scholarly journals DNA methylation as a marker for prenatal smoke exposure in adults

2017 ◽  
Author(s):  
R.C. Richmond ◽  
M. Suderman ◽  
R. Langdon ◽  
C.L. Relton ◽  
Smith G. Davey
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Smoke Exposure ◽  
P Value ◽  
Prenatal Smoking ◽  
Cpg Sites ◽  
Smoking In Pregnancy ◽  
Parents And Children ◽  
Avon Longitudinal Study ◽  
Methylation Signal

AbstractPrenatal cigarette smoke is an environmental stressor that has a profound effect on DNA methylation in the exposed offspring. We have previously shown that some of these effects persist throughout childhood and into adolescence. Of interest is whether these signals persist into adulthood.We conducted an analysis to investigate associations between reported maternal smoking in pregnancy and DNA methylation in peripheral blood of women in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=754; mean age 30 years). We observed associations at 15 CpG sites in 11 gene regions, MYO1G, FRMD4A, CYP1A1, CNTNAP2, ARL4C, AHRR, TIFAB, MDM4, AX748264, DRD1, FTO (FDR < 5%). All but two of these CpG sites have previously been identified in relation to prenatal smoke exposure in the offspring at birth and the majority showed persistent hypermethylation among the offspring of smokers.We confirmed that most of these associations were not driven by own smoking and that they were still present 18 years later (N = 656; mean age 48 years). In addition, we replicated findings of a persistent methylation signal related to prenatal smoke exposure in peripheral blood among men in the ALSPAC cohort (N = 230; mean age 53 years). For both participant groups, there was a strong signal of association above that expected by chance at CpG sites previously associated with prenatal smoke exposure in newborns (Wilcoxon rank sum p-value < 2.2 × 10−4). Furthermore, we found that a prenatal smoking score, derived by combining methylation values at these CpG sites, could predict whether the mothers of the ALSPAC women smoked during pregnancy with an AUC 0.69 (95% 0.67, 0.73).

scholarly journals Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies

2021 ◽  
Author(s):  
Alexandre A. Lussier ◽  
Yiwen Zhu ◽  
Brooke J. Smith ◽  
Andrew J. Simpkin ◽  
Andrew D.A.C. Smith ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Childhood Adversity ◽  
Reference Points ◽  
Time Dependent ◽  
P Value ◽  
Prenatal Smoking ◽  
Parents And Children ◽  
Successful Replication ◽  
The Impact

ABSTRACTIntroductionBiomedical research has grown increasingly cooperative, with several large consortia compiling and sharing epigenomic data. Since data are typically preprocessed by consortia prior to distribution, the implementation of new pipelines can lead to different versions of the same dataset. Analytic frameworks also constantly evolve to incorporate cutting-edge methods and shifting best practices. However, it remains unknown how differences in data and analytic versions alter the results of epigenome-wide analyses, which has broad implications for the replicability of epigenetic associations. Thus, we assessed the impact of these changes using a subsample of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.MethodsWe analyzed two versions of DNA methylation data, processed using separate preprocessing and analytic pipelines, to examine associations between childhood adversity and prenatal smoking exposure on DNA methylation at age 7. We performed two sets of analyses: (1) epigenome-wide association studies (EWAS); (2) Structured Life Course Modeling Approach (SLCMA), a two-stage method that models time-dependent effects. We also compared results from the SLCMA using more recent methodological recommendations.ResultsDifferences between ALSPAC data versions impacted both EWAS and SLCMA analyses, yielding different sets of associations at conventional p-value thresholds. However, the magnitude and direction of associations was generally consistent between data versions, regardless of significance thresholds. Updating the SLCMA analytic version similarly altered top associations, but time-dependent effects remained concordant.ConclusionsChanges to data and analytic versions influenced the results of epigenome-wide studies, particularly when using p-value thresholds as reference points for successful replication and stability.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

