Association of BMI Trajectory in Earlier Childhood with Lung Function in Adulthood Is Mediated by DNA Methylation

Abstract Purpose Body mass index (BMI) is associated with asthma but associations of BMI temporal patterns with asthma incidence are unclear. Previous studies suggest that DNA methylation (DNAm) is associated with asthma status and variation in DNAm is a consequence of BMI changes. This study assessed the direct and indirect (via DNAm) effects of BMI trajectories in childhood on asthma incidence at young adulthood. Methods Data from the Isle of Wight (IoW) birth cohort were included in the analyses. Group-based trajectory modelling was applied to infer latent BMI trajectories from ages 1 to 10 years. An R package, ttscreening, was applied to identify differentially methylated CpGs at age 10 years associated with BMI trajectories, stratified for sex. Logistic regressions were used to further exclude CpGs with DNAm at age 10 years not associated with asthma incidence at 18 years. CpGs discovered via path analyses that mediated the association of BMI trajectories with asthma incidence in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Children and Parents (ALSPAC). Results Two BMI trajectories (high vs. normal) were identified. Of the 442,474 CpG sites, DNAm at 159 CpGs in males and 212 in females were potentially associated with BMI trajectories. Assessment of their association with asthma incidence identified 9 CpGs in males and 6 CpGs in females. DNAm at 4 of these 15 CpGs showed statistically significant mediation effects (p-value < 0.05). At two of the 4 CpGs (cg23632109 and cg10817500), DNAm completely mediated the association (i.e., only statistically significant indirect effects were identified). In the ALSPAC cohort, at all four CpGs, the same direction of mediating effects were observed as those found in the IoW cohort, although statistically insignificant. Conclusion The association of BMI trajectory in childhood with asthma incidence at young adulthood is possibly mediated by DNAm.

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DNA methylation is associated with airflow obstruction in patients living with HIV

Thorax ◽

10.1136/thoraxjnl-2020-215866 ◽

2020 ◽

pp. thoraxjnl-2020-215866

Author(s):

Ana I Hernandez Cordero ◽

Chen Xi Yang ◽

Maen Obeidat ◽

Julia Yang ◽

Julie MacIsaac ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Viral Infections ◽

Airflow Obstruction ◽

Normal Lung ◽

People Living With Hiv ◽

Global Methylation ◽

Age Related ◽

Impaired Lung Function ◽

Living With Hiv

IntroductionPeople living with HIV (PLWH) suffer from age-related comorbidities such as COPD. The processes responsible for reduced lung function in PLWH are largely unknown. We performed an epigenome-wide association study to investigate whether blood DNA methylation is associated with impaired lung function in PLWH.MethodsUsing blood DNA methylation profiles from 161 PLWH, we tested the effect of methylation on FEV1, FEV1/FVC ratio and FEV1 decline over a median of 5 years. We evaluated the global methylation of PLWH with airflow obstruction by testing the differential methylation of transposable elements Alu and LINE-1, a well-described marker of epigenetic ageing.ResultsAirflow obstruction as defined by a FEV1/FVC<0.70 was associated with 1393 differentially methylated positions (DMPs), while 4676 were associated with airflow obstruction based on the FEV1/FVC<lower limit of normal. These DMPs were enriched for biological pathways associated with chronic viral infections. The airflow obstruction group was globally hypomethylated compared with those without airflow obstruction. 103 and 7112 DMPs were associated with FEV1 and FEV1/FVC, respectively. No positions were associated with FEV1 decline.ConclusionA large number of DMPs were associated with airflow obstruction and lung function in a unique cohort of PLWH. Airflow obstruction in even relatively young PLWH is associated with global hypomethylation, suggesting advanced epigenetic ageing compared with those with normal lung function. The disturbance of the epigenetic regulation of key genes not previously identified in non-HIV COPD cohorts could explain the unique risk of COPD in PLWH.

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Smoking, DNA methylation and lung function: a Mendelian randomization analysis to investigate causal relationships

10.1101/19003335 ◽

2019 ◽

Author(s):

Emily Jamieson ◽

Roxanna Korologou-Linden ◽

Robyn E. Wootton ◽

Anna L. Guyatt ◽

Thomas Battram ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Mendelian Randomization ◽

Causal Effect ◽

Forced Expiratory Volume ◽

Multiple Trait ◽

Genome Wide ◽

Causal Variants ◽

Association Data ◽

Randomization Analysis

AbstractWhether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in one second (FEV1) in two-sample Mendelian randomization (MR) using methylation quantitative trait loci and genome-wide association data for FEV1. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p<1.2×10−4). Replication analysis supported a causal effect at three CpGs (cg21201401 (ZGPAT), cg19758448 (PGAP3) and cg12616487 (AHNAK) (p<0.0028). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites may influence lung function via effects on smoking. Using multiple-trait colocalization, we found evidence of shared causal variants between lung function, gene expression and DNA methylation. Findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although large, tissue-specific datasets are required to confirm these results.

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Long-term PM2.5 Exposure, Genome-wide DNA Methylation and Lung Function in Korean Adults

10.1109/bibm52615.2021.9669818 ◽

2021 ◽

Author(s):

Ye-Eun Han ◽

Nak-Hyeon Choi ◽

Mi Jin Cho ◽

Min Gu Kang ◽

Young-Youl Kim

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Korean Adults ◽

Genome Wide ◽

Pm2.5 Exposure

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DNA methylation is associated with lung function in never smokers

Respiratory Research ◽

10.1186/s12931-019-1222-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Maaike de Vries ◽

◽

Ivana Nedeljkovic ◽

Diana A. van der Plaat ◽

Alexandra Zhernakova ◽

...

Keyword(s):

Dna Methylation ◽

Lung Function ◽

Ribosome Biogenesis ◽

Meta Analysis ◽

Smoking History ◽

Rotterdam Study ◽

Main Risk Factor ◽

Cpg Sites ◽

Never Smokers ◽

Integrative Omics

Abstract Background Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. Methods We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). Results A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. Conclusions With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.

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