eprintid: 1532717 rev_number: 27 eprint_status: archive userid: 608 dir: disk0/01/53/27/17 datestamp: 2016-12-19 13:53:13 lastmod: 2021-12-06 00:14:53 status_changed: 2016-12-19 13:53:13 type: article metadata_visibility: show creators_name: Ligthart, S creators_name: Marzi, C creators_name: Aslibekyan, S creators_name: Mendelson, MM creators_name: Conneely, KN creators_name: Tanaka, T creators_name: Colicino, E creators_name: Waite, LL creators_name: Joehanes, R creators_name: Guan, W creators_name: Brody, JA creators_name: Elks, C creators_name: Marioni, R creators_name: Jhun, MA creators_name: Agha, G creators_name: Bressler, J creators_name: Ward-Caviness, CK creators_name: Chen, BH creators_name: Huan, T creators_name: Bakulski, K creators_name: Salfati, EL creators_name: Fiorito, G creators_name: Wahl, S creators_name: Schramm, K creators_name: Sha, J creators_name: Hernandez, DG creators_name: Just, AC creators_name: Smith, JA creators_name: Sotoodehnia, N creators_name: Pilling, LC creators_name: Pankow, JS creators_name: Tsao, PS creators_name: Liu, C creators_name: Zhao, W creators_name: Guarrera, S creators_name: Michopoulos, VJ creators_name: Smith, AK creators_name: Peters, MJ creators_name: Melzer, D creators_name: Vokonas, P creators_name: Fornage, M creators_name: Prokisch, H creators_name: Bis, JC creators_name: Chu, AY creators_name: Herder, C creators_name: Grallert, H creators_name: Yao, C creators_name: Shah, S creators_name: McRae, AF creators_name: Lin, H creators_name: Horvath, S creators_name: Fallin, D creators_name: Hofman, A creators_name: Wareham, NJ creators_name: Wiggins, KL creators_name: Feinberg, AP creators_name: Starr, JM creators_name: Visscher, PM creators_name: Murabito, JM creators_name: Kardia, SL creators_name: Absher, DM creators_name: Binder, EB creators_name: Singleton, AB creators_name: Bandinelli, S creators_name: Peters, A creators_name: Waldenberger, M creators_name: Matullo, G creators_name: Schwartz, JD creators_name: Demerath, EW creators_name: Uitterlinden, AG creators_name: van Meurs, JB creators_name: Franco, OH creators_name: Chen, YI creators_name: Levy, D creators_name: Turner, ST creators_name: Deary, IJ creators_name: Ressler, KJ creators_name: Dupuis, J creators_name: Ferrucci, L creators_name: Ong, KK creators_name: Assimes, TL creators_name: Boerwinkle, E creators_name: Koenig, W creators_name: Arnett, DK creators_name: Baccarelli, AA creators_name: Benjamin, EJ creators_name: Dehghan, A title: DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases ispublished: pub divisions: UCL divisions: B02 divisions: D14 keywords: Body mass index, C-reactive protein, Coronary heart disease, DNA methylation, Diabetes, Epigenome-wide association study, Inflammation note: © The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. abstract: BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation. date: 2016-12-12 date_type: published official_url: http://dx.doi.org/10.1186/s13059-016-1119-5 oa_status: green full_text_type: pub primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1195895 doi: 10.1186/s13059-016-1119-5 pii: 10.1186/s13059-016-1119-5 language_elements: eng lyricists_name: Shah, Sonia lyricists_id: SSHAH98 actors_name: Bracey, Alan actors_id: ABBRA90 actors_role: owner full_text_status: public publication: Genome Biology volume: 17 article_number: 255 event_location: England issn: 1474-760X citation: Ligthart, S; Marzi, C; Aslibekyan, S; Mendelson, MM; Conneely, KN; Tanaka, T; Colicino, E; ... Dehghan, A; + view all <#> Ligthart, S; Marzi, C; Aslibekyan, S; Mendelson, MM; Conneely, KN; Tanaka, T; Colicino, E; Waite, LL; Joehanes, R; Guan, W; Brody, JA; Elks, C; Marioni, R; Jhun, MA; Agha, G; Bressler, J; Ward-Caviness, CK; Chen, BH; Huan, T; Bakulski, K; Salfati, EL; Fiorito, G; Wahl, S; Schramm, K; Sha, J; Hernandez, DG; Just, AC; Smith, JA; Sotoodehnia, N; Pilling, LC; Pankow, JS; Tsao, PS; Liu, C; Zhao, W; Guarrera, S; Michopoulos, VJ; Smith, AK; Peters, MJ; Melzer, D; Vokonas, P; Fornage, M; Prokisch, H; Bis, JC; Chu, AY; Herder, C; Grallert, H; Yao, C; Shah, S; McRae, AF; Lin, H; Horvath, S; Fallin, D; Hofman, A; Wareham, NJ; Wiggins, KL; Feinberg, AP; Starr, JM; Visscher, PM; Murabito, JM; Kardia, SL; Absher, DM; Binder, EB; Singleton, AB; Bandinelli, S; Peters, A; Waldenberger, M; Matullo, G; Schwartz, JD; Demerath, EW; Uitterlinden, AG; van Meurs, JB; Franco, OH; Chen, YI; Levy, D; Turner, ST; Deary, IJ; Ressler, KJ; Dupuis, J; Ferrucci, L; Ong, KK; Assimes, TL; Boerwinkle, E; Koenig, W; Arnett, DK; Baccarelli, AA; Benjamin, EJ; Dehghan, A; - view fewer <#> (2016) DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biology , 17 , Article 255. 10.1186/s13059-016-1119-5 <https://doi.org/10.1186/s13059-016-1119-5>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1532717/1/art%253A10.1186%252Fs13059-016-1119-5.pdf