Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.

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.

Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery ß = 0.0561, Q = 4.05 × 10-10; ß = 0.0421, Q = 1.12 × 10-3; and ß = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; ß = -4.3 ml/yr, Q = 0.049; ß = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Protein Markers of Diabetes Discovered in an African American Cohort.

Proteomics has been used to study type 2 diabetes, but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans in the Jackson Heart Study (n = 1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and sample batch (false discovery rate q < 0.05) measured using a single-stranded DNA aptamer affinity-based method on fasting plasma samples. A subset was independent of established markers of diabetes development pathways, such as adiposity, glycemia, and/or insulin resistance, suggesting potential novel biological processes associated with disease development. Thirty-six associations remained significant after additional adjustments for BMI, fasting plasma glucose, cholesterol levels, hypertension, statin use, and renal function. Twelve associations, including the top associations of complement factor H, formimidoyltransferase cyclodeaminase, serine/threonine-protein kinase 17B, and high-mobility group protein B1, were replicated in a meta-analysis of two self-identified White cohorts-the Framingham Heart Study and the Malmö Diet and Cancer Study-supporting the generalizability of these biomarkers. A selection of these diabetes-associated proteins also improved risk prediction. Thus, we uncovered both novel and broadly generalizable associations by studying a diverse population, providing a more complete understanding of the diabetes-associated proteome.

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Contributors to Early Mortality in African Americans, the Jackson Heart Study.

Introduction: In recent years, premature "deaths of despair" (ie, due to alcohol, drug use, and suicide) among middle-aged White Americans have received increased attention in the popular press, yet there has been less discussion on what explains premature deaths among young African Americans. In this study, we examined factors related to deaths of despair (alcohol use, drug use, smoking) and contextual factors (perceived discrimination, socioeconomic status, neighborhood conditions) as predictors of premature deaths before the age of 65 years among African Americans. Methods: The Jackson Heart Study (JHS) is a longitudinal cohort study of African Americans in the Jackson, Mississippi, metropolitan statistical area. We included participants younger than 65 years at baseline (n=4000). Participant enrollment began in 2000 and data for these analyses were collected through 2019. To examine predictors of mortality, we calculated multivariable adjusted hazard ratios (HRs; 95% CI), using Cox proportional hazard models adjusted for age, sex, ideal cardiovascular health metrics, drug use, alcohol intake, functional status, cancer, chronic kidney disease, asthma, waist circumference, depression, income, education, health insurance status, perceived neighborhood safety, and exposure to lifetime discrimination. Results: There were 230 deaths in our cohort, which spanned from 2001-2019. After adjusting for all covariates, males (HR, 1.50; 95% CI, 1.11-2.03), participants who used drugs (HR, 1.53; 95% CI, 1.13-2.08), had a heavy alcohol drinking episode (HR, 1.71; 95% CI, 1.22-2.41), reported 0-1 ideal cardiovascular health metrics (HR, 1.78; 95% CI, 1.06-3.02), had cancer (HR, 2.38; 95% CI, 1.41-4.01), had poor functional status (HR, 1.68; 95% CI, 1.19-2.37), or with annual family income less than $25,000 (HR, 1.63; 95% CI, 1.02-2.62) were more likely to die before 65 years of age. Conclusions: In our large cohort of African American men and women, clinical predictors of premature death included poor cardiovascular health and cancer, and social predictors included low income, drug use, heavy alcohol use, and being a current smoker. Clinical and social interventions are warranted to prevent premature mortality in African Americans.

Digital Connectedness in the Jackson Heart Study: Cross-sectional Study.

