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

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.

Download Full-text

Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia

10.1101/19008524 ◽

2019 ◽

Author(s):

Leif Karlsson ◽

Michela Barbaro ◽

Ewoud Ewing ◽

David Gomez-Cabrero ◽

Svetlana Lajic

Keyword(s):

Dna Methylation ◽

Congenital Adrenal Hyperplasia ◽

Hdl Cholesterol ◽

Adrenal Hyperplasia ◽

Blood Lipid Profile ◽

Glucocorticoid Treatment ◽

C Peptide ◽

Genome Wide ◽

Metabolic Outcome

AbstractBackgroundPatients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome.MethodsWe analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 ±6.5 years [y]) and 37 population controls (mean age=17.0 ±6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, glucose homeostasis, blood lipid profile and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age=19.1, ±6.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment.ResultsWe identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p=0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p=0.044 and p=0.034) and genotype (p=0.044 and p=0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035).ConclusionIn conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH.

Download Full-text