Protein quantitative trait locus analysis in African American and non-Hispanic White individuals.

Background: Substantial efforts have been dedicated to exploring the link between genetic regulation and the proteome, informing studies of complex trait mechanisms. Most of these efforts have been limited to populations of European ancestry.

Results: We conduct an Olink protein quantitative trait locus (pQTL) analysis on 1245 proteins involving 1033 self-identified African American (AA) and 1764 non-Hispanic White (NHW) participants from the Women's Health Initiative and Framingham Heart Study.

Integrating Whole Genome and Transcriptome Sequencing to Characterize the Genetic Architecture of Isoform Variation and its Implications for Health and Disease.

We created a comprehensive whole blood splice variation quantitative trait locus (sQTL) resource by analyzing isoform expression ratio (isoform-to-gene) in Framingham Heart Study (FHS) participants (discovery: n=2,622; validation: n=1,094) with whole genome (WGS) and transcriptome sequencing (RNA-seq) data. External replication was conducted using WGS and RNA-seq from the Jackson Heart Study (JHS, n=1,020). We identified over 3.

Plasma Protein Biomarkers of Spirometry Measures of Impaired Lung Function.

Background: Impaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders.

Research Question: Can circulating protein biomarkers of pulmonary function provide insight into the pathophysiologic features of lung function impairment and links to comorbidities?

Study Design And Methods: We analyzed plasma levels of 2,922 proteins in 32,493 UK Biobank participants (53% female; mean [SD] age, 57 [8] years) to investigate their associations with spirometry measures of lung function (FEV, FVC, FEV to FVC ratio), and with obstructive (n = 4,713) and restrictive (n = 3,886) spirometry patterns. Significant protein signatures were annotated functionally and validated externally in 740 Framingham Heart Study (FHS) participants.

Expression quantitative trait locus mapping of extracellular microRNAs in human plasma.

MicroRNAs, crucial in regulating protein-coding gene expression, are implicated in various diseases. We performed a genome-wide association study of plasma miRNAs (ex-miRNAs) in 3,743 Framingham Heart Study (FHS) participants and identified 1,027 ex-miRNA-eQTLs (exQTLs) for 37 ex-miRNAs, with 55% replication in an independent study. Colocalization analyses suggested potential genetic coregulation of ex-miRNAs with whole blood mRNAs.

Impaired kidney function, cerebral small vessel disease and cognitive disorders: the Framingham Heart Study.

Background And Hypothesis: It remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants.

Methods: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments.

Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.

Background: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.

Methods: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.

Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population.

Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma.

Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases.

Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs).

Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study.

Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.

Integrative Mendelian randomization reveals the soluble receptor for advanced glycation end products as protective in relation to rheumatoid arthritis.

Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations.

Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study.

Background: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone.

Methods: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871).

Transcriptome-wide association study of circulating IgE levels identifies novel targets for asthma and allergic diseases.

Measurement of circulating immunoglobulin E (IgE) concentration is helpful for diagnosing and treating asthma and allergic diseases. Identifying gene expression signatures associated with IgE might elucidate novel pathways for IgE regulation. To this end, we performed a discovery transcriptome-wide association study to identify differentially expressed genes associated with circulating IgE levels in whole-blood derived RNA from 5,345 participants in the Framingham Heart Study across 17,873 mRNA gene-level transcripts.

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

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS.

Systemic Inflammation is Associated with Cardiometabolic Risk Factors and Clinical Outcomes.

Purpose: Assessing an individual's systemic inflammatory state is vital to understand inflammation's role in cardiometabolic diseases and identify those at the greatest risk of disease. We generated global inflammation scores and investigated their associations with cardiometabolic risk factors and adverse outcomes.

Patients And Methods: Aggregate Inflammation Scores (AIS) and Principal Component Analysis (PCA) scores were generated for 7287 Framingham Heart Study participants using up to 26 inflammation-related proteins, with higher scores reflecting a pro-inflammatory milieu.

The inflammatory proteome, obesity, and medical weight loss and regain in humans.

Objective: Weight regain occurs after medical weight loss via mechanisms of post-weight-loss "metabolic adaptation." The relationship of inflammatory proteins with weight loss/regain was studied to determine a role for inflammation in metabolic adaptation.

Methods: Seventy-four proteins central to inflammation and immune regulation (Olink) were analyzed in plasma from up to 490 participants in a trial of medical weight-loss maintenance.