Incident Heart Failure Risk Reclassification With Race-Independent Estimated Glomerular Filtration Rate: A National Heart, Lung, and Blood Institute Pooled Cohorts Analysis.

BACKGROUND: This study compared the predictive value of the race-independent creatinine- and cystatin C-based estimated glomerular filtration rate (eGFRcr-cys) and the race-dependent creatinine-based eGFR (eGFRcr) for incident heart failure (HF). METHODS: This study combined the participant-level data from ARIC (Atherosclerosis Risk in Communities) (visit 4) and MESA (Multi-Ethnic Study of Atherosclerosis) (visit 1) to calculate eGFRcr-cys and eGFRcr. The primary outcome of the study was adjudicated incident HF over a follow-up period of 10 years. Multivariable Cox models were used to assess the risk of incident HF with the quartiles of eGFRcr-cys and eGFRcr. RESULTS: Among 15,615 individuals (median age: 62 [57-68] years; 55.0% females; 23.9% Black), the median eGFRcr-cys and eGFRcr were 91.4 (79.4, 102.0) mL/min/1.73m2 and 84.7 (72.0, 94.7) mL/min/1.73m2, respectively. Compared with the fourth quartile of eGFRcr-cys, the hazard ratio for incident HF was 1.02 (95% CI:0.80-1.30) in the third quartile, 1.02 (95% CI:0.80-1.30) in the second quartile, and 1.47 (95% CI:1.16-1.86) in the first quartile. Compared with the 4th quartile of the eGFRcr, the risk of incident HF was similar in the 3rd (HRadj:0.90 [95% CI:0.73-1.12]), 2nd (HRadj: 0.96 [95% CI:0.77-1.20]), and 1st (HRadj:1.15 [95% CI:0.93-1.44]) quartiles. C-statistics were similar for the multivariable-adjusted Cox models for incident HF using eGFRcr (0.80 [0.79-0.81]) and eGFRcr-cys (0.80 [0.79-0.82]). CONCLUSION: The eGFRcr and eGFRcr-cys had comparable predictive values for incident HF.

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.

Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.

Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature.

BACKGROUND: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. METHODS: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases-based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. RESULTS: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). CONCLUSIONS: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease.

BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, ß=0.61±0.05, P=3.27×10-30) and MMP-3 (ß=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, ß=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Determinants of transthyretin levels and their association with adverse clinical outcomes among UK Biobank participants.

Transthyretin is a transport protein whose misfolding has been implicated in the development of cardiac amyloidosis. Here, we examine the clinical correlates of transthyretin levels, the differences in transthyretin levels according to the pathogenic V142I TTR variant carrier status, and the association of transthyretin levels with outcomes among 35,206 UK Biobank participants who underwent plasma profiling and were free from prevalent cardiovascular disease and chronic renal disease. Transthyretin levels are lower in females, decrease with increasing C-reactive protein levels, and increase with body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, albumin levels, triglyceride levels, and creatinine levels. V142I non-carriers [n = 35,167, mean: -0.1 (0.3)] have higher adjusted transthyretin levels compared with the carriers [n = 39, mean: -0.5 (0.3)] (p:<0.001). A standard deviation decrease in transthyretin levels increases the risk of heart failure [HRadj: 1.17 (95% Confidence Interval = 1.08-1.26)] and all-cause mortality [HRadj: 1.18 (95% Confidence Interval = 1.14-1.24)]. This study shows that individuals with low transthyretin levels, such as those carrying the V142I variant, are at a higher risk of heart failure and mortality.

High-proportion spliced-in titin truncating variants in African and European ancestry in the All of Us Research Program.

High-proportion spliced-in titin truncating variants (hiPSI TTNtvs) have been associated with an increased risk of atrial fibrillation, dilated cardiomyopathy (DCM) and heart failure in individuals of European ancestry1. However, similar data in individuals of African ancestry are lacking. Here we examined the association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure in individuals of African ancestry using data from the All of Us Research Program. Among 38,154 individuals of African ancestry, 169 (0.4%) individuals carried a hiPSI TTNtv. hiPSI TTNtv carriers were at a higher risk of developing atrial fibrillation (adjusted hazard ratio (HRadj) 2.42, 95% confidence interval (CI) 1.52-3.85), DCM (HRadj 2.82, 95% CI 1.81-4.39) and heart failure (HRadj 2.07, 95% CI 1.43-3.00) compared with noncarriers. The association of hiPSI TTNtvs with atrial fibrillation, DCM and heart failure was similar in individuals of African ancestry and those of European ancestry. Therefore, genetic testing for hiPSI TTNtvs may permit early identification of carriers and support preventive measures to reduce the likelihood of heart failure development both in individuals of European ancestry and in individuals of African ancestry.

Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure.

High-proportion spliced-in (hiPSI) titin truncating variant (TTNtv) carriers have a higher risk of atrial fibrillation and heart failure1. However, the role of cardiovascular risk factors in modifying the risk of atrial fibrillation and heart failure attributed to hiPSI TTNtv carriers is unknown. Here, we investigate the role of cardiovascular risk, quantified using the pooled cohort equations (PCEs), in influencing the hazard of outcomes attributed to hiPSI TTNtvs among UK Biobank participants without baseline cardiovascular disease. The cohort was stratified based on hiPSI TTNtv carrier status and cardiovascular risk (low: <5%, intermediate: 5.0-7.5% and high: >7.5%). The primary outcome was a composite of atrial fibrillation, heart failure or death. TTNtv noncarriers with low cardiovascular risk were used as the reference group for all analyses. Among 179,752 participants (median age: 56 (49, 62) years; 57.5% female), the risk of the primary outcome was lower in hiPSI TTNtv carriers with low cardiovascular risk (adjusted hazard ratio: 2.23 (95% confidence interval: 1.62-3.07)) than those with high cardiovascular risk (adjusted hazard ratio: 8.21 (95% confidence interval: 6.63-10.18)). A favorable cardiovascular risk factor profile may partially offset the risk of clinical outcomes among hiPSI TTNtv carriers.

Carpal Tunnel Syndrome and Transthyretin Amyloidosis in the All of Us Research Program.

OBJECTIVE: To evaluate the association of carpal tunnel syndrome (CTS) with incident heart failure and incident amyloidosis and to assess the risk of CTS in pathogenic TTR genetic variant carriers. METHODS: This prospective cohort study included multiethnic US adults 18 years of age and older without prevalent heart failure and amyloidosis with available genotypic data from the All of Us Research Program. The primary outcomes were incident heart failure and incident amyloidosis. The association of incident heart failure and incident amyloidosis with CTS was assessed using multivariable adjusted Cox models accounting for age, sex, race and ethnicity, obesity, hypertension, diabetes, statin use, and smoking status. RESULTS: Of the 166,987 individuals included, the median age was 54 (38 to 66) years; 105,279 (63.0%) were female, and 92,780 (55.6%) were non-Hispanic White individuals; CTS was identified in 12,407 (7.4%) individuals. Compared with individuals without CTS, the adjusted hazard ratio for incident heart failure was 1.13 (95% CI, 1.02 to 1.26) in individuals with CTS. The risk of amyloidosis was ∼3-fold higher (adjusted hazard ratio, 2.86; 95% CI, 1.71 to 4.77) in individuals with CTS compared with those without CTS. Individuals carrying a pathogenic TTR variant had an approximately 40% higher risk (adjusted hazard ratio, 1.38; 95% CI, 1.16 to 1.65) for development of CTS compared with noncarriers. CONCLUSION: Cardiac amyloidosis screening programs may use CTS as a sentinel event and use genetic testing to identify individuals at a higher risk of TTR amyloidosis.

Procedural Volume and Outcomes After Septal Reduction Therapies in Hypertrophic Obstructive Cardiomyopathy.

BACKGROUND: Septal myectomy and alcohol septal ablation (ASA) are septal reduction therapies for patients with symptomatic obstructive hypertrophic cardiomyopathy. Operator and hospital volume may influence outcomes, but contemporary data on this relationship are limited. METHODS AND RESULTS: This retrospective cohort study used data from the Vizient Clinical Data Base (2016-2022). Patients with undergoing septal myectomy and ASA were identified using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and stratified into low-, medium-, and high-volume groups based on annualized operator and hospital volumes. The outcomes were 30-day in-hospital mortality and 90-day readmission, analyzed using multivariable adjusted logistic and Cox models. Among 5725 patients with hypertrophic cardiomyopathy (3990 septal myectomy; 1735 ASA), most operators and hospitals performed <10 procedures annually. For septal myectomy, low-volume operators were associated with higher odds of 30-day mortality (adjusted odds ratio [aOR], 1.86 [95% CI, 1.11-3.15]) and greater risk for 90-day readmission (aOR, 1.51 [95% CI, 1.22-1.88]), and medium-volume operators had higher odds of 30-day mortality (aOR, 1.93 [95% CI, 1.05-3.55]). Medium-volume hospitals had higher 30-day mortality (aOR, 2.29 [95% CI, 1.32-3.99]), with low-volume hospitals showing greater risk for 90-day readmission (aOR, 1.60 [95% CI, 1.14-2.23]). For ASA, low- and medium-volume operators had increased 30-day mortality (aOR, 2.99 [95% CI, 1.15-7.75] and aOR, 3.86 [95% CI, 1.30-11.46]), but the risk of 90-day readmission was similar. Hospital volumes did not significantly impact outcomes for ASA. CONCLUSIONS: Low operator and hospital volumes were associated with worse outcomes for septal reduction therapies, emphasizing the need to refer patients with hypertrophic cardiomyopathy to high-volume centers with experienced operators.

