Publications by authors named "Bruce M Psaty"

812 Publications

Sugar-sweetened Beverage Consumption May Modify Associations between Genetic Variants in the CHREBP Locus and HDL-C and TG Concentrations.

Circ Genom Precis Med 2021 Jul 16. Epub 2021 Jul 16.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

- Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the locus have separately been linked to high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. We hypothesized SSB consumption would modify the association between genetic variants in the locus and dyslipidemia. - Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (N=63,599) and the UK Biobank (UKB) (N=59,220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and TG concentrations using linear regression models. A total of 1,606 single-nucleotide polymorphisms (SNPs) within or near were considered. SSB consumption was estimated from validated questionnaires and participants were grouped by their estimated intake. - In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers [β (95% CI) = 2.12 (1.16, 3.07) mg/dl; <0.0002], but not significantly among the lowest SSB consumers (=0.81; <0.0001). Similar results were observed for two additional variants (rs35709627 and rs71556736). For TG, rs55673514 was positively associated with TG concentrations only among the highest SSB consumers [β (95% CI): 0.06 (0.02, 0.09) per allele count for log(mg/dl), =0.001], but not the lowest SSB consumers (=0.84; =0.0005). - Our results identified genetic variants in the locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in TG concentrations.
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http://dx.doi.org/10.1161/CIRCGEN.120.003288DOI Listing
July 2021

Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.

Heart 2021 Jul 13. Epub 2021 Jul 13.

Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Objectives: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults.

Methods: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years.

Results: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations.

Conclusion: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.
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http://dx.doi.org/10.1136/heartjnl-2021-319296DOI Listing
July 2021

Multiethnic Genome-wide Association Study of Subclinical Atherosclerosis in Individuals with Type 2 Diabetes.

Circ Genom Precis Med 2021 Jul 9. Epub 2021 Jul 9.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC.

- Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease (CVD). Type 2 diabetes (T2D) is an independent CVD risk factor that accelerates atherosclerosis. - We performed meta-analyses of genome-wide association studies (GWAS) in up to 2,500 T2D individuals of European ancestry (EA) and 1,590 T2D individuals of African ancestry (AA) with or without exclusion of prevalent CVD, for CAC measured by cardiac computed tomography, and 3,608 EA and 838 AA with T2D for cIMT measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. - We replicated two loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0×10 in EA. No additional loci were identified with the meta-analyses of EA and AA. The expression QTL analysis with nearby expressed genes derived from arterial wall and metabolic tissues from GTEx pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1×10) for three previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT). - Our results provide potential biological mechanisms that could link CAC and cIMT to increased CVD risk in individuals with T2D.
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http://dx.doi.org/10.1161/CIRCGEN.120.003258DOI Listing
July 2021

Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis.

JCI Insight 2021 Jul 8;6(13). Epub 2021 Jul 8.

Department of Medicine.

BackgroundImmunomodulatory therapy may help prevent heart failure (HF). Data on immune cells and myocardial remodeling in older adults with cardiovascular risk factors are limited.MethodsIn the Multi-Ethnic Study of Atherosclerosis cohort, 869 adults had 19 peripheral immune cell subsets measured and underwent cardiac MRI during the baseline exam, of which 321 had assessment of left ventricular global circumferential strain (LV-GCS). We used linear regression with adjustment for demographics, cardiovascular risk factors, and cytomegalovirus serostatus to evaluate the cross-sectional association of immune cell subsets with left ventricular mass index (LVMI) and LV-GCS.ResultsThe average age of the cohort was 61.6 ± 10.0 years and 53% were women. Higher proportions of γ/δ T cells were associated with lower absolute (worse) LV-GCS (-0.105% [95% CI -0.164%, -0.046%] per 1 SD higher proportion of γ/δ T cells, P = 0.0006). This association remained significant after Bonferroni's correction. Higher proportions of classical monocytes were associated with worse absolute LV-GCS (-0.04% [95% CI -0.07%, 0.00%] per 1 SD higher proportion of classical monocytes, P = 0.04). This did not meet significance after Bonferroni's correction. There were no other significant associations with LV-GCS or LVMI.ConclusionPathways associated with γ/δ T cells may be potential targets for immunomodulatory therapy targeted at HF prevention in populations at risk.FundingContracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and grant R01 HL98077 from the National Heart, Lung, and Blood Institute/NIH and grants KL2TR001424, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences/NIH.
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http://dx.doi.org/10.1172/jci.insight.149193DOI Listing
July 2021

Adverse Cardiovascular Outcomes and Antihypertensive treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS).

