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.

Metabolites Associated with Polygenic Risk of Breast Cancer.

While hundreds of germline genetic variants have been associated with breast cancer risk, the mechanisms underlying the impacts of most of these variants on breast cancer remain uncertain. Metabolomics may offer valuable insights into the mechanisms underlying genetic risks of breast cancer. Among 143 cancer-free female participants, we used linear regression analyses to explore associations between the genetic risk of breast cancer, as determined by a previously developed polygenic risk score (PRS) that included 266 single-nucleotide polymorphisms (SNPs), and 223 measures of metabolites obtained from blood samples using nuclear magnetic resonance (NMR). A false discovery rate of 10% was applied to account for multiple comparisons. PRS was statistically significantly associated with 45 metabolite measures. These were primarily measures of very low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs), including triglycerides, cholesterol, and phospholipids. For example, the strongest effect was observed with the percent ratio of medium VLDL triglycerides to total lipids (0.53 unit increase in mean-standardized ln-transformed percent ratio per unit increase in PRS; q = 0.1). While larger-scale studies are needed to confirm these results, this exploratory study presents biologically plausible findings that are consistent with previously reported associations between lipids and breast cancer risk. If confirmed, these lipids could be targeted for lifestyle and pharmaceutical interventions among women at increased genetic risk of breast cancer.

Obstructive sleep apnea severity, circulating biomarkers, and cancer risk.

STUDY OBJECTIVES: To determine if obstructive sleep apnea (OSA) severity and/or biomarkers of inflammation/angiogenesis are associated with incident cancer in this clinical cohort. METHODS: Consenting adult patients at the University of British Columbia Hospital between 2003-2014 completed a questionnaire about their medical history and sleep habits prior to undergoing a polysomnogram (PSG). Blood samples were collected the morning after PSG and processed for biomarkers of inflammation and angiogenesis. The clinical, PSG, and biomarker data were linked to the British Columbia Cancer Registry to ascertain incident cancer diagnoses. Cox proportional hazard regression were used to assess the association between OSA severity and biomarker concentrations with cancer risk. RESULTS: A total of 1,990 patients were included in the analysis with a mean follow-up time of 12.8 years; 181 of them (9.1%) developed cancer after PSG. OSA severity was significantly associated with cancer risk after controlling for relevant covariates (hazard ratio (HR) = 1.08 per 10 events/h apnea-hypopnea index (AHI) increase, CI = 1.02-1.15, p=0.015). In an exploratory analysis, two biomarkers were significantly associated with an increased cancer risk after controlling for relevant covariates (HR per interquartile range (IQR) pg/mL increase of endostatin = 1.45, CI = 1.12-1.87, p=0.01 and HR for IQR pg/mL increase of VCAM-1 = 1.48, CI = 1.04-2.11, p=0.03, respectively). CONCLUSIONS: OSA severity was an independent risk factor for cancer. Furthermore, two circulating markers were significantly associated with cancer risk. If these preliminary findings can be reproduced in other cohorts, biomarkers could potentially be used to prognosticate OSA patients with respect to cancer risk.

Diet Quality and Epigenetic Aging in the Women's Health Initiative.

BACKGROUND: Higher diet quality scores are associated with a lower risk for many chronic diseases and all-cause mortality; however, it is unclear if diet quality is associated with aging biology. OBJECTIVE: This study aimed to examine the association between diet quality and a measure of biological aging known as epigenetic aging. DESIGN: A cross-sectional data analysis was used to examine the association between three diet quality scores based on self-reported food frequency questionnaire data and five measures of epigenetic aging based on DNA methylation (DNAm) data from peripheral blood. PARTICIPANTS/SETTING: This study included 4,500 postmenopausal women recruited from multiple sites across the United States (1993-98), aged 50 to 79 years, with food frequency questionnaire and DNAm data available from the Women's Health Initiative baseline visit. MAIN OUTCOME MEASURES: Five established epigenetic aging measures were generated from HumanMethylation450 Beadchip DNAm data, including AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno, AgeAccelGrim, and DunedinPACE. STATISTICAL ANALYSES PERFORMED: Linear mixed models were used to test for associations between three diet quality scores (Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores) and epigenetic aging measures, adjusted for age, race and ethnicity, education, tobacco smoking, physical activity, Women's Health Initiative substudy from which DNAm data were obtained, and DNAm-based estimates of leukocyte proportions. RESULTS: Healthy Eating Index, Dietary Approaches to Stop Hypertension, and alternate Mediterranean diet scores were all inversely associated with AgeAccelPheno, AgeAccelGrim, and DunedinPACE (P < 0.05), with the largest effects with DunedinPACE. A one standard deviation increment in diet quality scores was associated with a decrement (ß ± SE) in DunedinPACE z score of -0.097 ± 0.014 (P = 9.70 x 10-13) for Healthy Eating Index, -0.107 ± 0.014 (P = 1.53 x 10-14) for Dietary Approaches to Stop Hypertension, and -0.068 ± 0.013 (P = 2.31 x 10-07) for the alternate Mediterranean diet. CONCLUSIONS: In postmenopausal women, diet quality scores were inversely associated with DNAm-based measures of biological aging, particularly DunedinPACE.

