DNA Methylation and 28-Year Incidence of Kidney Disease in Type 1 Diabetes.

Background: Prior epigenome-wide association studies (EWAS) of DNA methylation (DNAm) and diabetic kidney disease (DKD) in type 1 diabetes (T1D) focused on advanced disease. We hypothesized DNAm is a biomarker of earlier manifestations of DKD, microalbuminuria (MA) and overt nephropathy (ON), independent of traditional risk factors in T1D. We thus performed separate EWAS of 28-year MA and ON in the Pittsburgh Epidemiology of Diabetes Complications (EDC) T1D cohort.

Associations of interstitial lung disease subtype and CT pattern with lung function and survival.

Background: Prior work suggests different interstitial lung diseases (ILDs) that share the radiological usual interstitial pneumonia (UIP) pattern have an overall worse prognosis. However, epidemiological data with longitudinal sampling and replication remains lacking.

Methods: Data was used from the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) (n=932) and a meta-cohort of ILD research studies (n=1579).

Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.

Background: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants.

DNA methylation and 28 year incidence of two neuropathy phenotypes in type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications cohort study.

Aims/hypothesis: Diabetic peripheral neuropathy (DPN) and neuropathic pain (NP) are common complications of type 1 diabetes that can greatly affect quality of life. Studying DNA methylation (DNAm) may help identify potential therapeutic targets; however, epigenome-wide association studies (EWAS) of DPN and NP are lacking. We thus performed prospective EWAS of 28 year DPN and NP incidence in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (<17 years) type 1 diabetes.

Alterations in DNA Methylation, Proteomic, and Metabolomic Profiles in African Ancestry Populations with APOL1 Risk Alleles.

Key Points: We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which variants may be linked to kidney disease. We report distinct methylation profiling between risk allele carriers and noncarriers, many near gene family. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers.

Cross-Ancestry Comparison of Aptamer and Antibody Proteomics Measures.

Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants (pQTL) and phenotypes. Here, we examined 2,157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1,930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2,157 proteins followed a bimodal distribution (median r=0.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program.

Metabolomic profiles of infants classified as sudden infant death syndrome: a case-control analysis.

Background: Sudden Infant Death Syndrome (SIDS) is a leading cause of postneonatal mortality. The absence of specific biomarkers of SIDS diagnosis and risk leaves a significant gap in understanding SIDS pathophysiology. Metabolomics offers an avenue to better understand SIDS biology and identifying potential biomarkers.

Rare variants and survival of patients with idiopathic pulmonary fibrosis.

Background: The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival.

Proteomics of left ventricular structure in the Multi-Ethnic Study of Atherosclerosis.

Aims: Proteomic profiling offers an expansive approach to biomarker discovery and mechanistic hypothesis generation for LV remodelling, a critical component of heart failure (HF). We sought to identify plasma proteins cross-sectionally associated with left ventricular (LV) size and geometry in a diverse population-based cohort without known cardiovascular disease (CVD).

Methods And Results: Among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we quantified plasma abundances of 1305 proteins using an aptamer-based platform at exam 1 (2000-2002) and exam 5 (2010-2011) and assessed LV structure by cardiac magnetic resonance (CMR) at the same time points.

Single-Ancestry versus Multi-Ancestry Polygenic Risk Scores for CKD in Black American Populations.

Key Points: The predictive performance of an African ancestry–specific polygenic risk score (PRS) was comparable to a European ancestry–derived PRS for kidney traits. However, multi-ancestry PRSs outperform single-ancestry PRSs in Black American populations. Predictive accuracy of PRSs for CKD was improved with the use of race-free eGFR.

Organ weights and length anthropometry measures at autopsy for sudden infant death syndrome cases and other infant deaths in the Chicago infant mortality study.

Organ weights are a possible diagnostic or pathophysiological clue to distinguishing sudden infant death syndrome (SIDS) cases from other infant deaths but suffer from major confounding. Using autopsy data from the Chicago Infant Mortality Study, a majority African-American case-control study of deceased infants under 1 year conducted 1993-96, we assessed differences in the weights of brain, thymus, kidneys, lungs, liver, spleen, total body, and four length anthropometry measures in SIDS-diagnosed infants compared to controls. Using exact and coarsened matching, we ran Bayesian linear models with these anthropometry outcomes and repeated the analyses substituting the corresponding fitted allometrically-scaled organ weight indices to account for body size.

Biological Age, Chronological Age, and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis.

Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis discovery cohort.

Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification.

Background And Aims: Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed.

Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program.

An Epigenome-Wide Association Study of DNA Methylation and Proliferative Retinopathy over 28 Years in Type 1 Diabetes.

Purpose: To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D).

Design: Prospective observational cohort study.

Participants: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D.

Leveraging type 1 diabetes human genetic and genomic data in the T1D knowledge portal.

To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.

DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study.

Background: The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.

Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the MESA.

Background: Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown.

Methods: Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255).

Associations between Ambient Air Pollutants and Clonal Hematopoiesis of Indeterminate Potential.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related somatic mutation associated with incident hematologic cancer. Environmental stressors which, like air pollution, generate oxidative stress at the cellular level, may induce somatic mutations and some mutations may provide a selection advantage for persistence and expansion of specific clones.

Methods: We used data from the Multi-Ethnic Study of Atherosclerosis (MESA) N = 4,379 and the Women's Health Initiative (WHI) N = 7,701 to estimate cross-sectional associations between annual average air pollution concentrations at participant address the year before blood draw using validated spatiotemporal models.

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. To identify and validate molecular determinants of IPF survival.