Changes of DNA methylation are associated with changes in lung function during adolescence

Sunny, Shadia Khan; Zhang, Hongmei; Rezwan, Faisal I.; Relton, Caroline L; Henderson, A. John; Merid, Simon Kebede; Hallberg, Jenny; Arshad, Syed Hasan; Ewart, Susan; Holloway, John W.

doi:10.1186/s12931-020-01342-y

Cited by 12 publications

(12 citation statements)

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“…We hypothesized that differential methylation at certain cytosine-phosphate-guanine dinucleotide sites (CpGs) in childhood is associated with the trajectories of lung function. Given that lung function growth and decline is sex-dependent and such dependence is attributable to multiple biological determinants, including dimensional/anatomical, immunological, and hormonal determinants [ 20 – 23 ], we examined the hypothesis in male and female participants, separately [ 12 , 24 ]. The study was carried out in the birth cohort located on the Isle of Wight (IOW) in the UK.…”

Section: Introductionmentioning

confidence: 99%

Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood

et al. 2021

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Background The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood. Methods DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex. Results High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases. Conclusion The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

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Section: Introductionmentioning

confidence: 99%

Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood

et al. 2021

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“…Additionally, physiological changes, such as hormonal changes during adolescence, were not considered. Moreover, sex-stratified analysis, for lung function, has proven informative in other studies [ 17 , 30 ], and therefore, this could be implemented in this study as well. However, this would further lower the samples size (43.25% female) and may be impractical for this study.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that DNAm, measured in peripheral blood, is associated with lung functions [ 29 ]. Changes in DNAm from childhood to adolescence have been found to be associated with lung function during adolescence in females [ 30 ]. Therefore, changes in DNAm aging from childhood to adolescence may have potential effects on lung function.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Lung Function in Adolescence Using Epigenetic Aging: A Machine Learning Approach

Arefeen

Nimi

Rahman

et al. 2020

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Epigenetic aging has been found to be associated with a number of phenotypes and diseases. A few studies have investigated its effect on lung function in relatively older people. However, this effect has not been explored in the younger population. This study examines whether lung function in adolescence can be predicted with epigenetic age accelerations (AAs) using machine learning techniques. DNA methylation based AAs were estimated in 326 matched samples at two time points (at 10 years and 18 years) from the Isle of Wight Birth Cohort. Five machine learning regression models (linear, lasso, ridge, elastic net, and Bayesian ridge) were used to predict FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) at 18 years from feature selected predictor variables (based on mutual information) and AA changes between the two time points. The best models were ridge regression (R2 = 75.21% ± 7.42%; RMSE = 0.3768 ± 0.0653) and elastic net regression (R2 = 75.38% ± 6.98%; RMSE = 0.445 ± 0.069) for FEV1 and FVC, respectively. This study suggests that the application of machine learning in conjunction with tracking changes in AA over the life span can be beneficial to assess the lung health in adolescence.

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“…Interestingly, six genetic variants (rs28565347, rs12442778, rs12440213, rs8030857, rs8031576, and rs748508), which can affect the methylation pattern of CpG sites (mQTLs) in blood leukocytes, were identified for cg23161492 [ 106 ]. The methylation level of another site cg05312779, localized in 3'UTR of the ANPEP gene, is statistically significantly associated with the lung function; in particular, an increase in DNA methylation was associated with a decrease in the Tiffeneau index in adolescent girls [ 107 ]. These findings are consistent with clinical observations that smokers have a higher risk of developing COVID-19 symptoms when infected with SARS-CoV-2 [ 100 ].…”

Section: Genetic Factors Of the Susceptibility To Sars-cov-2 In Humansmentioning

confidence: 99%

Genetic Control of Human Infection with SARS-CoV-2

et al. 2021

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In 2019, the SARS-CoV-2 beta-coronavirus, which caused a pandemic of severe acute respiratory viral infection COVID-19 (from COronaVIrus Disease 2019), was first detected. The susceptibility to SARS-CoV-2 and the nature of the course of the COVID-19 clinical picture are determined by many factors, including genetic characteristics of both the pathogen and the human. The SARS-CoV-2 genome has a similarity to the genomes of other coronaviruses, which are pathogenic for humans and cause a severe course of infection: 79% to the SARS-CoV genome and 50% to the MERS-CoV genome. The most significant differences between SARS-CoV-2 and other coronaviruses are recorded in the structure of the gene of the S protein, a key protein responsible for the virus binding to the receptor of the host organism cells. In particular, substitutions in the S protein of SARS-CoV-2, leading to the formation of the furin cleavage site that is absent in other SARS-like coronaviruses, were identified, which may explain the high pathogenicity of SARS-CoV-2. In humans, the genes that are significant for the initial stages of infection include ACE2 , ANPEP , DPP4 (encode receptors for coronavirus binding); TMPRSS2 , FURIN , TMPRSS11D , CTSL , CTSB (encode proteases involved in the entry of the coronavirus into the cell); DDX1 (the gene of ATP-dependent RNA helicase DDX1, which promotes replication of coronaviruses); and IFITM1 , IFITM2 , and IFITM3 (encode interferon-induced transmembrane proteins with an antiviral effect). These genes are expressed in many tissues (including those susceptible to the effects of SARS-CoV-2); rare and frequent variants that affect the structure of the encoded protein and its properties and expression level are described in them. A number of common genetic variants with proven functional significance are characterized by the variability in the allele frequency in the world’s populations, which can determine interpopulation differences in the prevalence of COVID-19 and in the clinical features of the course of this pathology. The expression level of genes that are important for the formation of the susceptibility to SARS-CoV-2 is affected by epigenetic modifications, comorbidities at the time of infection, taking medications, and bad habits.

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Changes of DNA methylation are associated with changes in lung function during adolescence

Cited by 12 publications

References 72 publications

Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood

Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood

Prediction of Lung Function in Adolescence Using Epigenetic Aging: A Machine Learning Approach

Genetic Control of Human Infection with SARS-CoV-2

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