2008 ◽  
Vol 31 (4) ◽  
pp. 11
Author(s):  
Manda Ghahremani ◽  
Courtney W Hannah ◽  
Maria Peneherrera ◽  
Karla L Bretherick ◽  
Margo R Fluker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Premature Ovarian Failure ◽  
Promoter Region ◽  
Gene Promoter ◽  
Ovarian Failure ◽  
P Value ◽  
Epigenetic Alterations ◽  
Methylation Array ◽  
Cpg Sites ◽  
Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

scholarly journals Diet quality associated peripheral blood DNA methylation signatures

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Jiantao Ma ◽  
Casey Rebholz ◽  
Kim Braun ◽  
Lindsay Reynolds ◽  
Stella Aslibekyan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Diet Quality ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Healthy Eating Index ◽  
European Ancestry ◽  
P Value ◽  
Primary Analysis ◽  
Habitual Diet ◽  
Methylation Patterns

AbstractLeukocyte DNA methylation patterns associated with habitual diet may reveal molecular mechanisms involved in the pathogenesis of diet-related chronic diseases and highlight targets for prevention and treatment. We aimed to examine peripheral blood derived leukocyte DNA methylation signatures associated with diet quality. We meta-analyzed epigenome-wide associations between diet quality and DNA methylation levels at over 400,000 cytosine-guanine dinucleotides (CpGs). We conducted analysis primarily in 6,662 European ancestry (EA) participants and secondarily in a group additionally including 3,062 participants of non-European ancestry from five population-based cohort studies. DNA methylation profiles were measured in whole blood, CD4 + T-cells, or CD14 + monocytes. We used food frequency questionnaires to assess habitual intake and constructed two diet quality scores: the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI). Our primary analysis identified 32 diet-associated CpGs, 12 CpGs for MDS and 24 CpGs for AHEI (at FDR < 0.05, corresponding p-values = 1.2×10-6 and 3.1×10-6, respectively) in EA participants. Four of these CpGs were associated with both MDS and AHEI. In addition, Mendelian randomization analysis indicated that seven diet-associated CpGs were causally linked to at least one of the CVD risk factors. For example, hypermethylation of cg11250194 (FADS2), which was associated with higher diet quality scores, was also associated with lower fasting triglycerides concentrations (p-value = 1.5×10-14) and higher high-density lipoprotein cholesterol concentrations (p-value = 1.7×10-8). Transethnic meta-analysis identified nine additional CpGs associated with diet quality (either MDS or AHEI) at FDR < 0.05. Overall quality of habitual diet was associated with differential peripheral leukocyte DNA methylation levels of 32 CpGs in EA participants. The diet-associated CpGs may serve as biomarkers and targets for preventive measures in CVD health. Future studies are warranted to examine diet-associated DNA methylation patterns in larger, ethnically diverse study samples.

scholarly journals DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2804 ◽  
Author(s):  
Odintsova ◽  
Hagenbeek ◽  
Suderman ◽  
Caramaschi ◽  
van Beijsterveldt ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Empirical Studies ◽  
Total Sample ◽  
Buccal Cells ◽  
Maternal Characteristics ◽  
Parents And Children ◽  
Median Split ◽  
Duration Of Breastfeeding ◽  
Stratified Analysis

Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized (‘never‘ vs. ‘ever’). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10–8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

scholarly journals Epigenome-wide association study of seizures in childhood and adolescence

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Doretta Caramaschi ◽  
Charlie Hatcher ◽  
Rosa H. Mulder ◽  
Janine F. Felix ◽  
Charlotte A. M. Cecil ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Independent Study ◽  
Childhood And Adolescence ◽  
Parents And Children ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
The Brain ◽  
Avon Longitudinal Study

AbstractThe occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study, we analyzed the association of genome-wide blood DNA methylation with the occurrence of seizures in ~ 800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood, and adolescence (peripheral blood). We also analyzed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e., using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1–5% absolute methylation difference at pFDR < 0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In conclusion, we show a suggestive link between seizures and blood DNA methylation while at the same time exploring the limitations of conducting such study.

scholarly journals P13.15 DNA methylation abnormalities in non-promoter regulatory regions are associated with invasive behavior in pituitary tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii65-iii66
Author(s):  
M Q S Mosella ◽  
T S Sabedot ◽  
T M Malta ◽  
J Rock ◽  
M Felicella ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Meta Analysis ◽  
Differentially Expressed Gene ◽  
Cell Movement ◽  
Pituitary Tumors ◽  
P Value ◽  
Regulatory Regions ◽  
Cpg Sites ◽  
Invasive Behavior