Genetic Risk and Coronary Artery Calcium in Personalizing Antihypertensive Treatment: A Pooled Cohort Analysis.

OBJECTIVE: To assess the role of the systolic blood pressure polygenic risk score (SBP-PRS) in antihypertensive treatment initiation and its comparative efficacy with coronary artery calcium (CAC) scores. PATIENTS AND METHODS: This retrospective cohort study included participants with whole genome sequencing data who underwent CAC scanning between 1971 and 2008, were free of prevalent cardiovascular disease (CVD), and were not taking antihypertensive medications. The cohort was stratified by blood pressure (BP) treatment group and SBP-PRS (low/intermediate, first and second tertiles; high, third tertile) and CAC score (0 vs >0) subgroups. The primary outcome was the first occurence of adjudicated coronary heart disease, heart failure, or stroke during 10-year follow-up. The 10-year number needed to treat (NNT) to prevent 1 event of the primary outcome was estimated. A relative risk reduction of 25% for the primary outcome based on the treatment effect of intensive control (SBP <120 mm Hg) of hypertension in SPRINT (Systolic Blood Pressure Intervention Trial) was used for estimating the NNT. RESULTS: Among the 5267 study participants, the median age was 59 years (interquartile range, 51-68 years); 2817 (53.5%) were women and 2880 (54.7%) were non-White individuals. Among 1317 individuals with elevated BP/low-risk stage 1 hypertension not recommended treatment, the 10-year incidence rate of the primary outcome was 5.6% for low/intermediate SBP-PRS and 6.3% for high SBP-PRS with NNTs of 63 and 59, respectively. Similarly, the 10-year incidence rate of the primary outcome was 2.9% for CAC score 0 and 9.7% for CAC score greater than 0, with NNTs of 117 and 37, respectively. CONCLUSION: Including genetic information in risk estimation of individuals with elevated BP/low-risk stage 1 hypertension has modest value in the initiation of antihypertensive therapy. Genetic risk and CAC both have efficacy in personalizing antihypertensive therapy.

Utility of a Systolic Blood Pressure Polygenic Risk Score With Chlorthalidone Response.

Importance: The clinical utility of polygenic risk scores (PRS) for blood pressure (BP) response to antihypertensive treatment (AHT) has not been elucidated. Objective: To investigate the ability of a systolic BP (SBP) PRS to predict AHT response and apparent treatment-resistant hypertension (aTRH). Design, Setting, and Participants: The Genetics of Hypertension Associated Treatments (GenHAT) study was an ancillary pharmacogenomic study to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT, which enrolled participants aged 55 years or older with hypertension (HTN) starting in February 1994, completed follow-up in March 2002. The current study was conducted from a subset of Black GenHAT participants randomized to the treatment groups of either chlorthalidone (n = 3745) or lisinopril (n = 2294), with genetic data available from a prior genetic association study. The current study's objective was to examine the association of the SBP PRS to AHT response over 6 months, as well as to examine the predictive accuracy of the SBP PRS with aTRH. The current analysis took place in February 2023, with additional analyses conducted in July 2024. Exposure: An SBP PRS (comprising 1 084 157 genetic variants) stratified as quintiles and per SD. Main Outcomes and Measures: The primary outcome was change in SBP (ΔSBP) and diastolic BP (ΔDBP) over 6 months. aTRH was defined as the use of 3 AHTs with uncontrolled HTN at year 3 of follow-up or taking 4 or more AHTs at year 3 of follow-up, regardless of BP. Baseline demographics were compared across PRS quintiles using Kruskal-Wallis or χ2 tests as appropriate. The least-square means of BP response were calculated through multivariable adjusted linear regression, and multivariable adjusted logistic regression was used to calculate the odds ratios and 95% confidence intervals for aTRH. Results: Among 3745 Black GenHAT participants randomized to chlorthalidone treatment, median (IQR) participant age was 65 (60-71) years, and 2064 participants (55.1%) were female. Each increasing quintile of the SBP PRS from 1 to 5 was associated with a reduced BP response to treatment over 6 months. Participants in the lowest quintile experienced a mean ΔSBP of -10.01 mm Hg (95% CI, -11.11 to -8.90) compared to -6.57 mm Hg (95% CI, -7.67 to -5.48) for participants in the median quintile. No associations were observed between the SBP PRS and BP response to lisinopril. Participants in the highest PRS quintile had 67% higher odds of aTRH compared to those in the median quintile (odds ratio, 1.67; 95% CI, 1.19-2.36). These associations were independently validated. Conclusions and Relevance: In this genetic association study, Black individuals with HTN at a lower genetic risk of elevated BP experienced an approximately 3.5 mm Hg-greater response to chlorthalidone compared with those at an intermediate genetic risk of elevated BP. SBP PRS may also identify individuals with HTN harboring a higher risk of treatment-resistant HTN. Overall, SBP PRS demonstrates potential to identify those who may have greater benefit from chlorthalidone, but future research is needed to determine if PRS can inform initiation and choice of treatment among individuals with HTN.

