Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations.

Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy.

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage.

Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study).

Background And Purpose: Emerging evidence suggests that an underlying atrial cardiopathy may result in thromboembolism before atrial fibrillation (AF) develops. We examined the association between various markers of atrial cardiopathy and the risk of ischemic stroke.

Methods: The CHS (Cardiovascular Health Study) prospectively enrolled community-dwelling adults ≥65 years of age.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression.

Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study).

Background: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.

Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study.

Background: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs.

Methods And Results: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation.

Association of lipoprotein-associated phospholipase A and risk of incident atrial fibrillation: Findings from 3 cohorts.

Background: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A (Lp-PLA) mass and activity and incident AF has not been extensively evaluated.

Methods: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data.

New statin use and left ventricular structure: Estimating long-term associations in the Multi-Ethnic Study of Atherosclerosis (MESA).

Purpose: Only small and short-term studies have evaluated statins in relation to changes in heart structure. We estimated the association between new statin use and 10-year remodeling of the left ventricle.

Methods: The Multi-Ethnic Study of Atherosclerosis collected data on statin use over approximately 10 years, conducting cardiac magnetic resonance (CMR) imaging at baseline and the 10-year exam.

Left Ventricular Hypertrophy and Remodeling and Risk of Cognitive Impairment and Dementia: MESA (Multi-Ethnic Study of Atherosclerosis).

Limited information exists on the longitudinal association between the left ventricular (LV) structure and function and future cognitive impairment and dementia in a large population without clinically recognized cardiovascular disease at baseline. The aim of the present study was to investigate the association between cardiac structure and function and risk of dementia and cognitive impairment in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. Measures of LV structure and function were determined using magnetic resonance imaging at baseline in 4999 participants free of clinically diagnosed cardiovascular disease and dementia.

The relationship of circulating fibroblast growth factor 21 levels with incident atrial fibrillation: The Multi-Ethnic Study of Atherosclerosis.

Background And Aims: Elevated circulating levels of fibroblast growth factor 21 (FGF21) are associated with multiple cardiovascular disease (CVD) risk factors and incident events. Previous small cross-sectional studies, mainly in Chinese populations, have suggested FGF21 may play a role in the development of atrial fibrillation (AF). We therefore investigated the relationship of FGF21 levels with incident AF in participants free of clinically apparent CVD at baseline in a large, multi-ethnic cohort.

The association of estimated salt intake with blood pressure in a Viet Nam national survey.

Objective: To evaluate the association of salt consumption with blood pressure in Viet Nam, a developing country with a high level of salt consumption.

Design And Setting: Analysis of a nationally representative sample of Vietnamese adults 25-65 years of age who were surveyed using the World Health Organization STEPwise approach to Surveillance protocol. Participants who reported acute illness, pregnancy, or current use of antihypertensive medications were excluded.

Sex hormone levels and change in left ventricular structure among men and post-menopausal women: The Multi-Ethnic Study of Atherosclerosis (MESA).

Objective: Sex hormone (SH) levels may contribute to sex differences in the risk of heart failure with preserved ejection fraction (HFpEF). We examined the associations of SH levels with left ventricular mass (LVM) and mass (M):volume (V) ratio, which are risk markers for HFpEF.

Study Design: We studied 1941 post-menopausal women and 2221 men, aged 45-84 years, participating in the Multi-Ethnic Study of Atherosclerosis (MESA).

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases.

Association of Elevated NT-proBNP With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) is considered a marker that is expressed in response to myocardial strain and possibly fibrosis. However, the relationship to myocardial fibrosis in a community-based population is unknown.

Objectives: The authors evaluated the relationship between cardiac magnetic resonance (CMR) measures of fibrosis and NT-proBNP levels in the MESA (Multi-Ethnic Study of Atherosclerosis) study.

Administrative billing codes accurately identified occurrence of electrical cardioversion and ablation/maze procedures in a prospective cohort study of atrial fibrillation patients.

Background: Administrative billing codes for electrical cardioversion and ablation/maze procedures may be useful for atrial fibrillation (AF) research if the codes are accurate relative to medical record documentation.

Hypothesis: Administrative billing codes accurately identify occurrence of electrical cardioversion and ablation/maze procedures in AF patients.

Methods: We studied adults ages 30 to 84 who experienced new-onset AF between October 2001 and December 2004 in Group Health Cooperative (acquired by Kaiser Permanente in 2017), an integrated healthcare system in Washington state and northern Idaho.

GWAS of the electrocardiographic QT interval in Hispanics/Latinos generalizes previously identified loci and identifies population-specific signals.

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies.

Galectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study.

Background: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied.

Objectives: To assess the prospective association of plasma galectin-3 and the rs4644 SNP with VTE incidence.

Normal findings on noninvasive cardiac assessment and the prediction of heart failure: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background: It is unknown if normal findings on noninvasive cardiac assessment are able to identify individuals who are low risk for developing heart failure (HF).

Methods: We examined if normal findings on the routine electrocardiogram (ECG) and cardiac magnetic resonance imaging (MRI) were able to identify individuals who are low risk for developing HF in 4986 (mean age=62±10years; 52% women; 39% White; 13% Chinese-American; 26% Black; 22% Hispanic) participants from the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent HF at baseline. A normal ECG was defined as the absence of major abnormalities by Minnesota Code Classification, and a normal MRI was defined as absence of structural abnormalities and systolic dysfunction.

Atrial ectopy as a mediator of the association between race and atrial fibrillation.

Background: Blacks have a lower risk of atrial fibrillation (AF) despite having more AF risk factors, but the mechanism remains unknown. Premature atrial contraction (PAC) burden is a recently identified risk factor for AF.

Objective: The purpose of this study was to determine whether the burden of PACs explains racial differences in AF risk.

Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.

The exploding volume of whole-genome sequence (WGS) and multi-omics data requires new approaches for analysis. As one solution, we have created a cloud-based Analysis Commons, which brings together genotype and phenotype data from multiple studies in a setting that is accessible by multiple investigators. This framework addresses many of the challenges of multi-center WGS analyses, including data sharing mechanisms, phenotype harmonization, integrated multi-omics analyses, annotation, and computational flexibility.

Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.

Background: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.

Soluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study.

Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up.

Clinical characteristics and 12-month outcomes of patients with valvular and non-valvular atrial fibrillation in Kenya.

Background: Atrial fibrillation (AF) is a major contributor to the global cardiovascular disease burden. The clinical profile and outcomes of AF patients with valvular heart diseases in sub-Saharan Africa (SSA) have not been adequately described. We assessed clinical features and 12-month outcomes of patients with valvular AF (vAF) in comparison to AF patients without valvular heart disease (nvAF) in western Kenya.

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF).