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Abstract Excessive peripheral microvascular constriction during acute psychological stress reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. Among individuals with coronary artery disease (CAD), we sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. A total of 580 stable CAD individuals from two prospective cohort studies underwent mental stress testing. Digital pulse wave amplitude was continuously measured and the stress/rest (sPAT) ratio of pulse wave amplitude was calculated. Race stratified genome-wide association studies (GWAS) of sPAT-ratio were conducted using linear regression of additive genetic models. A trans-ethnic meta-analysis integrated the four sets of GWAS results. Participants were followed for the outcome of recurrent cardiovascular events (myocardial infarction, heart failure, revascularization, and CV death) for a median of 5 years. We used Wei-Lin-Weissfeld (WLW) model to assess the association between sPAT-ratio with recurrent events. Mean age was 63 ± 9. We identified three SNPs in linkage disequilibrium, closely related to chr7:111,666,943 T > C (rs6466396) that were associated with sPAT-ratio (p = 6.68E-09). Participants homozygous for the T allele had 80% higher risk of incident adverse events (HR 1.8, 95% CI, 1.4–2.2). Also, participants with a lower sPAT-ratio (

Abstract Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 24.5 million primary-care health records in over 740,000 individuals in the UK Biobank, Million Veteran Program USA, and Estonian Biobank, to discover and validate the genetic architecture of adiposity trajectories. Using multiple BMI measurements over time increases power to identify genetic factors affecting baseline BMI by 14%. In the largest reported genome-wide study of adiposity-change in adulthood, we identify novel associations with BMI-change at six independent loci, including rs429358 (APOE missense variant). The SNP-based heritability of BMI-change (1.98%) is 9-fold lower than that of BMI. The modest genetic correlation between BMI-change and BMI (45.2%) indicates that genetic studies of longitudinal trajectories could uncover novel biology of quantitative traits in adulthood.

Summary: Polygenic scores (PGSs) are a promising tool for estimating individual-level genetic risk of disease based on the results of genome-wide association studies (GWASs). However, their promise has yet to be fully realized because most currently available PGSs were built with genetic data from predominantly European-ancestry populations, and PGS performance declines when scores are applied to target populations different from the populations from which they were derived. Thus, there is a great need to improve PGS performance in currently under-studied populations. In this work we leverage data from two large and diverse cohorts the Million Veterans Program (MVP) and All of Us (AoU), providing us the unique opportunity to compare methods for building PGSs for multi-ancestry populations across multiple traits. We build PGSs for five continuous traits and five binary traits using both multi-ancestry and single-ancestry approaches with popular Bayesian PGS methods and both MVP META GWAS results and population-specific GWAS results from the respective African, European, and Hispanic MVP populations. We evaluate these scores in three AoU populations genetically similar to the respective African, Admixed American, and European 1000 Genomes Project superpopulations. Using correlation-based tests, we make formal comparisons of the PGS performance across the multiple AoU populations. We conclude that approaches that combine GWAS data from multiple populations produce PGSs that perform better than approaches that utilize smaller single-population GWAS results matched to the target population, and specifically that multi-ancestry scores built with PRS-CSx outperform the other approaches in the three AoU populations.

Abstract Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life’s Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population.

Background Heart failure (HF) is a serious condition with increasing prevalence, high morbidity, and increased mortality. Obesity is an established risk factor for HF. Fluctuation in body mass index (BMI) has shown a higher risk of cardiovascular outcomes. We investigated the association between BMI variability and incident HF. Methods and Results In the UK Biobank, we established a prospective cohort after excluding participants with prevalent HF or cancer at enrollment. A total of 99 368 White participants with ≥3 BMI measures during >2 years preceding enrollment were included, with a median follow‐up of 12.5 years. The within‐participant variability of BMI was evaluated using standardized SD and coefficient of variation. The association of BMI variability with incident HF was assessed using Fine and Gray's competing risk model, adjusting for confounding factors and participant‐specific rate of BMI change. Higher BMI variability measured in both SD and coefficient of variation was significantly associated with higher risk in HF incidence (SD: hazard ratio [HR], 1.05 [95% CI, 1.03–1.08], P

