.1%, respectively. The 10-year ASCVD risk associated with both FH and ASCVD was extremely high (observed risk of 50.7%; hazard ratio, 14.53 [95% CI, 12.14-17.38]; P<0.0001). CONCLUSIONS:This study strongly suggests that the observed risk of FH patients with diabetes, history of ASCVD, and FH-Risk-Score >20% is as high or higher than non-FH individuals with a history of ASCVD. More aggressive management should be recommended for these patients.

Background: Modifiable cardiovascular risk factors (CRF) have been proposed to be responsible for 80-90% of the risk for incident coronary artery disease (CAD). However, these studies were conducted prior to the era of preventive medications, novel biomarkers, and genetic risk scores. The relative contributions of traditional and contemporary CRF in light of secular trends in worsening cardiometabolic health globally have not been assessed. Hypothesis: Including genetic risk scores and contemporary biomarkers will enhance discrimination and explainability of myocardial infarction (MI) incidence prediction. Methods: The UKBiobank was used to identify traditional CRF (hypertension, diabetes, dyslipidemia, smoking, waist-to-hip ratio (WHR), diet, exercise, alcohol intake and socioeconomic deprivation), and contemporary/genetic CRF (lipoprotein(a), high-sensitivity C-reactive protein [hsCRP], familial hypercholesterolemia [FH] variants, and polygenic risk score for CAD [PRS CAD ]). Incident MI was defined as first-time MI diagnosis or coronary revascularization. Base model discrimination was assessed using C-statistics from Cox proportional hazards models. Percent contribution of each risk factor was calculated by explanatory power lost via Nagelkerke R 2 after removal of the CRF from the full model. Population attributable risks (PAR) were additionally assessed for each model and CRF individually. Results: Over a median [IQR] follow-up of 11.0 [9.6, 12.5] years, 17409/299707 (5.8%) of participants developed incident CAD. C-statistics sequentially increased from base model to traditional CRF to contemporary/genetic CRF model with PAR of 84.3% (95% CI 82.4%-86.5%) ( Table 1 ). Among CRFs, hypertension (C 0.74, R 2 loss 15.2%, PAR 32.5%) and PRS CAD (C 0.72, R 2 loss 12.4%, PAR 38.4%) most strongly explained MI incidence by all 3 indices. Based on discriminability, ApoB:ApoA1 ratio (C 0.71, R 2 loss 3.4%), presence of diabetes (C 0.71, R 2 loss 2.2%), and log(hsCRP) (C 0.71, R 2 loss 1.82%) were subsequently prioritized. PAR analyses included prevalence in prioritization where WHR, presence of diabetes, and log(lipoprotein(a)) levels rose higher. Conclusions: The addition of genetic risk factors and contemporary biomarkers to explanatory models for CAD shows previously underappreciated importance of contemporary CRFs such as PRS, hsCRP, and lipoprotein(a) alongside traditional CRFs such as hypertension, dyslipidemia and presence of diabetes.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR–CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification. A multi-ancestry genetic meta-analysis identifies 12 new loci associated with preeclampsia and gestational hypertension and proposes the integration of polygenic scores and clinical factors for disease prediction

AIMS:To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors. METHODS AND RESULTS:Cross-sectional analysis of UK Biobank participants without pre-existing coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRSCAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios. Among 166 714 individuals, 72 052 (43.2%) participants reported an FHHD. In a multivariable model, genetic risk factors PRSCAD (OR 1.30, CI 1.27-1.33) and HeFH (OR 1.31, 1.11-1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15-1.21), lipoprotein(a) (OR 1.17, CI 1.14-1.20), apolipoprotein B-to-apolipoprotein AI ratio (OR 1.13, 95% CI 1.10-1.16), and triglycerides (OR 1.07, CI 1.04-1.10). For the PAR analyses: 21.9% (CI 18.19-25.63) of the risk of reporting an FHHD is attributed to clinical factors, 22.2% (CI% 20.44-23.88) is attributed to genetic factors, and 36.0% (CI 33.31-38.68) is attributed to genetic and clinical factors combined. CONCLUSIONS:A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.

