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Smoking-associated AHRR demethylation in cord blood DNA: impact of CD235a+ nucleated red blood cells.

ABSTRACT: BACKGROUND:Numerous studies have demonstrated that DNA methylation levels in the aryl hydrocarbon receptor repressor (AHRR) gene measured in cord blood are significantly associated with prenatal tobacco smoke exposure and can be used as a fetal exposure biomarker. The mechanism driving this demethylation has not been determined and it is unclear if all cord blood cell types are impacted. Nucleated red blood cells (nRBCs/CD235a+?cells) are developmentally immature RBCs that display genome-wide hypomethylation and are observed at increased frequency in the cord blood of smoking mothers. We tested if AHRR methylation levels in CD235a+?nRBCs or nRBC counts influenced AHRR methylation in whole cord blood. METHODS:Cord blood was collected from smoking (n?=?34) and nonsmoking (n?=?19) mothers and DNA was prepared from whole cord blood, isolated CD235a+?nRBCs, and CD14+ monocytes. AHRR methylation in cord blood DNA was measured using Illumina 850K arrays (cg05575921, chr5:373378). Pyrosequencing was used to compare methylation levels among cord blood, CD235a+, and CD14+ cells. We measured nRBC percentages using conventional complete blood counts and estimated percent nRBCs by a deconvolution model. RESULTS:Methylation levels in AHRR were significantly lower in nRBCs relative to whole cord blood and CD14+ monocytes. While AHRR methylation levels in the cell types were significantly correlated across all subjects, methylation values at the chr5:373378 CpG averaged 14.6% lower in nRBCs (range 0.4 to 24.8%; p?=?3.8E-13) relative to CD14+, with nonsmokers showing a significantly greater hypomethylation (-?4.1%, p?=?1.8E-02). Methylation level at the AHRR chr5:373378 CpG was strongly associated with self-reported smoking in both CD14+ monocytes (t test p?=?5.7E-09) and nRBCs (p?=?4.8E-08), as well as cotinine levels (regression p?=?1.1E-07 and p?=?3.6E-04, respectively). For subjects with whole blood 850K data, robust linear regression models adjusting for estimated cell type composition, either including nRBCs counts or estimates, modestly increased the association between smoking and cg05575921 methylation. CONCLUSIONS:Prenatal smoke exposure was highly significantly associated with AHRR methylation in cord blood, CD14+ monocytes, and CD235a+?nRBCs. AHRR methylation levels in nRBCs and nRBC counts had minimal effect on cord blood methylation measurements. However, regression models using estimated nRBCs or actual nRBC counts outperformed those lacking these covariates.

SUBMITTER: Bergens MA

PROVIDER: S-EPMC6558773 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Smoking-associated AHRR demethylation in cord blood DNA: impact of CD235a+ nucleated red blood cells.

Bergens Matthew A MA Pittman Gary S GS Thompson Isabel J B IJB Campbell Michelle R MR Wang Xuting X Hoyo Cathrine C Bell Douglas A DA

Clinical epigenetics 20190610 1

<h4>Background</h4>Numerous studies have demonstrated that DNA methylation levels in the aryl hydrocarbon receptor repressor (AHRR) gene measured in cord blood are significantly associated with prenatal tobacco smoke exposure and can be used as a fetal exposure biomarker. The mechanism driving this demethylation has not been determined and it is unclear if all cord blood cell types are impacted. Nucleated red blood cells (nRBCs/CD235a+ cells) are developmentally immature RBCs that display genome ...[more]

PMID: 31182156

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Project description:BackgroundLittle is known about risk factors associated with out-of-hospital outcomes in survivors of critical illness. We hypothesized that the presence of nucleated red blood cells in patients who survived critical care would be associated with adverse outcomes following hospital discharge.MethodsWe performed a two-center observational cohort study of patients treated in medical and surgical intensive care units in Boston, Massachusetts. All data were obtained from the Research Patient Data Registry at Partners HealthCare. We studied 2878 patients, age???18 years, who received critical care between 2011 and 2015 and survived hospitalization. The exposure of interest was nucleated red blood cells occurring from 2 days prior to 7 days after critical care initiation. The primary outcome was mortality in the 90 days following hospital discharge. Secondary outcome was unplanned 30-day hospital readmission. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both nucleated red blood cells and outcome. Adjustment included age, race (white versus nonwhite), gender, Deyo-Charlson Index, patient type (medical versus surgical), sepsis and acute organ failure.ResultsIn patients who received critical care and survived hospitalization, the absolute risk of 90-day postdischarge mortality was 5.9%, 11.7%, 15.8% and 21.9% in patients with 0/?l, 1-100/?l, 101-200/?l and more than 200/?l nucleated red blood cells respectively. Nucleated red blood cells were a robust predictor of postdischarge mortality and remained so following multivariable adjustment. The fully adjusted odds of 90-day postdischarge mortality in patients with 1-100/?l, 101-200/?l and more than 200/?l nucleated red blood cells were 1.77 (95% CI, 1.23-2.54), 2.51 (95% CI, 1.36-4.62) and 3.72 (95% CI, 2.16-6.39) respectively, relative to patients without nucleated red blood cells. Further, the presence of nucleated red blood cells is a significant predictor of the odds of unplanned 30-day hospital readmission.ConclusionIn critically ill patients who survive hospitalization, the presence of nucleated red blood cells is a robust predictor of postdischarge mortality and unplanned hospital readmission.

Project description:Aryl-hydrocarbon receptor repressor (AHRR) hypomethylation in peripheral blood is tightly linked with tobacco smoking and lung cancer. Here, we investigated AHRR methylation in non-Hodgkin lymphoma (NHL), a non-smoking-associated cancer. In a case-cohort study within the population-based Danish Diet, Cancer and Health cohort, we measured AHRR (cg23576855) methylation in prediagnostic blood from 161 participants who developed NHL within 13.4 years of follow-up (median: 8.5 years), with a comparison group of 164 randomly chosen participants. We measured DNA-methylation levels using bisulfite pyrosequencing and estimated incidence rate ratios (IRR) using Cox proportional hazards models with adjustment for baseline age, sex, educational level, smoking status, body mass index, alcohol intake, physical activity, and diet score. Global DNA-methylation levels were assessed by long interspersed nucleotide element 1 (LINE-1) analysis. Overall, the IRR for AHRR hypomethylation (lowest vs. other quartiles) was 2.52 [95% confidence interval (CI), 1.24-5.15]. When stratified according to time between blood draw and diagnosis, low AHRR methylation levels were associated with a future diagnosis of NHL [IRR: 4.50 (95% CI, 1.62-12.50) at 0-<5 years, 7.04 (95% CI, 2.36-21.02) at 5-<10 years, and 0.56 (95% CI, 0.21-1.45) at ≥10 years]. There was no association between global DNA-methylation levels and risk of NHL. Our results show that AHRR hypomethylation in blood leukocytes is associated with a higher risk of NHL in a time-dependent manner, suggesting that it occurs as a response to tumor development.SignificanceOur population-based study demonstrated that lower AHRR methylation levels in peripheral blood leukocytes were associated with an increased risk of NHL. This association was independent of tobacco smoking, sex, and lifestyle characteristics, but was highly dependent on time to diagnosis. These findings highlight the potential of AHRR methylation as a biomarker for NHL risk, effective up to 10 years after blood draw.

Dataset Information

Smoking-associated AHRR demethylation in cord blood DNA: impact of CD235a+ nucleated red blood cells.

Publications

Smoking-associated AHRR demethylation in cord blood DNA: impact of CD235a+ nucleated red blood cells.

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