Abstract We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Introduction: People with HIV (PWH) of African ancestry have faster decline of kidney function and faster progression to end-stage renal disease than PWH of European ancestry. DNA methylation have been associated with kidney function in the general population, however, their relationships are unclear for PWH of African ancestry. Methods: We performed epigenome-wide association studies (EWAS) of estimated glomerular filtration rate (eGFR) among PWH of African ancestry in 2 subsets of the Veterans Aging Cohort Study cohort (N = 885), followed by a meta-analysis to combine the results. Replication was conducted among independent African American samples without HIV. Results: DNA methylation sites cg17944885 near Zinc Finger Family Member 788 (ZNF788) and Zinc Finger Protein 20 (ZNF20), and cg06930757 in SHANK1 were significantly associated with eGFR among PWH of African ancestry (false discovery rate < 0.05). DNA methylation site cg17944885 was also associated with eGFR among different populations including African Americans without HIV. Conclusions: Our study attempted to address an important gap in the literature and to understand the role of DNA methylation in renal diseases in PWH of African ancestry. Replication of cg17944885 among different populations suggests there may be a common pathway for renal diseases progression among PWH and people without HIV, and across different ancestral groups. Our results suggest that genes ZNF788/ZNF20 and SHANK1 could be involved in a pathway linking DNA methylation to renal diseases among PWH and are worth further investigation.

Background Mental stress–induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease and is associated with a greater risk of future cardiovascular events. The association between chronic symptoms of psychological distress and mental stress–induced ischemia is not clear. Methods and Results We used a composite score of psychological distress derived from symptoms of depression, posttraumatic stress disorder, anxiety, anger, and perceived general stress. Participants underwent myocardial perfusion imaging with both mental (public speaking task) and conventional (exercise or pharmacological) stress testing. Overall, 142 (15.9%) patients experienced mental stress–induced myocardial ischemia. After adjusting for demographic factors, medical history, and medication use, patients in the highest tertile of psychological distress score had 35% higher odds of having mental stress–induced ischemia compared to those in the lowest tertile (odds ratio [OR], 1.35 [95% CI, 1.06–2.22]). Stratified analyses showed that the association between psychological distress score and mental stress–induced myocardial ischemia was significantly associated only within the subgroup of patients with a prior myocardial infraction, with patients with a prior myocardial infarction in the highest tertile having a 93% higher odds of developing myocardial ischemia with mental stress (95% CI, 1.07–3.60). There was no significant association between psychological distress and conventional stress–induced ischemia (OR, 1.19 [95% CI, 0.87–1.63]). Conclusions Among patients with a history of myocardial infarction, a higher level of psychosocial distress is associated with mental stress–induced myocardial ischemia but not with ischemia induced by a conventional stress test.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Elevated body mass index is heritable and associated with many health conditions that impact morbidity and mortality. Here, the authors identify greater than 900 genetic loci for body mass index (BMI) and find over 300 diagnoses associated with increasing BMI.

While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.

Heart failure is a major cause of cardiovascular morbidity and mortality. Here, the authors report results of a genome-wide association study meta-analysis, characterizing the role of common genetic variants in heart failure, finding overlap with common cardiovascular risk factors and imaging measures of cardiac structure/function.