Background: CD34 is a transmembrane phosphoglycoprotein that is a marker of hematopoietic stem cells and is used clinically to aid in enumeration of blast cells for identification of advanced myeloid neoplasms. Megakaryocytes are differentiated cells from the myeloid lineage that reside in the bone marrow and generally stain negative for CD34 (CD34-). However, CD34 positive (CD34+) megakaryocytes have been observed in hematological disorders such as myelodysplastic syndrome, myeloproliferative neoplasms, and acute leukemias. CD34+ megakaryocytes are proposed to be relatively specific for malignant hematologic conditions and have been reported to associate with a worse prognosis. However, the general clinical, biochemical, and cytogenic characteristics for bone marrow cases of CD34+ megakaryocytes versus CD34- megakaryocytes remains unclear. Objective: We sought to determine the clinical, biochemical, and cytogenetic characteristics associated with finding CD34+ megakaryocytes on bone marrow biopsies. Methods: We identified 281 independent, index bone marrow biopsy cases between 2011-01-01 and 2017-12-31 from Vancouver General Hospital, Canada that underwent CD34 immunohistochemistry at clinical request. The clinical, biochemical, and cytogenetic characteristics of patients were compared based on megakaryocytes being CD34+ vs CD34- on immunohistochemistry. Cases of CD34+ megakaryocytes were defined as having >5% of megakaryocytes staining CD34+, but sensitivity analyses were performed using different percentage cut-offs of 10, 30, and 50%. Results: Out of 281 cases, 134 had CD34+ megakaryocytes (58.2% male sex; mean age = 64.1 years [SD = 15.2 years]) and 147 had CD34- megakaryocytes (57.1% male sex; mean age = 60.0 years [SD = 16.6 years]). There was a significant difference in the distribution of diagnostic categories observed between cases of CD34+ versus CD34- megakaryocytes: myelodysplastic syndromes 35.1% (n=47) versus 21.8% (n=32), acute myeloid leukemias 20.9% (n=28) versus 21.1% (n=31), non-diagnostic etiology 17.9% (n=24) versus 14.3% (n=21), and myeloproliferative neoplasms 10.4% (n=14) versus 19.7% (n=29) (Figure A; Chi-square p-value=0.0004). Sensitivity analyses using different percentage cut-offs to define cases of CD34+ from CD34- megakaryocytes yielded similar results. The differences in biochemical characteristics between cases of CD34+ versus CD34- megakaryocytes were generally unremarkable. The median (IQR) for biochemical parameters between cases of CD34+ and CD34- megakaryocytes were hemoglobin 99 (28) versus 100 (34) g/L, mean corpuscular volume 94 (14) versus 93 (10) fL, neutrophil count 2.20 (3.68) versus 2.46 (3.63) x10 9/L, platelet count 98 (158) versus 112 (194) x10 9/L, and bone marrow blasts 7 (4) versus 3 (14)%. Lastly, there were notable trends in cytogenetic results associated with 90 cases with CD34+ versus 84 cases with CD34- megakaryocytes including: complex karyotypes for 15.6% (n=14) versus 6.0% (n=5), isolated deletion 5q for 7.8% (n=7) versus 1.2% (n=1), and/or isolated trisomy 8 for 5.6% (n=5) versus 2.4% (n=2). Similar cytogenetic results were observed when cases were restricted to only cases of CD34+ versus CD34- megakaryocytes with a diagnosis of myelodysplastic syndrome (Figure B). Conclusion: The presence of CD34+ megakaryocytes is more common in cases of myelodysplastic syndrome relative to other neoplastic hematologic disorders, but does not appear to help with discriminating between neoplastic and non-neoplastic hematological disorders ( e.g. non-diagnostic etiology). Cases with CD34+ megakaryocytes tend to associate with complex karyotype and deletion 5q abnormalities relative to cases with CD34- megakaryocytes.

