Background
Methods
Study population
Measurements
Lung function
DNA methylation
Statistical analysis
Epigenome-wide association study and meta-analysis
Expression quantitative trait methylation (eQTM) analysis
Results
Subject characteristics
LL COPD&C | LLDEEP | RS-III-1 | RS-BIOS | |
---|---|---|---|---|
Number of subjects, N (%) | 903 | 166 | 150 | 206 |
Male, N (%) | 508 (56.3) | 71 (42.8) | 74 (49.3) | 80 (38.8) |
Age (yrs), median (min-max) | 46 (18–80) | 42 (20–78) | 63 (53–93) | 68 (52–79) |
Airway obstruction (FEV1/FVC< 70%), N (%) | 316 (35.0) | 15 (9.0) | 13 (8.7) | 19 (9.0) |
- FEV1 (L), mean (SE) | 3.5 (0.9) | 3.6 (0.9) | 3.2 (0.8) | 2.7 (0.7) |
- FEV1/FVC, mean (SE) | 84.5 (8.2) | 78.6 (6.2) | 77.8 (5.9) | 77.9 (5.9) |
Meta-analysis of the four epigenome-wide association studies
Meta-analysis | LL COPD&C | LLDEEP | RS-III-1 | RS-BIOS | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Beta | SE | P-value | Beta | SE | P-value | Beta | SE | P-value | Beta | SE | P-value | Beta | SE | P-value | ||
cg10012512 | Intergenic | −38.27 | 7.67 | 5.94E-07 | −45.54 | 12.14 | 1.76E-04 | −16.71 | 26.68 | 5.31E-01 | −33.86 | 15.33 | 2.72E-02 | −38.23 | 14.78 | 9.71E-03 |
cg02885771 | LTV1 | 20.66 | 4.48 | 4.10E-06 | 21.53 | 8.76 | 1.40E-02 | 27.73 | 15.33 | 7.05E-02 | 21.95 | 6.05 | 2.86E-04 | 5.67 | 13.95 | 6.84E-01 |
cg25105536 | KLHL32 | −59.71 | 13.46 | 9.09E-06 | −76.36 | 44.35 | 8.51E-02 | −97.80 | 235.46 | 6.78E-01 | −54.41 | 14.81 | 2.38E-04 | −94.28 | 47.91 | 4.91E-02 |
cg20102034 | RTKN | 36.14 | 8.28 | 1.28E-05 | 42.57 | 15.29 | 5.35E-03 | 29.70 | 15.94 | 6.25E-02 | 40.85 | 14.65 | 5.29E-03 | 22.02 | 24.20 | 3.63E-01 |
cg03703840 | KIAA1731 | 84.04 | 19.38 | 1.45E-05 | 100.48 | 42.84 | 1.90E-02 | −43.70 | 187.80 | 8.16E-01 | 88.13 | 23.36 | 1.61E-04 | 33.87 | 62.55 | 5.88E-01 |
cg21614201 | SYNPO2 | −22.66 | 5.23 | 1.45E-05 | −28.17 | 13.55 | 3.76E-02 | −25.53 | 28.56 | 3.71E-01 | −21.10 | 6.11 | 5.58E-04 | −25.22 | 17.72 | 1.55E-01 |
cg07957088 | PRIC285 | 35.48 | 8.33 | 2.06E-05 | 49.48 | 15.72 | 1.64E-03 | 31.33 | 16.68 | 6.03E-02 | 38.68 | 13.97 | 5.62E-03 | −0.10 | 24.74 | 9.97E-01 |
cg05304461 | C1orf127 | −80.31 | 19.00 | 2.37E-05 | −95.35 | 36.04 | 8.16E-03 | 152.12 | 153.04 | 3.20E-01 | −82.63 | 25.66 | 1.28E-03 | −68.52 | 47.73 | 1.51E-01 |
cg11749902 | Intergenic | −22.32 | 5.30 | 2.55E-05 | −26.22 | 7.75 | 7.17E-04 | −16.37 | 12.44 | 1.88E-01 | −12.69 | 14.61 | 3.85E-01 | −24.69 | 11.32 | 2.91E-02 |
cg02207312 | PRPF19 | 75.53 | 18.05 | 2.87E-05 | 79.32 | 53.44 | 1.38E-01 | − 177.08 | 222.75 | 4.27E-01 | 77.18 | 20.22 | 1.35E-04 | 74.46 | 63.10 | 2.38E-01 |
cg19734370 | NPTX1 | 12.65 | 3.04 | 3.19E-05 | 12.29 | 4.11 | 2.76E-03 | 12.09 | 6.95 | 8.21E-02 | 9.23 | 8.85 | 2.97E-01 | 17.64 | 8.07 | 2.88E-02 |
cg03077331 | FN3K | 14.19 | 3.45 | 3.99E-05 | 16.08 | 4.94 | 1.14E-03 | 9.62 | 8.41 | 2.52E-01 | 29.01 | 16.49 | 7.85E-02 | 11.51 | 6.31 | 6.84E-02 |
cg18387671 | ANKRD13B | −88.73 | 21.86 | 4.92E-05 | − 110.71 | 69.61 | 1.12E-01 | 4.44 | 272.02 | 9.87E-01 | −87.37 | 24.33 | 3.30E-04 | −83.43 | 73.78 | 2.58E-01 |