Background: Adverse mental health conditions including depression, posttraumatic stress disorder (PTSD), and anxiety are prevalent among patients who survive myocardial infarctions (MI) and are associated with adverse outcomes. The mechanisms underlying these associations, however, are not well understood. Inflammatory pathways may mediate the cardiovascular outcomes of patients with mental health disorders. We examined the bidirectional association between PTSD symptoms and inflammatory biomarkers in a young/middle-aged post MI population. We further examined how this association may differ between women and men as well as between Black and non-Black individuals. Methods: Participants included individuals with early onset MI between the ages 25 and 60. Mental health scores for depression, PTSD, perceived stress, and anxiety as well as inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), were collected at baseline and at six-month follow up. We examined the bidirectional changes in mental health symptoms and inflammatory biomarkers between baseline and follow-up. Results: Among 244 patients in the study (mean age: 50.8, 48.4% female, 64.3% Black), the geometric means for IL-6 level and hsCRP at rest were 1.7 pg/mL and 2.76 mg/L, respectively. Mental health scores at baseline did not consistently predict changes in inflammatory biomarkers at follow-up. However, baseline levels of both IL-6 and hsCRP were robustly associated with an increase in re-experiencing PTSD symptoms at 6 months: in adjusted linear mixed models, there was a 1.58-point increase in re-experiencing PTSD symptoms per unit of baseline hsCRP (p = 0.01) and 2.59-point increase per unit of baseline IL-6 (p = 0.02). Once the analysis was stratified by race, the association was only noted in Black individuals. Baseline inflammation was not associated with change in any of the other mental health symptom scores. Conclusion: Markers of inflammation are associated with an increase in post-event PTSD symptoms in younger or middle-aged patients who experienced an MI, especially Black patients. These results suggest a mechanistic link between inflammation and the development of PTSD among individuals with cardiovascular disease.

Graphical Abstract

Background Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Methods and findings Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. Conclusions We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study. Author summary Adult height has been associated with several clinical traits, for example with increased risk of atrial fibrillation and with decreased risk of cardiovascular disease. Using data from the VA Million Veteran Program that includes genetic data linked to clinical records in >200,000 non-Hispanic White adults and >50,000 non-Hispanic Black adults, we examined associations of measured height and genetically-predicted height with clinical traits phenome-wide. By comparing associations of traits with measured and with genetically-predicted height, we aimed to discriminate between potentially causal associations (those associated with genetically-predicted height) from associations that may be confounded by environmental exposures over the life course (those associated with measured height but not with genetically-predicted height). Of approximately 350 traits associated with measured height, we found 127 associated with genetically-predicted height in non-Hispanic White individuals. While only 2 were also statistically significant in non-Hispanic Black individuals, we found evidence for consistent directions of effect for associations of traits with genetically-predicted height in non-Hispanic Black and White individuals. We conclude that height may be an unrecognized non-modifiable risk factor for several common conditions in adults.

Abstract Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.

Background Early life trauma has been associated with increased cardiovascular risk, but the arrhythmic implications are unclear. We hypothesized that in patients with coronary artery disease, early life trauma predicts increased arrhythmic risk during mental stress, measured by elevated microvolt T‐wave alternans (TWA), a measure of repolarization heterogeneity and sudden cardiac death risk. Methods and Results In a cohort with stable coronary artery disease (NCT04123197), we examined early life trauma with the Early Trauma Inventory Self Report‐Short Form. Participants underwent a laboratory‐based mental stress speech task with Holter monitoring, as well as a structured psychiatric interview. We measured TWA during rest, mental stress, and recovery with ambulatory electrocardiographic monitoring. We adjusted for sociodemographic factors, cardiac history, psychiatric comorbidity, and hemodynamic stress reactivity with multivariable linear regression models. We examined 320 participants with noise‐ and arrhythmia‐free ECGs. The mean (SD) age was 63.8 (8.7) years, 27% were women, and 27% reported significant childhood trauma (Early Trauma Inventory Self Report‐Short Form ≥10). High childhood trauma was associated with a multivariable‐adjusted 17% increase in TWA (P=0.04) during stress, and each unit increase in the Early Trauma Inventory Self Report‐Short Form total score was associated with a 1.7% higher stress TWA (P=0.02). The largest effect sizes were found with the emotional trauma subtype. Conclusions In a cohort with stable coronary artery disease, early life trauma, and in particular emotional trauma, is associated with increased TWA, a marker of increased arrhythmic risk, during mental stress. This association suggests that early trauma exposures may affect long‐term sudden cardiac death risk during emotional triggers, although more studies are warranted.

SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations.