BACKGROUND: Although new approaches for data collection, such as mobile technology and teleresearch, have demonstrated new opportunities for the conduct of more timely and less costly surveys in community-based studies, literature on the feasibility of conducing cardiovascular disease research using mobile health (mHealth) platforms among middle-aged and older African Americans has been limited. OBJECTIVE: The purpose of this study was to contribute to the knowledge regarding the penetrance of internet and mobile technologies, such as cellphones or smartphones in existing large cohort studies of cardiovascular disease. METHODS: A digital connectedness survey was conducted in the Jackson Heart Study (JHS), a Mississippi-based African American cohort study, as part of the annual follow-up calls with participants from July 2017 to February 2019. RESULTS: Of the 4024 participants contacted, 2564 (63.7%) completed the survey. Among survey respondents, 2262 (88.2%) reported use of internet or cellphone, and 1593 (62.1%) had a smartphone. Compared to nonusers (n=302), internet or cellphone users (n=2262) were younger (mean age 80.1, SD 8.0 vs 68.2, SD 11.3 years), more likely to be affluent (n=778, 40.1% vs n=39, 15.4%), and had greater than high school education (n=1636, 72.5% vs n=85, 28.1%). Internet or cellphone users were less likely to have cardiovascular disease history compared to nonusers (136/2262, 6.6% vs 41/302, 15.8%). The prevalence of current smoking and average BMI were similar between internet or cellphone users and nonusers. Among internet or cellphone users, 1316 (58.3%) reported use of email, 504 (22.3%) reported use of apps to track or manage health, and 1269 (56.1%) expressed interest in using JHS-developed apps. CONCLUSIONS: Our findings suggest that it is feasible to use mHealth technologies to collect survey data among African Americans already enrolled in a longitudinal study. Our findings also highlight the need for more efforts to reduce the age and education divide in access and use of internet and smartphones for tracking health and research in African American communities.

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.

Plant-based diets and incident cardiovascular disease and all-cause mortality in African Americans: A cohort study.

BACKGROUND: Prior studies have documented lower cardiovascular disease (CVD) risk among people with a higher adherence to a plant-based dietary pattern. Non-Hispanic black Americans are an understudied group with high burden of CVD, yet studies of plant-based diets have been limited in this population. METHODS AND FINDINGS: We conducted an analysis of prospectively collected data from a community-based cohort of African American adults (n = 3,635) in the Jackson Heart Study (JHS) aged 21-95 years, living in the Jackson, Mississippi, metropolitan area, US, who were followed from 2000 to 2018. Using self-reported dietary data, we assigned scores to participants' adherence to 3 plant-based dietary patterns: an overall plant-based diet index (PDI), a healthy PDI (hPDI), and an unhealthy PDI (uPDI). Cox proportional hazards models were used to estimate associations between plant-based diet scores and CVD incidence and all-cause mortality. Over a median follow-up of 13 and 15 years, there were 293 incident CVD cases and 597 deaths, respectively. After adjusting for sociodemographic characteristics (age, sex, and education) and health behaviors (smoking, alcohol intake, margarine intake, physical activity, and total energy intake), no significant association was observed between plant-based diets and incident CVD for overall PDI (hazard ratio [HR] 1.06, 95% CI 0.78-1.42, p-trend = 0.72), hPDI (HR 1.07, 95% CI 0.80-1.42, p-trend = 0.67), and uPDI (HR 0.95, 95% CI 0.71-1.28, p-trend = 0.76). Corresponding HRs (95% CIs) for all-cause mortality risk with overall PDI, hPDI, and uPDI were 0.96 (0.78-1.18), 0.94 (0.76-1.16), and 1.06 (0.86-1.30), respectively. Corresponding HRs (95% CIs) for incident coronary heart disease with overall PDI, hPDI, and uPDI were 1.09 (0.74-1.61), 1.11 (0.76-1.61), and 0.79 (0.52-1.18), respectively. For incident total stroke, HRs (95% CIs) for overall PDI, hPDI, and uPDI were 1.00 (0.66-1.52), 0.91 (0.61-1.36), and 1.26 (0.84-1.89) (p-trend for all tests > 0.05). Limitations of the study include use of self-reported dietary intake, residual confounding, potential for reverse causation, and that the study did not capture those who exclusively consume plant-derived foods. CONCLUSIONS: In this study of black Americans, we observed that, unlike in prior studies, greater adherence to a plant-based diet was not associated with CVD or all-cause mortality.

Association of clonal hematopoiesis with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

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.

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure.

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10-7 ) to 3.08 years (EEAA, p < 3.7 × 10-18 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p < 4.1 × 10-8 ) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10-6 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.

Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults.

BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort. METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women). RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; ß=0.04; P=2×10-8; hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; ß=0.05; P=5×10-15). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups. CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.

Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

Cigarette Smoking, Incident Coronary Heart Disease, and Coronary Artery Calcification in Black Adults: The Jackson Heart Study.

Background Although Black adults are more likely to die from coronary heart disease (CHD) compared with White adults, few studies have examined the relationship between cigarette smoking and CHD risk among Black adults. We evaluated the relationship between cigarette smoking, incident CHD, and coronary artery calcification in the JHS (Jackson Heart Study). Methods and Results We classified JHS participants without a history of CHD (n=4432) by self-reported baseline smoking status into current, former (smoked at least 400 cigarettes/life) or never smokers at baseline (2000-2004). We further classified current smokers by smoking intensity (number of cigarettes smoked per day [1-19 or ≥20]) and followed for incident CHD (through 2016). Hazard ratios (HR) for incident CHD for each smoking group compared with never smokers were estimated with adjusted Cox proportional hazard regression models. At baseline, there were 548 (12.4%) current, 782 (17.6%) former, and 3102 (70%) never smokers. During follow-up (median, 13.8 years), 254 participants developed CHD. After risk factor adjustment, CHD risk was significantly higher in current smokers compared with never smokers (HR, 2.11; 95% CI, 1.39-3.18); the difference between former smokers and never smokers (HR, 1.37; 95% CI, 1.0-1.90) did not achieve statistical significance. Among current smokers, we did not observe a dose-response effect for CHD risk. Additionally, in multivariable logistic regression models with a subset of our analytic cohort, current smokers had greater odds of coronary artery calcification score >0 compared with never smokers (odds ratio, 2.63; 95% CI, 1.88-3.68). Conclusions In a large prospective cohort of Black adults, current smoking was associated with a >2-fold increased risk of CHD over a median follow-up of greater than a decade.

Obesity and overall mortality: findings from the Jackson Heart Study.

BACKGROUND: Overall mortality has been reported to be lower among individuals classified as overweight/obese when compared with their normal weight counterparts ("obesity paradox") when obesity classification is based on the body mass index (BMI). One possible reason for this apparent paradox is that BMI is not a reliable measure of obesity-related risk as it does not differentiate fat mass from lean muscle mass or fat mass phenotypes. Waist circumference (WC), as a measure of central adiposity, may be a better indicator of obesity-related risk. We examined the association of overall mortality with BMI and with WC measures, including WC, waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR). METHODS: Data from 3976 African American participants (551 deaths) in the Jackson Heart Study (JHS) were analyzed. Cox regression models were used to perform survival analysis. Obesity measures were analyzed as dichotomous (obese/non-obese) and continuous variables. Baseline covariates included age, sex and smoking status. RESULTS: Comparing obese to non-obese participants, adjusted hazard ratios (95% CI) for overall mortality were 1.14 (0.96, 1.35), 1.30 (1.07, 1.59), 1.02 (0.73, 1.41) and 1.45 (1.18, 1.79) when using BMI, WC, WHtR and WHR, respectively. For BMI, WC and WHtR, a J-shaped relationship was observed with overall mortality. For WHR, a monotonic increasing relationship was observed with overall mortality. CONCLUSIONS: In the JHS, we found that obesity as defined by WC and WHR was associated with an increased risk of overall and CVD mortality, while obesity defined by BMI was associated only with an increased risk of CVD mortality. WHR was the only obesity measure that showed a monotonic increasing relationship with overall and CVD mortality.

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

Recovery From Mobility Limitation in Middle-Aged African Americans: The Jackson Heart Study.

BACKGROUND: Despite evidence that African Americans shoulder a high burden of mobility limitation, little is known about factors associated with recovery. METHOD: Participants from the Jackson Heart Study underwent 3 in-person exams from 2000 to 2013. Mobility limitations were assessed over this period by self-reported limitations in walking half a mile or climbing stairs during annual phone calls. The outcome of interest, recovery from mobility limitation, was defined as no mobility limitation the year following an incident event. Candidate predictor variables were assessed in logistic regression models, including sociodemographic, psychosocial, and health measures. Inverse probability weights were used to address missing data in the outcome. RESULTS: Among 4526 participants (mean [SD] age = 54.5 (12.8) years) without a mobility limitation at baseline, 1445 (32%) had an incident mobility limitation over 12 years of follow-up, and 709 (49%) reported recovery from mobility limitation by 1 year later. Low income and daily discrimination were associated with a lower likelihood of recovery even after adjustment for covariates. In adjusted models, greater comorbidity was associated with a lower likelihood of recovering (p-value for trend = .05). History of heart failure and cancer were associated with a lower likelihood of recovering from mobility limitation (OR: 0.52, 95% CI: 0.29, 0.94 and OR: 0.74, 95% CI: 0.55, 1.00). Adiposity, smoking status, and physical activity were not associated with recovery from mobility limitation. CONCLUSION: Half of incident mobility limitations in this population of middle-aged African Americans were transient. Adverse sociodemographic factors and comorbidities were associated with lower likelihood of recovery.

Association of Genetic West African Ancestry, Blood Pressure Response to Therapy, and Cardiovascular Risk Among Self-Reported Black Individuals in the Systolic Blood Pressure Reduction Intervention Trial (SPRINT).

IMPORTANCE: Self-identified Black race is associated with higher hypertension prevalence and worse blood pressure (BP) control compared with other race/ethnic groups. The contribution of genetic West African ancestry to these racial disparities appears not to have been completely determined. OBJECTIVE: To determine the association between the proportion of West African ancestry with the response to antihypertensive medication, BP control, kidney function, and risk of adverse cardiovascular (CV) events among self-identified Black individuals in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the SPRINT trial incorporated data from a multicenter study of self-identified Black participants with available West African ancestry proportion, estimated using 106 biallelic autosomal ancestry informative genetic markers. Recruitment started on October 20, 2010, and ended on August 20, 2015. Data were analyzed from May 2020 to September 2020. MAIN OUTCOMES AND MEASURES: Trajectories of BP and kidney function parameters on follow-up of the trial were assessed across tertiles of the proportion of West African ancestry using linear mixed-effect modeling after adjustment for potential confounders. Multivariable adjusted Cox models evaluated the association of West African ancestry with the risk of composite CV events (nonfatal myocardial infarction, CV death, and heart failure event). RESULTS: Among 2466 participants in the current analysis (1122 women [45.5%]; median West African ancestry, 81% [interquartile range, 73%-87%]), there were 120 composite CV events (4.9%) over a mean (SD) of 3.2 (0.9) years of follow-up. At baseline, mean (SD) high-density lipoprotein cholesterol levels were higher (tertile 3: 56.5 [15.0] mg/dL vs tertile 1: 54.2 [14.9] mg/dL; P = .006), smoking prevalence (never smoking: tertile 3: 367 [47.9%] vs tertile 1: 372 [42.2%]; P = .009) and mean (SD) Framingham Risk scores (tertile 3: 16.7 [9.7] vs tertile 1: 18.1 [10.2]; P = .01) were lower, and baseline BP was not different across increasing tertiles of West African ancestry. On follow-up, there was no evidence of differences in longitudinal trajectories of BP, kidney function parameters, or left ventricular mass (Cornell voltage by electrocardiogram) across tertiles of West African ancestry in either intensive or standard treatment arms. In adjusted Cox models, higher West African ancestry was associated with a lower risk of a composite CV event after adjustment for potential confounders (adjusted hazard ratio per 5% higher West African ancestry, 0.92 [95% CI, 0.85-0.99]). CONCLUSIONS AND RELEVANCE: Among self-reported Black individuals enrolled in SPRINT, the trajectories of BP, kidney function, and left ventricular mass over time were not different across tertiles of the proportion of West African ancestry. A higher proportion of West African ancestry was associated with a modestly lower risk for CV events. These findings suggest that extrinsic and structural societal factors, more than genetic ancestry, may be the major drivers of the well-established racial disparity in cardiovascular health associated with hypertension.