cg03224276 | ZFHX3 | 37.55 | 9.26 | 5.00E-05 | 52.17 | 19.25 | 6.73E-03 | 16.06 | 44.59 | 7.19E-01 | 28.97 | 11.60 | 1.25E-02 | 71.59 | 31.14 | 2.15E-02 |
cg02137691 | FGFR3 | 28.80 | 7.11 | 5.11E-05 | 13.24 | 13.60 | 3.30E-01 | 40.83 | 15.87 | 1.01E-02 | 35.10 | 10.64 | 9.74E-04 | 16.63 | 25.22 | 5.10E-01 |
cg25884324 | UNC45A | −36.97 | 9.16 | 5.45E-05 | −42.03 | 19.42 | 3.05E-02 | −32.96 | 50.06 | 5.10E-01 | −35.47 | 11.31 | 1.71E-03 | −36.84 | 30.86 | 2.32E-01 |
cg27158523 | PPIL4 | −49.97 | 12.40 | 5.54E-05 | −62.31 | 22.65 | 5.94E-03 | − 241.34 | 161.10 | 1.34E-01 | −37.48 | 14.71 | 1.09E-02 | −83.47 | 40.23 | 3.80E-02 |
cg01157143 | NAV2 | −23.11 | 5.74 | 5.63E-05 | −31.05 | 15.70 | 4.80E-02 | −10.87 | 23.51 | 6.44E-01 | −24.64 | 6.82 | 3.03E-04 | −8.89 | 18.20 | 6.25E-01 |
cg07160694 | DCAF5 | 77.84 | 19.34 | 5.69E-05 | 63.24 | 40.81 | 1.21E-01 | 54.41 | 155.03 | 7.26E-01 | 73.37 | 27.79 | 8.29E-03 | 98.91 | 36.83 | 7.24E-03 |
cg22127773 | KDM6B | −48.39 | 12.03 | 5.75E-05 | −58.63 | 19.17 | 2.22E-03 | 3.55 | 81.11 | 9.65E-01 | −56.26 | 21.72 | 9.60E-03 | −29.26 | 22.85 | 2.00E-01 |
cg20939319 | TEX15 | −14.90 | 3.71 | 5.84E-05 | −17.12 | 8.37 | 4.07E-02 | −26.90 | 17.30 | 1.20E-01 | −13.61 | 4.55 | 2.80E-03 | −13.49 | 12.02 | 2.62E-01 |
cg02206852 | PROCA1 | 23.87 | 5.97 | 6.39E-05 | 28.18 | 16.23 | 8.24E-02 | 26.98 | 20.97 | 1.98E-01 | 22.38 | 7.02 | 1.45E-03 | 27.78 | 24.10 | 2.49E-01 |
cg17075019 | Intergenic | 35.53 | 8.90 | 6.56E-05 | 49.59 | 13.38 | 2.12E-04 | 26.62 | 17.55 | 1.29E-01 | 13.65 | 25.97 | 5.99E-01 | 28.14 | 20.81 | 1.76E-01 |
cg25556432 | Intergenic | 23.02 | 5.78 | 6.75E-05 | 25.96 | 8.69 | 2.82E-03 | 21.69 | 13.17 | 9.95E-02 | 32.14 | 17.96 | 7.36E-02 | 15.46 | 11.29 | 1.71E-01 |
cg22742965 | TMEFF2 | −17.79 | 4.47 | 6.76E-05 | −24.96 | 11.10 | 2.45E-02 | 0.42 | 20.86 | 9.84E-01 | −17.82 | 5.43 | 1.03E-03 | −14.83 | 13.14 | 2.59E-01 |
cg16734845 | CTDSPL2 | −33.94 | 8.52 | 6.82E-05 | −54.67 | 21.90 | 1.26E-02 | −38.26 | 26.03 | 1.42E-01 | −31.88 | 10.86 | 3.32E-03 | −15.33 | 24.10 | 5.25E-01 |
cg09108394 | PRKCB | −14.93 | 3.76 | 7.11E-05 | −16.43 | 8.33 | 4.84E-02 | −27.78 | 14.95 | 6.31E-02 | −14.34 | 4.92 | 3.55E-03 | −9.74 | 9.71 | 3.16E-01 |
cg10034572 | Intergenic | −20.08 | 5.08 | 7.77E-05 | −19.86 | 13.39 | 1.38E-01 | −56.52 | 27.77 | 4.18E-02 | −19.29 | 5.90 | 1.09E-03 | −12.71 | 17.73 | 4.73E-01 |
cg20066227 | C1QL3 | 32.20 | 8.16 | 7.92E-05 | 26.51 | 18.29 | 1.47E-01 | 24.42 | 30.70 | 4.26E-01 | 40.00 | 10.35 | 1.12E-04 | 3.19 | 24.73 | 8.97E-01 |
cg07148038 | TNXB | 44.32 | 11.26 | 8.23E-05 | 51.79 | 16.72 | 1.95E-03 | 41.06 | 24.11 | 8.85E-02 | 55.29 | 30.47 | 6.96E-02 | 22.61 | 25.67 | 3.78E-01 |
cg23396786 | SFXN5 | 20.16 | 5.12 | 8.26E-05 | 22.48 | 7.68 | 3.43E-03 | 13.97 | 10.89 | 2.00E-01 | 45.93 | 18.48 | 1.30E-02 | 13.79 | 10.08 | 1.71E-01 |
cg06218079 | TBCD | 8.18 | 2.08 | 8.34E-05 | 5.68 | 3.00 | 5.79E-02 | 12.74 | 3.45 | 2.26E-04 | 3.33 | 8.96 | 7.10E-01 | 6.35 | 6.52 | 3.30E-01 |