Abstract BACKGROUND Despite histologically benign, pituitary tumors (PT) may invade important adjacent neurovascular structures which can incur in significant comorbidities preventing a complete surgical resection and contributing to resistance to medical treatment. DNA methylation clearly stratified PT based on their functional status i.e. nonfunctioning PTs (NFPTs) from functioning PT (FPTs). However associations of methylation aberrations with invasive behavior is less clear. MATERIAL AND METHODS In order to evaluate whether DNA methylation alterations in regulatory regions other than promoter and coding regions are associated with invasive behavior we performed a meta-analysis of the genome-wide methylome of three public available PT cohorts plus our own (Illumina HumanMethylation platforms- 450K/EPIC). Pituitary specimens comprised of 43 invasive pituitary tumors (InvPT) and 37 noninvasive (NInvPT); 12 FPT and 68 NFPTs, in addition to 20 non-tumor pituitaries. RNA-seq data were available for one cohort (n=23, 12 InvPT,11NInvPT) and integrated with DNA methylation. Invasiveness criteria was based on Knosp grade >= 2 and/or sphenoid or dural invasion. RESULTS Wilcoxon Rank-sum test; Δβ=0.15; p-value <0.001 identified 58 differentially methylated CpG sites in InvPT that were mainly hypomethylated (95%) in relation to NInvPT. NInvPT methylation profile was similar to non-tumor specimens, despite its heterogeneity. Thirty-four percent (n=20) of the differentially methylated CpG sites were located within predicted enhancer regions distributed in intronic (40%), intergenic (40%) and promoter (20%) regions. Predicted enhancer-target genes were enriched for actin filament cell movement, response to starvation, growth factor stimulus and protein autophosporilation pathways. Among them, ZNF625 and INO80E were found mostly negative correlated among methylation and expression data (-0.50 and -0.48, respectively), besides DOC2A found to be one potentially differentially expressed gene under enhancer control (log2FC > 0.2, pvalue <0.05). CONCLUSION Our results suggest that methylation alterations in predicted regulatory regions, such as enhancers, annotated in non-promoter regions (introns and intergenic) may contribute to the invasive behavior of PT.

Azacytidine as a Maintenance Therapy in Elderly AML Progressively Demethylates CpG Sites within the p16 Gene

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4466-4466
Author(s):  
Margaret Dellett ◽  
Michelle Lazenby ◽  
Alan K Burnett ◽  
Ken I Mills
Keyword(s):  
Dna Methylation ◽  
Maintenance Therapy ◽  
Peripheral Blood ◽  
Age Of Onset ◽  
Methylation Status ◽  
Global Methylation ◽  
Cpg Sites ◽  
Number Of Patients ◽  
Elderly Aml ◽  
Diagnostic Samples

