Epigenetics
Longitudinal DNA methylation highlights genes for COPD progression.
| Submitted by | Rafique, Omar
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| Authors | Omar Rafique1, Y. Huang1, K. H. Shutta1,2, R. Min Hyung1, K. Kim1, P. Kachroo1, C. Lopes-Ramos1, K. A. Pratte3, R. Bowler4, E. K.
Silverman1,5, V. J. Carey1, D. L. DeMeo1,5; 1Channing Div. of Network Med., Brigham and Women's Hosp., Harvard Medical School, Boston, MA, 2Harvard T.H. Chan Sch. of Publ. Hlth., Dept. of Biostatistics, Boston, MA, 3Div. of Biostatistics and Bioinformatics, Dept. of Med., Natl. Jewish Hlth., Denver, CO, 4Div. of Pulmonary and Critical Care Med., Dept. of Med., Natl. Jewish Hlth., Denver, CO, 5Div. of Pulmonary and Critical Care Med., Brigham and Women’s Hosp., Harvard Med. Sch., Boston, MA |
| Name and Date of Professional Meeting | ASHG Annual Meeting 2023 ( Nov 1 -5)
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| Working Group(s) | |
| Abstract Text |
Abstract:
To investigate the impact of time varying nature of DNA methylation (DNAm) on the progression of chronic obstructive pulmonary disease (COPD), we conducted a longitudinal epigenome-wide association study (EWAS). The EWAS findings were integrated with proteomic data to reveal the interplay between methylation and proteomics in COPD. Methods: Infinium MethylationEPIC BeadChip data was obtained from peripheral blood leukocyte DNA from 4,493 current and former smokers from the Genetic Epidemiology of COPD (COPDGene) study consisting of two time points of DNAm and FEV1 data (baseline and 5-year follow-up visits) of non-Hispanic white and African American subjects with a history of smoking, a median age of 62.2 years at enrollment and 51 percent male subjects. SomaScan blood proteomic data was available from the 5-year follow-up visit. Linear mixed-e"ects regression (LMER) was used to find the associations between longitudinal DNAm and longitudinal forced expiratory volume in 1 second (FEV1); adjusted for sex, age, race, cell counts, pack-years of smoking, current smoking status, height and time since baseline visit. Causal mediation analysis to identify proteins potentially mediating the relationship between DNAm and FEV1 was conducted using a nonparametric bootstrap procedure from the R package Mediation. Functional overlap analysis on the genome-wide significant CpGs was performed using the eFORGE tool. Results: From the longitudinal FEV1 and longitudinal DNAm data, LMER identified 66 CpGs having genome- wide significant associations with FEV1 (p ≤ 5 x 10-8). Intraclass correlation (ICC) of the 66 CpGs calculated using DNAm M-values from both time points revealed that the majority (40) have ICC between 0.5 and 0.8 and 22 CpGs have ICC greater than 0.8, suggesting that FEV1- associated CpGs are stable over 5 years. Chromosome 17 demonstrated three significant associations over a 440 base pair region annotated to the SOCS3 gene (cg13343932 with p = 2.12 x 10-18, cg11047325 with p = 8.77 x 10-16 and cg18181703 with p = 1.07 x 10-13). An X chromosome CpG near the zinc-finger repressor, BCOR, was also associated with longitudinal FEV1 (cg18422972 with p = 2.14 x10-8). Functional Overlap analysis of the 66 CpGs revealed significant enrichment in histone methylation (H3K4me1 and H3K4me3) in blood and lung tissue. Mediation analysis identified ITPRIPL1, NOTCH1 and IGFBP5 as three candidate proteins partially mediating the signal between DNAm and FEV1. Conclusions: EWAS of longitudinal DNAm data revealed that the CpG sites that are stable over time are associated with longitudinal lung function (FEV1) and are linked with epigenetic and inflammatory signals. |
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