cg06982745 | ADAMTS14 | −40.80 | 10.44 | 9.37E-05 | −36.77 | 18.57 | 4.77E-02 | 13.29 | 44.30 | 7.64E-01 | −48.83 | 14.67 | 8.71E-04 | −42.55 | 30.04 | 1.57E-01 |
cg05946118 | Intergenic | −20.27 | 5.19 | 9.38E-05 | −17.24 | 6.98 | 1.35E-02 | −23.39 | 14.23 | 1.00E-01 | −25.24 | 13.56 | 6.28E-02 | −23.41 | 12.66 | 6.46E-02 |
cg08065963 | Intergenic | −16.72 | 4.28 | 9.56E-05 | −18.12 | 5.84 | 1.93E-03 | −9.56 | 11.07 | 3.88E-01 | −29.63 | 11.66 | 1.10E-02 | −8.68 | 10.18 | 3.94E-01 |
cg12064372 | Intergenic | 32.85 | 8.43 | 9.75E-05 | 48.15 | 18.52 | 9.33E-03 | 26.64 | 92.88 | 7.74E-01 | 31.50 | 10.10 | 1.81E-03 | 7.96 | 28.48 | 7.80E-01 |
Expression quantitative trait methylation (eQTM) analysis
CpG-site | Gene annotation CpG-site | Genes located within 1 MB (N) | Gene (expression) | Beta | SE | p-value | Adjusted p-value |
---|---|---|---|---|---|---|---|
cg02137691 | FGFR3 | 31 | SLC26A1 | 0.0156 | 0.0038 | 3.53E-05 | 0.0011 |
cg02206852 | PROCA1 | 52 | NUFIP2 | 0.0084 | 0.0022 | 1.06E-04 | 0.0055 |
cg02206852 | PROCA1 | 52 | GIT1 | 0.0080 | 0.0023 | 6.11E-04 | 0.0318 |
cg02885771 | LTV1 | 11 | VDAC1P8 | 0.0096 | 0.0033 | 3.51E-03 | 0.0386 |
cg07148038 | TNXB | 89 | ATP6V1G2 | 0.0074 | 0.0021 | 3.79E-04 | 0.0337 |
cg07148038 | TNXB | 89 | STK19B | 0.0035 | 0.0010 | 3.77E-04 | 0.0335 |
cg08065963 | 12 | ABAT | 0.0127 | 0.0034 | 1.85E-04 | 0.0022 | |
cg20939319 | TEX15 | 10 | SARAF | −0.0029 | 0.0010 | 3.36E-03 | 0.0336 |
cg22127773 | KDM6B | 80 | TMEM88 | 0.0011 | 0.0003 | 1.82E-04 | 0.0146 |
cg23396786 | SFXN5 | 18 | CYP26B1 | 0.0024 | 0.0008 | 1.78E-03 | 0.0321 |
cg25105536 | KLHL32 | 4 | KLHL32 | −0.0004 | 0.0002 | 5.52E-03 | 0.0221 |
Discussion
Study | Study population | Trait | Adjustment included in model | DNA methylation platform | Number of CpG-sites available for comparison |
---|---|---|---|---|---|
Epigenome-wide association study of lung function level and its change Imboden et al., 2019 [17] | Discovery-replication approach. Discovery included 3 cohorts (N=2043) and replication included 7 cohorts (Adult: N=3327, Childhood: N=420) - Smoking status: self-reported, subjects with and without smoking history; never smokers only | - FEV1 - FVC - FEV1/FVC Analyses were performed twice: with and without adjustment for smoking status and pack years | - Age - Age2 - Height - Height2 deviation - Sex - Sex Age, Age2, height, Height2 deviation - Education - BMI - Spirometer type - Study Center - Blood cell composition | Discovery: Illumina Infinium Human Methylation 450 K BeadChip and EPIC BeadChip Replication: various arrays for the discovery-identified CpG-sites only | Without smoking adjustment: 56a With smoking adjustment: 12a Never smokers: 8 (from discovery). None of the CpG sites were replicateda |
No association between DNA methylation and COPD in never and current smokers De Vries et al., 2018 [16] | Non-random selection from LifeLines cohort (N=1561 subjects) - Smoking status: Stratified for smoking (658 smokers and 903 never smokers) | - COPD (defined as FEV1/FVC ≤ 0.7) | - Sex - Age - Pack years (in smoking stratified analysis) - Batch effects - Blood cell composition | Illumina Infinium Human Methylation450K BeadChip array - Number of included probes: 420,938 | Smokers: 19492b Never smokers: 19393b |