IMPORTANCE Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations. OBJECTIVE To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional analysis, pairs of first-degree (n = 19 899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184 764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023. EXPOSURE Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L. MAIN OUTCOME AND MEASURE Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels. RESULTS A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman. = 0.45; P < .001) and second-degree (Spearman. = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0%[95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8%[95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30 258 (16.4%[95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives. CONCLUSIONS AND RELEVANCE The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.

Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.

Background The association between familial hypercholesterolemia (FH) and premature atherosclerotic cardiovascular disease (ASCVD) is well established. Several risk factors other than the cumulative low-density lipoprotein cholesterol (LDL-C) have been shown to modulate the severity of the phenotype in these patients. However, the effect of the metabolic syndrome (MetS) on ASCVD risk in FH remains to be determined. Objectives The objective was to study the association between the presence of MetS and the incidence of different ASCVD endpoints and all-cause mortality. Methods This prospective follow up study used data from 5 independent FH cohorts from Europe and North America. We analysed data of 2401 adult heterozygous FH without history of a prior ASCVD event (21,139 person-years of follow-up). Multivariate Cox proportional hazards regression was used to estimate the association between MetS and the incidence of the different endpoints. Results The prevalence of MetS was 14% in the study population. The presence of MetS was a significant predictor of incident 10-year ASCVD after adjustment for traditional cardiovascular risk factors (HR 2.07, 95% CI 1.34-3.19), as well as of 10-year major adverse cardiovascular event (MACE) (HR 4.59, 95% CI 2.27-9.30), 10-year myocardial infarction (MI) (HR 4.29, 95% CI 1.91-9.63), and 30-year all-cause mortality (HR 4.87, 95% CI 1.99-11.89). Conclusion Our findings suggests that FH patients with MetS, have an increased cardiovascular risk that is independent from LDL-C and other traditional risk factors. Future studies are required to determine the most appropriate strategy to reduce the cardiovascular burden associated with MetS in this population.

BACKGROUND:Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma low-density lipoprotein cholesterol and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. We hypothesized that a subset of patients with clinically diagnosed heterozygous FH (HeFH) may in fact have HoFH, and this could be identified by genetic diagnosis.METHODS:We recruited patients with a clinical diagnosis of HeFH based on a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor adapter protein 1 (LDLRAP1) genes, followed by long-read sequencing of the LDLR gene in patients with >1 pathogenic LDLR variant. We examined lipid levels and cardiovascular events.RESULTS:Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) and >1 pathogenic variant in the LDLR gene in 11 patients (1.6%). We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygotes and 3 compound heterozygotes). The mean baseline low-density lipoprotein cholesterol and prevalence of premature cardiovascular disease of patients with genetically identified HoFH was significantly higher than patients with HeFH.CONCLUSIONS:In a cohort of patients with clinically diagnosed HeFH, genetic testing including long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe clinical phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.

Background and aims: Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid phenotypes, characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. The genetic inheritance of FCHL remains poorly understood. The goals of this study were to investigate the poly genetic architecture and cardiovascular risk associated with FCHL.& nbsp;Methods and results: We identified individuals with an FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n = 39,961), 5.01% (n =17,485), 1.48% (n = 5,153), 1.10% (n = 3,838), and 0.48% (n = 1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria and identified 175 independent loci associated with FCHL at genome-wide significance. We investigated the association of genetic and clinical risk with FCHL and found that polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome were associated with greater prevalence of FCHL. Participants with an FCHL phenotype had a similar risk of incident coronary artery disease compared to participants with monogenic familial hypercholesterolemia (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31-3.21] and 1.90 [1.30-2.78]).& nbsp;Conclusions: These results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. The cardiovascular risk associated with an FCHL phenotype is similar to that of monogenic familial hypercholesterolemia, despite being~& nbsp;5x more common.