Abstract Acute myeloid leukemia (AML) accounts for ~30% of adult leukaemia cases and is expected to increase as the population ages, due to median age of onset at ~60 years old. Recent evidence suggests that DNA methylation is actively involved in AML and myelodysplastic syndrome (MDS). Tumor suppressor genes, such as p16, have been shown to be silenced by methylation in AML. However, epigenetic events such as DNA methylation are reversible and therefore targets for chemotherapeutic intervention. It has been reported that ~30% of MDS patients with an abnormal karyotype show normalization of their methylation status after receiving a demethylating drug during early stages of their therapy. The UK NCRI AML16 programme for elderly patients (&gt;60 years old at diagnosis) with AML and high risk MDS has several therapeutic questions for patients considered fit for intensive treatment, one of which is to compare the use of azacytidine demethylation maintenance treatment with no maintenance therapy. Samples were obtained from patients entered into the AML16 trial, at diagnosis and from patients entered into the intensive arm of the trial who were randomized to receive azacytidine maintenance therapy were analyzed for the alterations for genomic methylation. Pyrosequencing was used to determine methylation within 17 CpG sites within p16, MLH1, and MGMT whilst LINE1 was used as a measure of global methylation. To date, approximately 714 patients have been entered into AML16. Of these 195 diagnostic samples have been analyzed, of which 103 were in the intensive arm of the trial. At the second randomization stage, 34 patient samples were analyzed and a further 26 samples were obtained following 3, 6 or 9 courses of azacytidine therapy. Statistical comparison of the methylation levels at each individual CpG or for the averaged CpG in each gene studies indicated that there was no difference whether the sample was derived from bone marrow or peripheral blood. This allowed the direct comparison of peripheral blood samples obtained at 2nd randomization and during azacytidine maintenance courses. Differential levels of methylation at individual CpG within the gene were seen at diagnosis. Higher levels of average p16 methylation were observed in the AML patients when compared to a small cohort of “well elderly” individuals. No difference was noted in the individual or averaged CpG methylation status for MGMT or LINE1 during the maintenance course of azacytidine. However, the methylation status of the CpG sites within the p16 and MLH1 genes reduced during maintenance by a median of 19% and 25% respectively. However, the number of patients completing three courses of azacytidine was only about 20% of those entering the intensive arm of AML16, however sequential samples from the same individual also showed demethylation of the CpG sites in p16 and MLH1. This study shows that azacytidine maintenance therapy in elderly AML patients does reduce the methylation status of some genes whilst others genes show no response. This is being investigated further using arrays containing 12,000 CpG sites which will be correlated with gene expression microarrays on the diagnostic samples from AML16.

scholarly journals Grandchild’s IQ is associated with grandparental environments prior to the birth of the parents

2021 ◽  
Vol 5 ◽  
pp. 198
Author(s):  
Jean Golding ◽  
Gerard van den Berg ◽  
Kate Northstone ◽  
Matthew Suderman ◽  
Genette Ellis ◽  
...  
Keyword(s):  
Animal Experiments ◽  
Education Level ◽  
Maternal Grandfather ◽  
Developmental Variation ◽  
Smoking In Pregnancy ◽  
Parents And Children ◽  
Paternal Grandfather ◽  
Paternal Grandmother ◽  
Avon Longitudinal Study ◽  
In Pregnancy

Background. Despite convincing animal experiments demonstrating the potential for environmental exposures in one generation to have demonstrable effects generations later, there have been few relevant human studies. Those that have been undertaken have demonstrated associations, for example, between exposures such as nutrition and cigarette smoking in the grandparental generation and outcomes in grandchildren. We hypothesised that such transgenerational associations might be associated with the IQ of the grandchild, and that it would be likely that there would be differences in results between the sexes of the grandparents, parents, and children. Method. We used three-generational data from the Avon Longitudinal Study of Parents and Children (ALSPAC).  We incorporated environmental factors concerning grandparents (F0) and focussed on three exposures that we hypothesised may have independent transgenerational associations with the IQ of the grandchildren (F2): (i) UK Gross Domestic Product (GDP) at grandparental birth year; (ii) whether grandfather smoked; and (iii) whether the grandmother smoked in the relevant pregnancy. Potential confounders were ages of grandparents when the relevant parent was born, ethnic background, education level and social class of each grandparent. Results. After adjustment, all three target exposures had specific associations with measures of IQ in the grandchild. Paternal grandfather smoking was associated with reduced total IQ at 15 years; maternal grandfather smoking with reduced performance IQ at 8 years and reduced total IQ at 15.  Paternal grandmother smoking in pregnancy was associated with reduced performance IQ at 8, especially in grandsons. GDP at grandparents’ birth produced independent associations of reduced IQ with higher GDP; this was particularly true of paternal grandmothers. Conclusions. These results are complex and need to be tested in other datasets. They highlight the need to consider possible transgenerational associations in studying developmental variation in populations.

scholarly journals Early Pregnancy Peripheral Blood DNA Methylation and Risk of Gestational Diabetes Mellitus: A Nested Case-Control Study