Lung function discordance in monozygotic twins and ssociated differences in blood DNA methylation Bolund et al., 2017 [11] | Sub-population of twins from the Middle-Aged Danish Twin (MADT) study (N=169 twin pairs) - Smoking status: subjects with and without smoking history | Intra-pair difference in z-score calculated as “superior” minus “inferior” twin at baseline and during follow-up period for: - FEV1 - FVC - FEV1/FVC | - Sex - Age - BMI - Pack years - Smoking status at follow-up - Blood cell composition Intra-pair difference was calculated for all the variables | Illumina Infinium Human Methylation450K BeadChip array - Number of included probes: 453,014 | 37a |
Epigenome-wide association study of chronic obstructive pulmonary disease and lung function in Koreans Lee et al., 2017 [12] | Sample of Korean COPD cohort (N=100 subjects) - Smoking status: subjects with and without smoking history | - COPD status (defined as FEV1/FVC < 0.7) - FEV1 - FVC - FEV1/FVC | - Sex - Age - Height - Smoking status - Pack years - Blood cell composition | Illumina Infinium Human Methylation450K BeadChip array - Number of included probes: 402,508 | 16a |
Differential DNA methylation marks and gene comethylation of COPD in African-Americans with COPD exacerbations Busch et al., 2016 [13] | Sample of PA-SCOPE AA study population (N=362 subjects) - Smoking status: smokers > 20 pack years | - COPD (defined as FEV1/FVC ≤ 0.7 and FEV1 ≤ 80%) | - Sex - Age - Pack years - Batch number - Blood cell composition | Illumina Infinium Human Methylation27K BeadChip array - Number of included probes: 19,302 | 12a |
The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort Marioni et al., 2015 [15] | The Lothian Birth Cohort of 1936 (N=1091) - Smoking status: self-reported, subjects with and without smoking history | - FEV1 | - Sex - Age - Height - Smoking status - Blood cell composition | Illumina Infinium Human Methylation450K BeadChip array - Number of included probes: 450,726 | 2a |
Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function Qiu et al., 2012 [10] | Test-replication approach in 2 family-based cohorts (N=1085 and 369 subjects) - Smoking status: subjects with and without smoking history | - COPD status (FEV1/FVC ≤0.7 and FEV1 ≤70%) - FEV1/FVC - FEV1 | - Random family effect | Illumina Infinium Human Methylation27K BeadChip array - Number of included probes: 26,485 | 349a |
Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population Bell et al., 2012 [14] | Sample of the TwinsUK cohort (N=172 female twin pairs) - Smoking status: unknown | - FEV1 - FVC | - Age - Batch effects | Illumina Infinium Human Methylation27K BeadChip array - Number of included probes: 24,641 | 1a |
CpG-site | CpG location | Gene annotation | Gene function | Previously associated with lung function |
---|---|---|---|---|
