Adolfo Correa

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS for cIMT involving up to 131,000 individuals. For the first time, we meta-analysed a diverse range of ancestries including populations with African, Asian (Chinese), Brazilian, European, and Hispanic ancestries. Our study identified 59 independent loci (53 loci from the multi-ancestry single variant analysis of which 19 are novel, P-8 ; 6 novel in gene-based analysis from single variant analysis, P=2.6x10 ^-6 , 2 novel in meta-regression) associated with cIMT. Gene-based, tissue-expression and gene-set enrichment analyses revealed novel genes of potential interest and highlighted significant relationships between vascular tissues (aorta, coronary and tibial arteries) and genetic associations. We found that circulatory levels of seven proteins, including ACAN, BCAM, DUT, ERI1, APOE, FN1, and GLRX were potentially causally associated with cIMT levels. We found a strong genome-wide correlation between cIMT and various cardiometabolic, smoking phenotypes, and lipid traits. Using Mendelian randomisation, our analyses provide robust evidence for causal associations between cIMT and several clinically relevant traits, including lipids, blood pressure, and waist circumference. Our study extends our genetic knowledge of atherosclerosis and highlights potential causal relations between risk factors, atherosclerosis and clinical diagnoses.

Background: Cigarette smoking has been associated with incident heart failure (HF). However, the association between cigarette smoking and smoking cessation with HF subtypes has not been well elucidated, particularly among Black people. Methods and results: We investigated 4189 (never smoker n=2934, former smoker n=761, current smoker n=464) Black participants (mean age 54 years, 64% women) without a history of HF or coronary heart disease at baseline in the Jackson Heart Study. We examined the association of cigarette smoking with incident HF hospitalization and HF subtypes (HF with preserved ejection fraction and HF with reduced ejection fraction). After adjustment for confounding factors, current smoking was associated with incident HF (both subtypes) compared with never smoking. Smoking intensity among those who identified as currently smoking and smoking burden among those who ever smoked were associated with higher incidence of HF with preserved ejection fraction compared with never smoking. Lung function evaluated by spirometry at baseline did not significantly influence these associations. The risk of developing HF decreased with more years after smoking cessation, and more than 20 years of smoking cessation were required to reach a risk comparable to that of never smoking. Conclusions: Smoking cigarettes was associated with developing both subtypes of HF and it was independent from the influences on baseline lung function. Long-term smoking cessation is necessary to prevent the onset of HF in people who smoke cigarettes.

BACKGROUND: Black adults show heightened cardiovascular risk compared with other groups despite comparable or lower coronary artery calcium (CAC) scores, indicating potential cardiovascular risk underestimation by CAC. Abdominal aortic calcification (AAC), preceding CAC, may predict cardiovascular events better in Black adults who are prone to early atherosclerotic cardiovascular disease and excess events at low CAC scores. METHODS: We included 2551 participants from the JHS (Jackson Heart Study) visit 2 examination (2005–2008) without cardiovascular disease, followed through 2016. Cox regression estimated hazard ratios for incident cardiovascular events defined as a composite of myocardial infarction, stroke, heart failure, and all-cause mortality. The predictive value of CAC and AAC, when added to the American College of Cardiology/American Heart Association cardiovascular risk algorithm (pool cohort equation), was assessed. RESULTS: Mean age was 57±10 years; 66% were women. Over a follow-up period of 12.6 years, 287 (11.3%) cardiovascular events and 360 (14.1%) mortality cases were observed. Adjusting for demographic and clinical variables, each 2-fold increase in CAC and AAC was associated with cardiovascular events (CAC: hazard ratio, 1.10 [95% CI, 1.06–1.13]; AAC: hazard ratio, 1.10 [95% CI, 1.06–1.13]) and all-cause mortality CAC: hazard ratio, 1.04 [95% CI, 1.01–1.08]; AAC: hazard ratio, 1.05 [95% CI, 1.01–1.08]). The incremental value of CAC (0.17 [95% CI, 0.08–0.23]) and AAC (0.15 [95% CI, 0.07–0.29]) to the pool cohort equation by net reclassification index was comparable. Notably, 45% of participants with 0 CAC showed some degree of AAC. Each 2-fold increase in AAC was associated with an increased risk of cardiovascular events (hazard ratio, 1.07 [95% CI, 1.01–1.19]) but not all-cause mortality among participants with 0 CAC. CONCLUSIONS: AAC is comparable to CAC in predicting cardiovascular events and all-cause mortality among Black adults, potentially valuable when CAC is absent.

