DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Publication Abstract

Ligthart, S., Linda J. Waite, Jennifer A. Smith, Hui-Sheng Lin, Sharon L. R. Kardia, Sarah E. Turner, C. Marzi, S. Aslibekyan, et al. 2016. "DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases." Genome Biology, 17.

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 x 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 x 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 x 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 x 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58x 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R-2) 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.

Dataset(s): TY - JOUR AB - 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 x 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 x 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 x 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 x 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58x 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R-2) 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. AU - Ligthart, S. AU - Marzi, C. AU - Aslibekyan, S. AU - Mendelson, M. M. AU - Conneely, K. N. AU - Tanaka, T. AU - Colicino, E. AU - Waite, L. L. AU - Joehanes, R. AU - Guan, W. H. AU - Brody, J. A. AU - Elks, C. AU - Marioni, R. AU - Jhun, M. A. AU - Agha, G. AU - Bressler, J. AU - Ward-Caviness, C. K. AU - Chen, B. H. AU - Huan, T. X. AU - Bakulski, K. AU - Salfati, E. L. AU - Wahl, S. AU - Schramm, K. AU - Sha, J. AU - Hernandez, D. G. AU - Just, A. C. AU - Smith, Jennifer A. AU - Sotoodehnia, N. AU - Pilling, L. C. AU - Pankow, J. S. AU - Tsao, P. S. AU - Liu, C. Y. AU - Zhao, W. AU - Guarrera, S. AU - Michopoulos, V. J. AU - Smith, A. K. AU - Peters, M. J. AU - Melzer, D. AU - Vokonas, P. AU - Fornage, M. AU - Prokisch, H. AU - Bis, J. C. AU - Chu, A. Y. AU - Herder, C. AU - Grallert, H. AU - Yao, C. AU - Shah, S. AU - McRae, A. F. AU - Lin, H. H. AU - Horvath, S. AU - Fallin, D. AU - Hofman, A. AU - Wareham, N. J. AU - Wiggins, K. L. AU - Feinberg, A. P. AU - Starr, J. M. AU - Visscher, P. M. AU - Murabito, J. M. AU - Kardia, Sharon L. R. AU - Absher, D. M. AU - Binder, E. B. AU - Singleton, A. B. AU - Bandinelli, S. AU - Peters, A. AU - Waldenberger, M. AU - Matullo, G. AU - Schwartz, J. D. AU - Demerath, E. W. AU - Uitterlinden, A. G. AU - van Meurs, J. B. J. AU - Franco, O. H. AU - Chen, Y. D. I. AU - Levy, D. AU - Turner, S. T. AU - Deary, I. J. AU - Ressler, K. J. AU - Dupuis, J. AU - Ferrucci, L. AU - Ong, K. K. AU - Assimes, T. L. AU - Boerwinkle, E. AU - Koenig, W. AU - Arnett, D. K. AU - Baccarelli, A. A. AU - Benjamin, E. J. AU - Dehghan, A. AU - Fiorito, Whi-Empc Invest Giovanni AU - Heart, Charge Epigenetics Coronary C7 - 255 DA - Dec DO - 10.1186/s13059-016-1119-5 KW - Inflammation DNA methylation Epigenome-wide association study C-reactive protein Body mass index Diabetes Coronary heart disease wide association atherosclerosis N1 - Ligthart, Symen Marzi, Carola Aslibekyan, Stella Mendelson, Michael M. Conneely, Karen N. Tanaka, Toshiko Colicino, Elena Waite, Lindsay L. Joehanes, Roby Guan, Weihua Brody, Jennifer A. Elks, Cathy Marioni, Riccardo Jhun, Min A. Agha, Golareh Bressler, Jan Ward-Caviness, Cavin K. Chen, Brian H. Huan, Tianxiao Bakulski, Kelly Salfati, Elias L. Wahl, Simon Schramm, Katharina Sha, Jin Hernandez, Dena G. Just, Allan C. Smith, Jennifer A. Sotoodehnia, Nona Pilling, Luke C. Pankow, James S. Tsao, Phil S. Liu, Chunyu Zhao, Wei Guarrera, Simonetta Michopoulos, Vasiliki J. Smith, Alicia K. Peters, Marjolein J. Melzer, David Vokonas, Pantel Fornage, Myriam Prokisch, Holger Bis, Joshua C. Chu, Audrey Y. Herder, Christian Grallert, Harald Yao, Chen Shah, Sonia McRae, Allan F. Lin, Honghuang Horvath, Steve Fallin, Daniele Hofman, Albert Wareham, Nicholas J. Wiggins, Kerri L. Feinberg, Andrew P. Starr, John M. Visscher, Peter M. Murabito, Joanne M. Kardia, Sharon L. R. Absher, Devin M. Binder, Elisabeth B. Singleton, Andrew B. Bandinelli, Stefania Peters, Annette Waldenberger, Melanie Matullo, Giuseppe Schwartz, Joel D. Demerath, Ellen W. Uitterlinden, Andre G. van Meurs, Joyce B. J. Franco, Oscar H. Chen, Yii-Der Ida Levy, Daniel Turner, Stephen T. Deary, Ian J. Ressler, Kerry J. Dupuis, Josee Ferrucci, Luigi Ong, Ken K. Assimes, Themistocles L. Boerwinkle, Eric Koenig, Wolfgang Arnett, Donna K. Baccarelli, Andrea A. Benjamin, Emelia J. Dehghan, Abbas PY - 2016 ST - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases T2 - Genome Biology TI - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases VL - 17 ID - 392 ER -

10.1186/s13059-016-1119-5

Keywords:
Inflammation DNA methylation Epigenome-wide association study C-reactive protein Body mass index Diabetes Coronary heart disease wide association atherosclerosis

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