BackgroundMitochondrial DNA (mtDNA) profiles and contributions of mtDNA variants to CD4+T-cell recovery in Euramerican people living with HIV (PLWH) may not be transferred to East-Asian PLWH, highlighting the need to consider more regional studies. We aimed to identify mtDNA characteristics and mutations that explain the variability of short-term CD4+T-cell recovery in East-Asian PLWH.MethodEight hundred fifty-six newly reported antiretroviral therapy (ART)-naïve Chinese PLWH from the Comparative HIV and Aging Research in Taizhou (CHART) cohort (Zhejiang Province, Eastern China) were enrolled. MtDNA was extracted from peripheral whole blood of those PLWH at HIV diagnosis, amplified, and sequenced using polymerase chain reaction and gene array. Characterization metrics such as mutational diversity and momentum were developed to delineate baseline mtDNA mutational patterns in ART-naïve PLWH. The associations between mtDNA genome-wide single nucleotide variants and CD4+T-cell recovery after short-term (within ~48 weeks) ART in 724 PLWH were examined using bootstrapping median regressions.ResultsOf 856 participants, 74.18% and 25.82% were male and female, respectively. The median age was 37 years; 94.51% were of the major Han ethnicity, and 69.04% and 28.62% were of the heterosexual and homosexual transmission, respectively. We identified 2,352 types of mtDNA mutations and mtDNA regions D-loop, ND5, CYB, or RNR1 with highest mutational diversity or volume. Female PLWH rather than male PLWH at the baseline showed remarkable age-related uptrends of momentum and mutational diversity as well as correlations between CD4+T C, m.1824T>C, m.3394T>C, m.4491G>A, m.7828A>G, m.9814T>C, m.10586G>A, m.12338T>C, m.13708G>A, and m.14308T>C (at the Bonferroni-corrected significance) were negatively associated with short-term CD4+T-cell recovery whereas m.93A>G, m.15218A>G, and m.16399A>G were positively associated with short-term CD4+T-cell recovery.ConclusionOur baseline mtDNA characterization stresses the attention to East-Asian female PLWH at risk of CD4+T-cell loss-related aging and noncommunicable chronic diseases. Furthermore, mtDNA variants identified in regression analyses account for heterogeneity in short-term CD4+T-cell recovery of East-Asian PLWH. These results may help individualize the East-Asian immune recovery strategies under complicated HIV management caused by CD4+T-cell loss.

The dystonias are a group of disorders characterized by excessive contraction of muscles leading to abnormal involuntary movements. The clinical manifestations are very heterogeneous, with numerous distinct syndromes. The etiologies for dystonia are also heterogeneous with idiopathic, acquired, and inherited forms. Technological advances in genetics over the past two decades have led to a rapid growth in the number of genes associated with dystonia. These genes encode proteins with very diverse biological functions. This review focusses on genes that have contributed to understanding shared biological pathways relevant to specific subgroups of dystonia syndromes. Although many potential shared biological pathways have been proposed, the ones addressed here include defects in dopamine signaling, mitochondrial dysfunction and energy maintenance, toxic accumulation of heavy metals in the brain, and calcium channels and abnormal calcium homeostasis. Elucidation of these and other shared pathways is important for understanding the biological basis for dystonia and for designing novel experimental therapeutics that have the broadest potential for multiple types of dystonia.

Introduction: Cigarette smoking has been associated with adverse health outcomes for mothers and children and is a major contributor to heart disease. Although cigarette smoking is known to affect the epigenome, few studies have been done in African American populations. In this study, we investigated the association between cigarette smoking and DNA methylation (DNAm) among African Americans from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN), and the Genetic Epidemiology Network of Arteriopathy (GENOA). Methods: The InterGEN study aims to examine the effects of genetic and psychological factors on blood pressure among African American women and their children. Current cigarette smoking was assessed at baseline. DNAm of saliva was assessed using the 850K EPIC Illumina BeadChip for Epigenome-Wide Association analyses. A replication study was conducted among 1100 participants in the GENOA study using the same BeadChip. Results: After controlling for age, body mass index, population structure and cell composition, 26 epigenome-wide significant sites (FDR q