Corin Missense Variants, Blood Pressure, and Hypertension in 11 322 Black Individuals: Insights From REGARDS and the Jackson Heart Study.

Background Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 [Q568P] and rs75770792 [T555I]) have been previously reported to have a modest association with blood pressure (BP) and hypertension. Methods and Results We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self-identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable-adjusted regression modeling. Multivariable-adjusted genotype-stratified differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and BNP (B-type natriuretic peptide) levels were assessed. Genotype-stratified NPPA and NPPB expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (ß±SE, 0.42±0.58; -1.24±0.82), diastolic BP (0.51±0.33; -0.41±0.46), mean arterial pressure (0.48±0.38; -0.68±0.51), and prevalent hypertension (odds ratio [OR], 0.93 [95% CI, 0.80-1.09]; OR, 0.79 [95% CI, 0.61-1.01]) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; -1.26±0.81), diastolic BP (0.52±0.33; -0.33±0.45), mean arterial pressure (0.50±0.38; -0.63±0.50), and prevalent hypertension (OR, 1.02 [95% CI, 0.84-1.23]; OR, 0.87 [95% CI, 0.67-1.13]) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 [95% CI, 0.94-1.93]; OR, 0.95 [95% CI, 0.64-1.39]) in the study cohorts. The NT-proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the NPPA and NPPB expression was similar between the genotype groups. Conclusions Corin gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.

Association of a Multiancestry Genome-Wide Blood Pressure Polygenic Risk Score With Adverse Cardiovascular Events.

BACKGROUND: Traditional cardiovascular risk factors and the underlying genetic risk of elevated blood pressure (BP) determine an individual's composite risk of developing adverse cardiovascular events. We sought to evaluate the relative contributions of the traditional cardiovascular risk factors to the development of adverse cardiovascular events in the context of varying BP genetic risk profiles. METHODS: Genome-wide polygenic risk score (PRS) was computed using multiancestry genome-wide association estimates among US adults who underwent whole-genome sequencing in the Trans-Omics for Precision program. Individuals were stratified into high, intermediate, and low genetic risk groups (>80th, 20-80th, and <20th centiles of systolic BP [SBP] PRS). Based on the ACC/AHA Pooled Cohort Equations, participants were stratified into low and high (10 year-atherosclerotic cardiovascular disease [CVD] risk: <10% or ≥10%) cardiovascular risk factor profile groups. The primary study outcome was incident cardiovascular event (composite of incident heart failure, incident stroke, and incident coronary heart disease). RESULTS: Among 21 897 US adults (median age: 56 years; 56.0% women; 35.8% non-White race/ethnicity), 1 SD increase in the SBP PRS, computed using 1.08 million variants, was associated with SBP (ß: 4.39 [95% CI, 4.13-4.65]) and hypertension (odds ratio, 1.50 [95% CI, 1.46-1.55]), respectively. This association was robustly seen across racial/ethnic groups. Each SD increase in SBP PRS was associated with a higher risk of the incident CVD (multivariable-adjusted hazards ratio, 1.07 [95% CI, 1.04-1.10]) after controlling for ACC/AHA Pooled Cohort Equations risk scores. Among individuals with a high SBP PRS, low atherosclerotic CVD risk was associated with a 58% lower hazard for incident CVD (multivariable-adjusted hazards ratio, 0.42 [95% CI, 0.36-0.50]) compared to those with high atherosclerotic CVD risk. A similar pattern was noted in intermediate and low genetic risk groups. CONCLUSIONS: In a multiancestry cohort of >21 000 US adults, genome-wide SBP PRS was associated with BP traits and adverse cardiovascular events. Adequate control of modifiable cardiovascular risk factors may reduce the predisposition to adverse cardiovascular events among those with a high SBP PRS.

