A methylation risk score for chronic kidney disease: a HyperGEN study.

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

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. After detailed analysis and adjustment for potential confounders, we found that matched SIDS infants were generally bigger than controls, with higher mean brain, liver, spleen, thymus, lung, and total body weights, and higher mean head and chest circumference, crown-heel, crown-rump lengths. SIDS infants also had higher mean thymus, liver, spleen, lung and total body weight indices. The association with thymus weight was proportionately greater in magnitude than any other outcome measure and independent of body size. The results of these more detailed analyses are consistent with recent findings from other studies with differing racial compositions, and substantially confirm the primary organ sites for more detailed mechanistic research into the biological dysregulation contributing to underlying pathophysiology of SIDS.

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

RATIONALE: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. OBJECTIVES: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. METHODS: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis (IPF) discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease (COPD) cohort. A proteomic-based measure of biological age was constructed and survival analysis performed assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. RESULTS: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the IPF discovery cohort (n=874), with nineteen remaining significant mediators of this relationship in the ILD validation cohort (n=983) and one mediating this relationship in the COPD cohort. Latent transforming growth factor beta binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. CONCLUSIONS: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

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. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes ( CFHR1 and LRP6 ) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.

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. METHODS: In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events); secondary outcomes included 4-year HF (183 events), HF with reduced ejection fraction (137 events), and HF with preserved ejection fraction (165 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multi-protein risk models was compared to the PCP-HF risk score. RESULTS: Over 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10-5. After adjustment for covariates including N-terminal pro-B-type natriuretic peptide, 17 proteins remained associated at P < 1 × 10-5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C-statistic (95% confidence interval [CI]) for the 48-protein model in CRIC was 0.790 (0.735, 0.844) vs. 0.703 (0.644, 0.762) for the PCP-HF model (P = .001). C-statistic (95% CI) for the protein model in ARIC was 0.747 (0.707, 0.787). CONCLUSIONS: Large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population.

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. Methods: Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n = 265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed. Main Outcome Measures: Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up). Results: PDR incidence was 53% over 28-years' follow-up. Greater DNAm of cg27512687 (KIF16B) was associated with reduced PDR incidence (P = 6.3 × 10-9; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs (P < 5 × 10-8) were identified. Mendelian randomization analysis using the sentinel meQTL as the instrumental variable supported a potentially causal association between cg27512687 and PDR. Cg27512687 was also associated with lower pulse rate and albumin excretion rate and higher estimated glomerular filtration rate, but its association with PDR remained independently significant after adjustment for those factors. In regional analyses, DNAm of FUT4, FKBP1A, and RIN2 was also associated with PDR incidence. Conclusions: DNA methylation of KIF16B, FUT4, FKBP1A, and RIN2 was associated with PDR incidence, supporting roles for epigenetic regulation of iron clearance, developmental pathways, and autophagy in PDR pathogenesis. Further study of those loci may provide insight into novel targets for interventions to prevent or delay PDR in T1D. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.