Potentially traumatic experiences have been associated with chronic diseases. Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed as an explanation for this association. We examined the association of experiences of trauma with epigenome-wide DNAm among African American mothers (n = 236) and their children aged 3–5 years (n = 232; N = 500), using the Life Events Checklist-5 (LEC) and Traumatic Events Screening Inventory—Parent Report Revised (TESI-PRR). We identified no DNAm sites significantly associated with potentially traumatic experience scores in mothers. One CpG site on the ENOX1 gene was methylome-wide-significant in children (FDR-corrected q-value = 0.05) from the TESI-PRR. This protein-coding gene is associated with mental illness, including unipolar depression, bipolar, and schizophrenia. Future research should further examine the associations between childhood trauma, DNAm, and health outcomes among this understudied and high-risk group. Findings from such longitudinal research may inform clinical and translational approaches to prevent adverse health outcomes associated with epigenetic changes.

Genome-wide association studies (GWAS) of circulating metabolites have revealed the role of genetic regulation on the human metabolome. Most previous investigations focused on European ancestry, and few studies have been conducted among populations of African descent living in Africa, where the infectious disease burden is high (e.g., human immunodeficiency virus (HIV)). It is important to understand the genetic associations of the metabolome in diverse at-risk populations including people with HIV (PWH) living in Africa. After a thorough literature review, the reported significant gene–metabolite associations were tested among 490 PWH in South Africa. Linear regression was used to test associations between the candidate metabolites and genetic variants. GWAS of 154 plasma metabolites were performed to identify novel genetic associations. Among the 29 gene–metabolite associations identified in the literature, we replicated 10 in South Africans with HIV. The UGT1A cluster was associated with plasma levels of biliverdin and bilirubin; SLC16A9 and CPS1 were associated with carnitine and creatine, respectively. We also identified 22 genetic associations with metabolites using a genome-wide significance threshold (p-value < 5 × 10−8). In a GWAS of plasma metabolites in South African PWH, we replicated reported genetic associations across ancestries, and identified novel genetic associations using a metabolomics approach.

Cardiovascular disease (CVD) is the leading cause of mortality in South Asia, with rapidly increasing prevalence of hypertension, type 2 diabetes (T2DM) and hyperlipidemia over the last two decades. Atherosclerotic CVD (ASCVD) affects South Asians earlier in life and at lower body weights, which is not fully explained by differential burden of conventional risk factors. Heart failure (HF) is a complex clinical syndrome of heterogeneous structural phenotypes including two major clinical subtypes, HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). The prevalence of HF in South Asians is also rising with other metabolic diseases, and HFpEF develops at younger age and leaner body mass index in South Asians than in Whites. Recent genome-wide association studies, epigenome-wide association studies and metabolomic studies of ASCVD and HF have identified genes, metabolites and pathways associated with CVD traits. However, these findings were mostly driven by samples of European ancestry, which may not accurately represent the CVD risk at the molecular level, and the unique risk profile of CVD in South Asians. Such bias, while formulating hypothesis-driven research studies, risks missing important causal or predictive factors unique to South Asians. Importantly, a longitudinal design of multi-omic markers can capture the life-course risk and natural history related to CVD, and partially disentangle putative causal relationship between risk factors, multi-omic markers and subclinical and clinical ASCVD and HF. In conclusion, combining high-resolution untargeted metabolomics with epigenomics of rigorous, longitudinal design will provide comprehensive unbiased molecular characterization of subclinical and clinical CVD among South Asians. A thorough understanding of CVD-associated metabolomic profiles, together with advances in epigenomics and genomics, will lead to more accurate estimates of CVD progression and stimulate new strategies for improving cardiovascular health.