Clin Pharmacol Ther 2021 Jul 7. Epub 2021 Jul 7.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA.

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-SNP interaction tests for four drug classes (β-blockers, n=9,195; calcium channel blockers [CCB], n=10,511; thiazide/thiazide-like diuretics, n=3,516; ACE-inhibitors/ARBs, n=2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among hypertensive patients of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent CHARGE study (n=21,267), blood pressure (BP) response in independent ICAPS studies (n=1,552), and ethnic validation in African Americans from GenHAT (n=5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P=1.56 x 10 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P=6 x 10 , Beta=3.09, diastolic BP response P=5 x 10 , Beta=1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients subgroup (P=2.35 x 10 , OR [95% CI] = 1.57 [1.23-1.99]). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an eQTL for the 50kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.
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http://dx.doi.org/10.1002/cpt.2355DOI Listing
July 2021

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

PLoS One 2021 2;16(7):e0253611. Epub 2021 Jul 2.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253404PMC
July 2021

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure.

J Am Coll Cardiol 2021 Jul;78(1):42-52

Department of Epidemiology, Brown University, Providence, Rhode Island, USA; Care New England, Center for Primary Care and Prevention, Pawtucket, Rhode Island, USA; Department of Family Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2021.04.085DOI Listing
July 2021

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.

Nat Commun 2021 06 28;12(1):3987. Epub 2021 Jun 28.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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http://dx.doi.org/10.1038/s41467-021-23556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190084PMC
June 2021

Variant-specific inflation factors for assessing population stratification at the phenotypic variance level.

Nat Commun 2021 06 9;12(1):3506. Epub 2021 Jun 9.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term 'variance stratification'. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We develop a procedure to compute variant-specific inflation factors, and show how it can be used for diagnosis of genetic association analyses on pooled individual level data from multiple studies. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We illustrate the variance stratification problem, its solutions, and the proposed diagnostic procedure, in simulations and in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI.
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http://dx.doi.org/10.1038/s41467-021-23655-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190158PMC
June 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Association of neighborhood physical activity opportunities with incident cardiovascular disease in the Cardiovascular Health Study.

Health Place 2021 Jun 3;70:102596. Epub 2021 Jun 3.

Urban Health Collaborative and Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA.

We determined associations of cumulative exposures to neighborhood physical activity opportunities with risk of incident cardiovascular disease (CVD). We included 3595 participants from the Cardiovascular Health Study recruited between 1989 and 1993 (mean age = 73; 60% women; 11% black). Neighborhood environment measures were calculated using Geographic Information Systems (GIS) and annual information from the National Establishment Time Series database, including the density of (1) walking destinations and (2) physical activity/recreational facilities in a 1- and 5-km radius around the respondent's home. Incident CVD was defined as the development of myocardial infarction, stroke, or cardiovascular death and associations with time to incident CVD were estimated using Cox proportional hazards models. A total of 1986 incident CVD cases occurred over a median follow-up of 11.2 years. After adjusting for baseline and time-varying individual and neighborhood-level confounding, a one standard deviation increase in walking destinations and physical activity/recreational facilities within 5 km of home was associated with a respective 7% (95% confidence interval (CI) = 0.87-0.99) and 12% (95% CI = 0.73-1.0) decreased risk of incident CVD. No significant associations were noted within a 1-km radius. Efforts to improve the availability of physical activity resources in neighborhoods may be an important strategy for lowering CVD.
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http://dx.doi.org/10.1016/j.healthplace.2021.102596DOI Listing
June 2021

Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.

Heart 2021 Jun 2. Epub 2021 Jun 2.

Cardiology Section, San Francisco VA Health Care System, San Francisco, California, USA

Objectives: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

Methods: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

Results: The cohort comprised 5795 participants (age 73±6, 42.2% male, 14.3% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69% (probable/definite) to 4.67% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88% to 3.71%. Of incident cases, about 85% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95% CI 0.23 to 0.81]).

Conclusions: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.
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http://dx.doi.org/10.1136/heartjnl-2021-319025DOI Listing
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Silent Myocardial Infarction and Subsequent Ischemic Stroke in the Cardiovascular Health Study.

Neurology 2021 May 24. Epub 2021 May 24.

Departments of Neurology and Epidemiology, University of Washington, Seattle, WA.

Objective: To test the hypothesis that silent MI is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.

Methods: The Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989-1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: non-lacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.