Stressful life events, social support, and epigenetic aging in the Women's Health Initiative.

BACKGROUND: Elevated psychosocial stress has been linked with accelerated biological aging, including composite DNA methylation (DNAm) markers that predict aging-related outcomes ("epigenetic age"). However, no study has examined whether stressful life events (SLEs) are associated with epigenetic age acceleration in postmenopausal women, an aging population characterized by increased stress burden and disease risk. METHODS: We leveraged the Women's Health Initiative, a large muti-ancestry cohort of postmenopausal women with available psychosocial stress measures over the past year and epigenomic data. SLEs and social support were ascertained via self-report questionnaires. Whole blood DNAm array (450 K) data were used to calculate five DNAm-based predictors of chronological age, health span and life span, and telomere length (HorvathAge, HannumAge, PhenoAge, GrimAge, DNAmTL). RESULTS: After controlling for potential confounders, higher SLE burden was significantly associated with accelerated epigenetic aging, as measured by GrimAge (ß: 0.34, 95% CI: 0.08, 0.59) and DNAmTL (ß: -0.016, 95% CI: -0.028, -0.004). Exploratory analyses showed that SLEs-GrimAge associations were stronger in Black women as compared to other races/ethnicities and in those with lower social support levels. In women with lower social support, SLEs-DNAmTL associations showed opposite association in Hispanic women as compared to other race/ethnicity groups. CONCLUSIONS: Our findings suggest that elevated stress burden is associated with accelerated epigenetic aging in postmenopausal women. Lower social support and/or self-reported race/ethnicity may modify the association of stress with epigenetic age acceleration. These findings advance understanding of how stress may contribute to aging-related outcomes and have important implications for disease prevention and treatment in aging women.

Strain-level characterization of health-associated bacterial consortia that colonize the human gut during infancy.

Background: The human gut microbiome develops rapidly during infancy, a key window of development coinciding with maturation of the adaptive immune system. However, little is known of the microbiome growth dynamics over the first few months of life and whether there are any generalizable patterns across human populations. We performed metagenomic sequencing on stool samples (n=94) from a cohort of infants (n=15) at monthly intervals in the first six months of life, augmenting our dataset with seven published studies for a total of 4,441 metagenomes from 1,162 infants. Results: Strain-level de novo analysis was used to identify 592 of the most abundant organisms in the infant gut microbiome. Previously unrecognized consortia were identified which exhibited highly correlated abundances across samples and were composed of diverse species spanning multiple genera. Analysis of a cohort of infants with cystic fibrosis identified one such novel consortium of diverse Enterobacterales which was positively correlated with weight gain. While all studies showed an increased community stability during the first year of life, microbial dynamics varied widely in the first few months of life, both by study and by individual. Conclusion: By augmenting published metagenomic datasets with data from a newly established cohort we were able to identify novel groups of organisms that are correlated with measures of robust human development. We hypothesize that the presence of these groups may impact human health in aggregate in ways that individual species may not in isolation.

Agreement between self-report and administrative health data on occurrence of non-cancer chronic disease among participants of the BC generations project.

Population-based studies of non-cancer chronic disease often rely on self-reported data for disease diagnosis, which may be incomplete, unreliable and suffer from bias. Recently, the British Columbia Generations Project (BCGP; n = 29,736) linked self-reported chronic disease history data to a Chronic Disease Registry (CDR) that applied algorithms to administrative health data to ascertain diagnoses of multiple chronic diseases in the Province of British Columbia. For the 10 diseases captured by both self-report and the CDR, including asthma, chronic obstructive pulmonary disease (COPD), diabetes, hypertension, multiple sclerosis, myocardial infarction, osteoarthritis, osteoporosis, rheumatoid arthritis, and stroke, we calculated Cohen's kappa coefficient to examine concordance of chronic disease status (i.e., ever/never diagnosed) between the data sources. Using CDR data as the gold standard, we also calculated sensitivity, specificity, and positive-predictive value (PPV) for self-reported chronic disease occurrence. The prevalence of each chronic disease was similar across both data sources. Substantial levels of concordance (0.66-0.73) and moderate to high sensitivities (0.64-0.92), specificities (0.98-0.99) and PPVs (0.55-0.84) were observed for diabetes, hypertension, multiple sclerosis, and myocardial infarction. We did observe degree of concordance to vary by age, sex, body mass index (BMI), health perception, and ethnicity across most of the chronic diseases that were evaluated. While administrative health data are imperfect, they are less likely to suffer from bias, making them a reasonable gold standard. Our results demonstrate that for at least some chronic diseases, self-report may be a reasonable method for case ascertainment. However, characteristics of the study population will likely have impacts on the quality of the data.