IntroductionGeneral life stress has been associated with altered DNA methylation in individuals of African Ancestry, although the relationship between parenting stress and DNA methylation has not been described. The purpose of this study was to examine the relationship between maternal parenting stress and DNA methylation among African Ancestry mother-child dyads.MethodsWe evaluated epigenome-wide DNA methylation relative to parenting stress in 74 mother-child dyads using linear mixed models.ResultsSignificant variation in maternal DNA methylation at 95 CpG sites was associated with level of parenting stress. Notably, we identified a change in DNA methylation associated with poly (ADP-ribose) polymerase-1, which plays a key role in stress signaling. We did not identify any significant variation in child DNA methylation related to maternal parenting stress.ConclusionsHowever, DNA methylation patterns observed in children mirrored patterns observed in their mothers. The results suggest that differential maternal DNA methylation is associated with higher levels of parenting stress.

Background Exposure to psychosocial stress and employment of high effort coping strategies have been identified as risk factors that may partially explain the high prevalence of hypertension among African Americans. One biological mechanism through which stress and coping may affect risk of hypertension is via epigenetic modifications (e.g., DNA methylation) in blood pressure-related genes; however, this area remains understudied in African Americans. Methods We used data from the ongoing Intergenerational Blood Pressure Study, a longitudinal study designed to investigate factors that contribute to hypertension risk in African American women (n = 120) and their young children, to investigate the association between stress overload, problem-solving coping, avoidance coping, and social support coping with DNA methylation in 25 candidate genes related to blood pressure. Multivariable linear regression and multilevel modeling were used to conduct methylation site-level and gene-level analyses, respectively. Results In site-level analyses, stress overload, problem-solving coping, social support coping, and avoidance coping were associated with 47, 63, 66, and 61 sites, respectively, at p

BackgroundThe response of progenitor cells (PCs) to transient myocardial ischemia in patients with coronary artery disease remains unknown. We aimed to investigate the PC response to exercise‐induced myocardial ischemia (ExMI) and compare it to flow mismatch during pharmacological stress testing. Methods and ResultsA total of 356 patients with stable coronary artery disease underwent 99mTc‐sestamibi myocardial perfusion imaging during exercise (69%) or pharmacological stress (31%). CD34+ and CD34+/chemokine (C‐X‐C motif) receptor 4 PCs were enumerated by flow cytometry. Change in PC count was compared between patients with and without myocardial ischemia using linear regression models. Vascular endothelial growth factor and stromal‐derived factor‐1α were quantified. Mean age was 63±9 years; 76% were men. The incidence of ExMI was 31% and 41% during exercise and pharmacological stress testing, respectively. Patients with ExMI had a significant decrease in CD34+/chemokine (C‐X‐C motif) receptor 4 (−18%, P=0.01) after stress that was inversely correlated with the magnitude of ischemia (r=−0.19, P=0.003). In contrast, patients without ExMI had an increase in CD34+/chemokine (C‐X‐C motif) receptor 4 (14.7%, P=0.02), and those undergoing pharmacological stress had no change. Plasma vascular endothelial growth factor levels increased (15%, P

African American women are affected by earlier onset of age-associated health deteriorations and obesity disproportionally, but little is known about the mechanism linking body mass index (BMI) and biological aging among this population. DNA methylation age acceleration (DNAm AA), measuring the difference between DNA methylation age and chronological age, is a novel biomarker of the biological aging process, and predicts aging-related disease outcomes. The present study estimated cross-tissue DNA methylation age acceleration using saliva samples from 232 African American mothers. Cross-sectional regression analyses were performed to assess the association of BMI with DNAm AA. The average chronological age and DNA methylation age were 31.67 years, and 28.79 years, respectively. After adjusting for smoking, hypertension diagnosis history, and socioeconomic factors (education, marital status, household income), a 1 kg/m2 increase in BMI is associated with 0.14 years increment of DNAm AA (95% CI: (0.08, 0.21)). The conclusion: in African American women, high BMI is independently associated with saliva-based DNA methylation age acceleration, after adjusting for smoking, hypertension, and socioeconomic status. This finding supports that high BMI accelerates biological aging, and plays a key role in age-related disease outcomes among African American women.