Results: Among 4,224 participants, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (HR, 1.51; 95% CI, 1.03-2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53-119) and long term (HR, 1.60; 95% CI, 1.04-2.44). In secondary analyses, the association between silent MI and stroke was limited to non-lacunar ischemic stroke (HR 2.40; 95% CI, 1.36-4.22).

Conclusion: In a community-based sample, we found an association between silent MI and ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000012249DOI Listing
May 2021

Longitudinal Measures of Blood Pressure and Subclinical Atrial Arrhythmias: The MESA and the ARIC Study.

J Am Heart Assoc 2021 Jun 20;10(11):e020260. Epub 2021 May 20.

Cardiovascular Division Department of Medicine University of Minnesota Medical School Minneapolis MN.

Background High blood pressure (BP) is a well-known risk factor for atrial fibrillation (AF), but a single BP measurement may provide limited information about AF risk in older adults. Methods and Results This study included 1256 MESA (Multi-Ethnic Study of Atherosclerosis) and 1948 ARIC (Atherosclerosis Risk in Communities) study participants who underwent extended ambulatory electrocardiographic monitoring and who were free of clinically detected cardiovascular disease, including AF. Using BP measurements from 6 examinations (2000-2018 in MESA and 1987-2017 in ARIC study), we calculated individual long-term mean, trend, and detrended visit-to-visit variability in systolic BP and pulse pressure for each participant. Outcomes, assessed at examination 6, included subclinical AF and supraventricular ectopy. Results from each study were combined with inverse variance-weighted meta-analysis. At examination 6, the mean age was 73 years in MESA and 79 years in ARIC study, and 4% had subclinical AF. Higher visit-to-visit detrended variability in systolic BP was associated with a greater prevalence of subclinical AF (odds ratio [OR], 1.20; 95% CI, 1.02-1.38) and with more premature atrial contractions/hour (geometric mean ratio, 1.08; 95% CI, 1.01-1.15). For pulse pressure as well, higher visit-to-visit detrended variability was associated with a greater prevalence of AF (OR, 1.18; 95% CI, 1.00-1.37). In addition, higher long-term mean pulse pressure was associated with a greater prevalence of subclinical AF (OR, 1.36; 95% CI, 1.08-1.70). Conclusions Antecedent visit-to-visit variability in systolic BP and pulse pressure, but not current BP, is associated with a higher prevalence of subclinical atrial arrhythmias. Prior longitudinal BP assessment, rather than current BP, may be more helpful in identifying older adults who are at higher risk of atrial arrhythmias.
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http://dx.doi.org/10.1161/JAHA.120.020260DOI Listing
June 2021

Association Between Myocardial Strain and Frailty in CHS.

Circ Cardiovasc Imaging 2021 May 17;14(5):e012116. Epub 2021 May 17.

Department of Epidemiology and Population Health, Stanford University, CA (A.X.T., M.C.O.).

Background: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve.

Methods: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having ≥3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography.

Results: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95% CI, 1.07-1.61] per 1-SD lower strain; =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95% CI, 1.08-1.61] per 1-SD lower strain; =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95% CI, 0.96-1.89] =0.086) and 1.58 ([95% CI, 1.11-2.27] =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95% CI, 1.81-2.66]; <0.0001).

Conclusions: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012116DOI Listing
May 2021

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

Nat Commun 2021 04 22;12(1):2329. Epub 2021 Apr 22.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.
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http://dx.doi.org/10.1038/s41467-021-22370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062567PMC
April 2021

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Am J Hum Genet 2021 05 21;108(5):874-893. Epub 2021 Apr 21.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206199PMC
May 2021

FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.

J Thromb Haemost 2021 Apr 20. Epub 2021 Apr 20.

Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

Background: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

Objectives: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

Methods: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

Results: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

Conclusion: This work provides new evidence for a role of FGL1 in hemostasis.
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http://dx.doi.org/10.1111/jth.15345DOI Listing
April 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

Nat Commun 2021 04 12;12(1):2182. Epub 2021 Apr 12.

Division of Cardiology, George Washington University School of Medicine and Healthcare Sciences, Washington, DC, USA.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
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http://dx.doi.org/10.1038/s41467-021-22339-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042019PMC
April 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Plasma epoxyeicosatrienoic acids and dihydroxyeicosatrieonic acids, insulin, glucose and risk of diabetes: The strong heart study.

EBioMedicine 2021 Apr 19;66:103279. Epub 2021 Mar 19.

Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.

Background: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians.

Methods: We measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts.

Findings: We observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose.

Interpretation: In this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2021.103279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010619PMC
April 2021