cg10012512 | 7:157224041 | Intergenic | NA | Yesa |
cg02885771 | 6:144163654 | LTV1 | Involved in ribosome biogenesis | No |
cg25105536 | 6:97372436 | KLHL32 | Only described as protein coding gene | No |
cg20102034 | 2:74653166 | RTKN | Negative regulator of GTPase activity of Rho proteins | Yesa |
cg03703840 | 11:93394809 | KIAA1731 | Mediating of centriole-to-centrosome conversion at late mitosis | No |
cg21614201 | 4:119888794 | SYNPO2 | Only described as protein coding gene | No |
cg07957088 | 20:62196387 | PRIC285 | Nuclear transcriptional co-activator for peroxisome proliferator activated receptor alpha | Yesa |
cg05304461 | 1:11019377 | C1orf127 | Only described as protein coding gene | No |
cg11749902 | 8:41093619 | Intergenic | NA | Yesa |
cg02207312 | 11:60674164 | PRPF19 | Involved in cell survival and DNA repair | No |
cg19734370 | 17:78444348 | NPTX1 | Exclusively localized to the nervous system as binding protein for taipoxin | Yesa |
cg03077331 | 17:80693076 | FN3K | Catalyzes the phosphorylation of fructosamines | Yesa |
cg18387671 | 17:27920246 | ANKRD13B | Only described as protein coding gene | Yesa |
cg03224276 | 16:72829831 | ZFHX3 | Regulates myogenic and neuronal differentiation | No |
cg02137691 | 4:1805671 | FGFR3 | Involved in bone development and maintenance | No |
cg25884324 | 15:91482502 | UNC45A | Regulator of the progesterone receptor chaperoning pathway | No |
cg27158523 | 6:149867355 | PPIL4 | Involved in protein folding, immunosuppression and infection of HIV-1 virions | Yesa |
cg01157143 | 11:19478542 | NAV2 | Plays a role in cellular growth and migration | No |
cg07160694 | 14:69619856 | DCAF5 | Only described as protein coding gene | No |
cg22127773 | 17:7754785 | KDM6B | Demethylation of di- or tri-methylated lysine 27 of histone H3 | Yesa |
cg20939319 | 8:30707701 | TEX15 | Involved in cell cycle processes of spermatocytes | No |
cg02206852 | 17:27030540 | PROCA1 | Only described as protein coding gene | No |
cg17075019 | 10:79541650 | Intergenic | NA | Yesa |
cg25556432 | 2:239628926 | Intergenic | NA | Yesa |
cg22742965 | 2:192891657 | TMEFF2 | Cellular context-dependent oncogene or tumor suppressor | Yes |
cg16734845 | 15:44781962 | CTDSPL2 | Only described as protein coding gene | No |
cg09108394 | 16:23850106 | PRKCB | As kinase involved in diverse cellular signaling pathways | No |
cg10034572 | 2:160921789 | Intergenic | NA | No |
cg20066227 | 10:16564552 | C1QL3 | Only described as protein coding gene | No |
cg07148038 | 6:32061160 | TNXB | Anti-adhesive protein involved in matrix maturation during wound healing | Yesa |
cg23396786 | 2:73299151 | SFXN5 | Only described as protein coding gene | Yesa |
cg06218079 | 17:80834228 | TBCD | As co-factor D involved in the correct folding of beta-tubulin | No |
cg06982745 | 10:72454006 | ADAMTS14 | The matured enzyme is involved in the formation of collagen fibers | No |
cg05946118 | 16:8985638 | Intergenic | NA | Yesa |
cg08065963 | 16:8985593 | Intergenic | NA | Yesa |
cg12064372 | 12:30948792 | Intergenic | NA | Yesa |