Objective: We aimed to investigate sociodemographic factors associated with self-reported COVID-19 infection. Methods: The study population was a prospective multicenter cohort of adult volunteers recruited from healthcare systems located in the mid-Atlantic and southern United States. Between April 2020 and October 2021, participants completed daily online questionnaires about symptoms, exposures, and risk behaviors related to COVID-19, including self-reports of positive SARS CoV-2 detection tests and COVID-19 vaccination. Analysis of time from study enrollment to self-reported COVID-19 infection used a time-varying mixed effects Cox-proportional hazards framework. Results: Overall, 1,603 of 27,214 study participants (5.9%) reported a positive COVID-19 test during the study period. The adjusted hazard ratio demonstrated lower risk for women, those with a graduate level degree, and smokers. A higher risk was observed for healthcare workers, those aged 18–34, those in rural areas, those from households where a member attends school or interacts with the public, and those who visited a health provider in the last year. Conclusions: We identified subgroups within healthcare network populations defined by age, occupational exposure, and rural location reporting higher than average rates of COVID-19 infection for our surveillance population. These subgroups should be monitored closely in future epidemics of respiratory viral diseases.

BACKGROUND: Increased hsCRP (high-sensitivity C-reactive protein), a marker of inflammation, is associated with incident cardiovascular events. We aim to determine whether the baseline or trajectory of hsCRP levels over time predicts incident heart failure (HF) hospitalization. METHODS: JHS (Jackson Heart Study) participants’ (n=3920 Black adults) hsCRP levels were measured over 3 visits (from 2000 to 2013). We assessed the association of hsCRP at baseline (visit 1) with incident HF hospitalization using Cox proportional hazards models. Furthermore, we assessed the association of the trajectory of hsCRP over repeated measurements (visits 1–3) with incident HF using joint models. Hazard ratios are reflective of an increase in hsCRP by 1 SD on a log2 scale. We also assessed the association of change in hsCRP between visit 1 and visit 3 with Cox proportional hazards models by grouping patients by low (0.05). Furthermore, changes in hsCRP from low-to-high and high-to-low levels were associated with incident HF ( P <0.05). CONCLUSIONS: While baseline hsCRP was not associated with incident HF, an increasing trajectory of hsCRP over time was associated with increased risk for incident HF (particularly HF with preserved ejection fraction). Temporal change in hsCRP may be an important marker of risk for incident HF with preserved ejection fraction in Black adults.

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification and a potential drug target for vascular calcific disease.

Objective: We aimed to investigate sociodemographic factors associated with self-reported COVID-19 infection. Methods: The study population is a multicenter prospective cohort of adult volunteers recruited from healthcare systems located in the mid-Atlantic and southern United States. Between April 2020 and October 2021 participants completed daily online questionnaires about symptoms, exposures, and risk behaviors related to COVID-19, including self-reports of positive SARS CoV-2 detection tests and COVID-19 vaccination. Analysis of time from study enrollment to self-reported COVID-19 infection used a time-varying mixed effects Cox-proportional hazards framework. Results: Overall, 1,603 of 27,214 study participants (5.9%) reported a positive COVID-19 test during the study period. The adjusted hazard ratio demonstrated lower risk for women, those with a graduate level degree, and smokers. A higher risk was observed for healthcare workers, those aged 18-34, those in rural areas, those from households where a member attends school or interacts with the public, and those who visited a health provider in the last year. Conclusions: Increased risk of self-reported COVID-19 was associated with specific demographic characteristics, which may help to inform targeted interventions for future pandemics.

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.