DNA methylation biomarker for cumulative lead exposure is associated with Parkinson's disease.
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ABSTRACT:
SUBMITTER: Paul KC
PROVIDER: S-EPMC7983295 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
DNA methylation biomarker for cumulative lead exposure is associated with Parkinson's disease.
Paul Kimberly C KC Horvath Steve S Del Rosario Irish I Bronstein Jeff M JM Ritz Beate B
Clinical epigenetics 20210322 1
Lead, a known neurotoxicant, has previously received attention in Parkinson's disease (PD) research, but epidemiologic studies have been limited in sample size and findings are equivocal. We generated two methylation-based biomarkers for cumulative tibia and patella bone-measured lead exposure in 1528 PD patients and 1169 controls. PD status was associated with increased levels of the DNAm biomarker for tibia-lead levels. We estimated a meta-OR for PD of 1.89 per unit DNAm tibia-lead increase (9 ...[more]
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Project description:BackgroundLead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels-validated measures of cumulative exposure-require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles-obtainable via Illumina 450K or IlluminaEPIC bead-chip assays.MethodsWe developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity.FindingsParticipants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity.InterpretationDNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.
| S-EPMC7170756 | biostudies-literature
Project description:Dementia is an important consequence of Parkinson's disease (PD), with few known modifiable risk factors. Cumulative exposure to lead, at levels experienced in the community, may exacerbate PD-related neural dysfunction, resulting in impaired cognition. Among 101 persons with PD ("cases") and, separately, 50 persons without PD ("controls"), we evaluated cumulative lead exposure, gauged by tibia and patella bone lead concentrations, in relation to cognitive function, assessed using a telephone battery developed and validated in a separate sample of PD patients. We also assessed the interaction between lead and case-control status. After multivariable adjustment, higher tibia bone lead concentration among PD cases was associated with worse performance on all of the individual telephone tests. In particular, tibia lead levels corresponded to significantly worse performance on a telephone analog of the Mini-Mental State Examination and tests of working memory and attention. Moreover, higher tibia bone lead concentration was associated with significantly worse global composite score encompassing all the cognitive tests (P = 0.04). The magnitude of association per standard deviation increment in tibia bone lead level was equivalent to the difference in global scores among controls in our study, who were approximately 7 years apart in age. The tibia lead-cognition association was notably stronger within cases than within controls (P(difference) = 0.06). Patella bone lead concentration was not consistently associated with performance on the tests. These data provide evidence suggesting that cumulative exposure to lead may result in worsened cognition among persons with PD.
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Project description:Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 (n = 749) and 15 (n = 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 μg/m3/day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 μg/m3/day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 μg/m3/day) was associated with a -0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: -0.0732, 0.0158, p = 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 μg/m3/day) was associated with a -0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.3038, 0.0095, p = 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a -0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.043, -0.005, p = 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment.
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Project description:We performed a genome-wide DNA methylation study in induced pluripotent stem cells (IPSC)-derived dopaminergic neurons (DAn) generated from keratinocytes of monogenic and sporadic Parkinson disease (PD) patients as well as of healthy subjects. We observed extensive DNA methylation changes in DAn from PD patients. These changes were neither present in the original keratinocytes nor in the undifferentiated IPSCs, suggesting latent molecular defects in PD keratinocytes that are manifested only upon differentiation into DAn. We also found that enhancers showing abnormal DNA hypermethylation in PD were enriched for binding sites of transcription factors such as FOXA1, NR3C1, HNF4A and FOSL2 which are involved in the survival of DAn and showed reduced expression. These data suggest that aberrant epigenomic remodeling of IPSC-derived DAn in PD is mediated by the down-regulation of key transcription factors. Our study suggests that future cell replacement strategies should pay careful attention to the correct epigenomic status of the reprogrammed cells, especially when using patient own skin cells.
2015-12-01 | GSE51921 | GEO
Project description:BackgroundThe epigenome may reflect Parkinson's disease (PD) risk, which serves as a point of convergence of genetic and environmental risk factors. Here, we investigate whether blood DNA methylation (DNAm) markers are associated with PD risk.MethodsWe selected 12 plasma proteins known as predictors of cardiovascular conditions and mortality to evaluate their effects on PD risk in a case-control study. In lieu of protein level measures, however, we assessed the influence of their DNAm surrogates. Primary analysis was restricted to 569 PD patients and 238 controls with DNAm data available. Using univariate logistic regression, we evaluated associations between the DNAm markers and PD.ResultsOf the 12 DNAm surrogates, the most robustly associated were DNAm EFEMP-1 and DNAm CD56, which were associated with PD with and without controlling for blood cell composition. DNAm EFEMP-1 was associated with a decreased risk of PD (OR = 0.83 per SD, 95% CI = 0.70, 0.98) whereas DNAm CD56 was associated with an increased risk of PD (OR = 1.41, 95% CI = 1.11, 1.79).ConclusionsSeveral DNAm markers, selected as part of a panel to track cardiovascular outcomes and mortality, were associated with PD risk. DNAm markers may inform of factors that are affected differentially in early PD patients compared with controls.
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