DNA Methylation Signature of Chronic Low-grade Inflammation and Its Role in Cardio-respiratory Diseases

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

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References

Prins B, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N . Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. PLoS Med. 2016; 13(6):e1001976. PMC: 4915710. DOI: 10.1371/journal.pmed.1001976. View

Houseman E, Accomando W, Koestler D, Christensen B, Marsit C, Nelson H . DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86. PMC: 3532182. DOI: 10.1186/1471-2105-13-86. View

Wu H, Zhang Y . Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 2014; 156(1-2):45-68. PMC: 3938284. DOI: 10.1016/j.cell.2013.12.019. View

Yang J, Weedon M, Purcell S, Lettre G, Estrada K, Willer C . Genomic inflation factors under polygenic inheritance. Eur J Hum Genet. 2011; 19(7):807-12. PMC: 3137506. DOI: 10.1038/ejhg.2011.39. View

Bautista L . Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence. J Hum Hypertens. 2003; 17(4):223-30. DOI: 10.1038/sj.jhh.1001537. View

Tobi E, Slieker R, Luijk R, Dekkers K, Stein A, Xu K . DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. Sci Adv. 2018; 4(1):eaao4364. PMC: 5792223. DOI: 10.1126/sciadv.aao4364. View

Huan T, Joehanes R, Song C, Peng F, Guo Y, Mendelson M . Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease. Nat Commun. 2019; 10(1):4267. PMC: 6753136. DOI: 10.1038/s41467-019-12228-z. View

Aryee M, Jaffe A, Corrada-Bravo H, Ladd-Acosta C, Feinberg A, Hansen K . Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30(10):1363-9. PMC: 4016708. DOI: 10.1093/bioinformatics/btu049. View

Schmidt M, Duncan B, Sharrett A, Lindberg G, Savage P, Offenbacher S . Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet. 1999; 353(9165):1649-52. DOI: 10.1016/s0140-6736(99)01046-6. View

10.

Davies N, Holmes M, Davey Smith G . Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018; 362:k601. PMC: 6041728. DOI: 10.1136/bmj.k601. View

11.

Zheng G, Freidlin B, Gastwirth J . Robust genomic control for association studies. Am J Hum Genet. 2006; 78(2):350-6. PMC: 1380242. DOI: 10.1086/500054. View

12.

Lykkegaard J, Christensen R, Davidsen J, Stovring H, Andersen M, Sondergaard J . Trends in the lifetime risk of COPD exacerbation requiring hospitalisation. Eur Respir J. 2013; 42(4):964-71. DOI: 10.1183/09031936.00129312. View

13.

Reese S, Xu C, den Dekker H, Lee M, Sikdar S, Ruiz-Arenas C . Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J Allergy Clin Immunol. 2018; 143(6):2062-2074. PMC: 6556405. DOI: 10.1016/j.jaci.2018.11.043. View

14.

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

15.

Wiklund P, Karhunen V, Richmond R, Parmar P, Rodriguez A, De Silva M . DNA methylation links prenatal smoking exposure to later life health outcomes in offspring. Clin Epigenetics. 2019; 11(1):97. PMC: 6604191. DOI: 10.1186/s13148-019-0683-4. View

16.

Kim J, Yoon S, Lee S, Hong H, Ha E, Joo Y . A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms. Nat Commun. 2020; 11(1):1898. PMC: 7171097. DOI: 10.1038/s41467-020-15655-5. View

17.

Dehghan A, van Hoek M, Sijbrands E, Stijnen T, Hofman A, Witteman J . Risk of type 2 diabetes attributable to C-reactive protein and other risk factors. Diabetes Care. 2007; 30(10):2695-9. DOI: 10.2337/dc07-0348. View

18.

Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M . Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation. 2003; 107(5):671-4. DOI: 10.1161/01.cir.0000055188.83694.b3. View

19.

Somineni H, Venkateswaran S, Kilaru V, Marigorta U, Mo A, Okou D . Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation. Gastroenterology. 2019; 156(8):2254-2265.e3. PMC: 6529254. DOI: 10.1053/j.gastro.2019.01.270. View

20.

Lawlor D, Tilling K, Davey Smith G . Triangulation in aetiological epidemiology. Int J Epidemiol. 2017; 45(6):1866-1886. PMC: 5841843. DOI: 10.1093/ije/dyw314. View