2021 ◽  
Author(s):  
Xiaolei Wang ◽  
Jin Huang ◽  
Sisi Long ◽  
Huijun Lin ◽  
Na Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Dna Methylation ◽  
Peripheral Blood ◽  
Case Control Study ◽  
Methylation Status ◽  
First Trimester ◽  
Case Control ◽  
Cpg Sites ◽  
Nested Case Control ◽  
Control Study

Abstract Introduction: Genome-wide DNA methylation profiling has been used to identify CpG sites relevant to gestational diabetes mellitus (GDM). However, these sites have not been verified in larger samples. Here, our aim was to evaluate the changes in target CpG sites in the peripheral blood of pregnant women with GDM in their first trimester. Research Design and Methods: This nested case-control study examined a large cohort of women with GDM in early pregnancy (10–15 weeks; n = 80). Target CpG sites were extracted from related published literature and bioinformatics analysis. The DNA methylation levels at 337 CpG sites located in 27 target genes were determined using MethylTarget™ sequencing. The best cut-off levels for methylation of CpG sites were determined using the generated ROC curve. The independent effect of CpG site methylation status on GDM was analyzed using conditional logistic regression. Results Methylation levels at 6 CpG sites were significantly higher in the GDM group than in controls, whereas those at 7 CpG sites were significantly lower (P < 0.05). The area under the ROC curve at each methylation level of the significant CpG sites ranged between 0.593 and 0.650 for GDM prediction. After adjusting for possible confounders, the hypermethylation status of candidate sites cg68167324 (OR = 3.168, 1.038–9.666) and cg24837915 (OR = 5.232, 1.659–16.506) was identified as more strongly associated with GDM; conversely, the hypermethylation of sites cg157130156 (OR = 0.361, 0.135–0.966) and cg89438648 (OR = 0.206, 0.065–0.655) might indicate lower risk of GDM. Conclusions The methylation status of target CpG sites in the peripheral blood of pregnant women during the first trimester is associated with GDM pathogenesis, and has potential as a predictor of GDM.

scholarly journals DNA methylation mediates the effect of cocaine use on HIV severity

2020 ◽  
Author(s):  
Chang Shu ◽  
Amy C. Justice ◽  
Xinyu Zhang ◽  
Zuoheng Wang ◽  
Dana B. Hancock ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cohort Study ◽  
Mediation Effect ◽  
Hiv Positive ◽  
P Value ◽  
Mediation Effects ◽  
Cocaine Use ◽  
Cpg Sites ◽  
Hiv Progression ◽  
Immunodeficiency Virus

Background: Cocaine use accelerates human immunodeficiency virus (HIV) progression and worsens HIV outcomes. We assessed whether DNA methylation in blood mediates the association between cocaine use and HIV severity in a veteran population. Methods: We analyzed 1,435 HIV-positive participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS-BC). HIV severity was measured by the Veteran Aging Cohort Study (VACS) index. We assessed the effect of cocaine use on VACS index and mortality among the HIV-positive participants. We selected candidate mediators that were associated with both persistent cocaine use and VACS index by epigenome-wide association (EWA) scans at a liberal p-value cutoff of 0.001. Mediation analysis of the candidate CpG sites between cocaine effect and the VACS index was conducted, and the joint mediation effect of multiple CpGs was estimated. A two-step epigenetic Mendelian randomization (MR) analysis was conducted as validation. Results: More frequent cocaine use was significantly associated with a higher VACS index (β=1.00, p=2.7E-04), and cocaine use increased the risk of 10-year mortality (hazard ratio=1.10, p=0.011) with adjustment for confounding factors. Fifteen candidate mediator CpGs were selected from the EWA scan. Twelve of these CpGs showed significant mediation effects, with each explaining 11.3%-29.5% of the variation. The mediation effects for 3 of the 12 CpGs were validated by the two-step epigenetic MR analysis. The joint mediation effect of the 12 CpGs accounted for 47.2% of cocaine effect on HIV severity. Genes harboring these 12 CpGs are involved in the antiviral response (IFIT3, IFITM1, NLRC5, PLSCR1, PARP9) and HIV progression (CX3CR1, MX1). Conclusions: We identified 12 DNA methylation CpG sites that appear to play a mediation role in the association between cocaine use and HIV severity.

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