Fibrillar Collagen Variants in Spontaneous Coronary Artery Dissection.

IMPORTANCE: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized nonatherosclerotic cause of acute myocardial infarction enriched among individuals with early-onset myocardial infarction but is of unclear etiology. OBJECTIVE: To assess which genes contribute to the development of SCAD. DESIGN, SETTING, AND PARTICIPANTS: To prioritize genes influencing risk for SCAD, whole-exome sequencing was performed among individuals with SCAD in the discovery and replication cohorts from a tertiary care hospital outpatient specialty clinic, and gene set enrichment analyses were also performed for disruptive coding variants. All patients were sequentially enrolled beginning July 2013. Aggregate prevalence of rare disruptive variants for prioritized gene sets was compared between individuals with SCAD with population-based controls comprising 46 468 UK Biobank participants with whole-exome sequencing. Complementary mice models were used for in vivo validation. Analysis took place between June 2020 and January 2021. MAIN OUTCOMES AND MEASURES: The frequency and identity of rare genetic variants in individuals with SCAD. RESULTS: Of 130 patients, 109 (83.8%) were female (26 of 32 [81.2%] in the discovery cohort and 83 of 98 [84.7%] in the replication cohort) with mean (SD) age at first SCAD event of 48.41 (8.76) years in the discovery cohort and 47.74 (10.09) years in the replication cohort. Across all patients with SCAD, rare disruptive variants were found within 10 collagen genes (COL3A1, COL5A1, COL4A1, COL6A1, COL5A2, COL12A1, COL4A5, COL1A1, COL1A2, and COL27A1) were 17-fold (P = 1.5 × 10-9) enriched among individuals with SCAD compared with a background of 2506 constrained genes expressed in coronary artery. Furthermore, compared with individuals from the UK Biobank, individuals with SCAD were 1.75-fold (P = .04) more likely to carry disruptive rare variants within fibrillar collagen genes. Complementary mice models haploinsufficient for Col3a1 or Col5a1, the 2 most common collagen gene variants identified in SCAD cases, demonstrated increased risk of arterial dissection and increased size of arterial diameters especially in female mice, with resulting changes in collagen fibril organization and diameter. CONCLUSIONS AND RELEVANCE: Unbiased gene discovery in patients with SCAD with independent human and murine validation highlights the role of the extracellular matrix dysfunction in SCAD.

Cold shock domain-containing protein E1 is a posttranscriptional regulator of the LDL receptor.

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current therapies and known causes of familial hypercholesterolemia. We found that cold shock domain-containing protein E1 (CSDE1) enhanced hepatic LDLR messenger RNA (mRNA) decay via its 3' untranslated region and regulated atherogenic lipoproteins in vivo. Using parallel phenotypic genome-wide CRISPR interference screens in a tissue culture model, we identified 40 specific regulators of the LDLR that were not previously identified by observational human genetic studies. Among these, we demonstrated that, in HepG2 cells, CSDE1 regulated the LDLR at least as strongly as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In addition, we showed that hepatic gene silencing of Csde1 treated diet-induced dyslipidemia in mice to a similar degree as Pcsk9 silencing. These results suggest the therapeutic potential of targeting CSDE1 to manipulate the posttranscriptional regulation of the LDLR mRNA for the prevention of cardiovascular disease. Our approach of modeling a clinically relevant phenotype in a forward genetic screen, followed by mechanistic pharmacologic dissection and in vivo validation, may serve as a generalizable template for the identification of therapeutic targets in other human disease states.

Proteomic profiling platforms head to head: Leveraging genetics and clinical traits to compare aptamer- and antibody-based methods.

High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K (N = 1301 reagents), the SomaScan5K platform (N = 4979 reagents), and the Olink Explore (N = 1472 reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome.

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

Whole genome sequence analysis of blood lipid levels in >66,000 individuals.

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.