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

Symen Ligthart, Carola Marzi, Stella Aslibekyan, Michael M. Mendelson, Karen N. Conneely, Toshiko Tanaka, Elena Colicino, Lindsay L. Waite, Roby Joehanes, Weihua Guan, Jennifer A. Brody, Cathy Elks, Riccardo Marioni, Min A. Jhun, Golareh Agha, Jan Bressler, Cavin K. Ward-Caviness, Brian H. Chen, Tianxiao Huan, Kelly BakulskiElias L. Salfati, Giovanni Fiorito, Simone Wahl, Katharina Schramm, Jin Sha, Dena G. Hernandez, Allan C. Just, Jennifer A. Smith, Nona Sotoodehnia, Luke C. Pilling, James S. Pankow, Phil S. Tsao, Chunyu Liu, Wei Zhao, Simonetta Guarrera, Vasiliki J. Michopoulos, Alicia K. Smith, Marjolein J. Peters, David Melzer, Pantel Vokonas, Myriam Fornage, Holger Prokisch, Joshua C. Bis, Audrey Y. Chu, Christian Herder, Harald Grallert, Chen Yao, Sonia Shah, Allan F. McRae, Honghuang Lin, Steve Horvath, Daniele Fallin, Albert Hofman, Nicholas J. Wareham, Kerri L. Wiggins, Andrew P. Feinberg, John M. Starr, Peter M. Visscher, Joanne M. Murabito, Sharon L R Kardia, Devin M. Absher, Elisabeth B. Binder, Andrew B. Singleton, Stefania Bandinelli, Annette Peters, Melanie Waldenberger, Giuseppe Matullo, Joel D. Schwartz, Ellen W. Demerath, André G. Uitterlinden, Joyce B J Meurs, Oscar H. Franco, Yii Der Ida Chen, Daniel Levy, Stephen T Turner, Ian J. Deary, Kerry J. Ressler, Josée Dupuis, Luigi Ferrucci, Ken K. Ong, Themistocles L. Assimes, Eric Boerwinkle, Wolfgang Koenig, Donna K. Arnett, Andrea A. Baccarelli, Emelia J. Benjamin, Abbas Dehghan

Research output: Contribution to journalArticle

73 Citations (Scopus)

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.

Original languageEnglish (US)
Article number255
JournalGenome Biology
Volume17
Issue number1
DOIs
StatePublished - Dec 12 2016

Fingerprint

methylation
DNA methylation
DNA Methylation
inflammation
Inflammation
DNA
C-reactive protein
C-Reactive Protein
protein
African American
gene expression
Genetic Loci
African Americans
loci
individual variation
meta-analysis
immune response
ancestry
Gene Expression
therapeutics

Keywords

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

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Ligthart, S., Marzi, C., Aslibekyan, S., Mendelson, M. M., Conneely, K. N., Tanaka, T., ... Dehghan, A. (2016). DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biology, 17(1), [255]. https://doi.org/10.1186/s13059-016-1119-5

DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. / 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.; Fiorito, Giovanni; Wahl, Simone; 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, André G.; Meurs, Joyce B J; Franco, Oscar H.; Chen, Yii Der Ida; Levy, Daniel; Turner, Stephen T; Deary, Ian J.; Ressler, Kerry J.; Dupuis, Josée; Ferrucci, Luigi; Ong, Ken K.; Assimes, Themistocles L.; Boerwinkle, Eric; Koenig, Wolfgang; Arnett, Donna K.; Baccarelli, Andrea A.; Benjamin, Emelia J.; Dehghan, Abbas.

In: Genome Biology, Vol. 17, No. 1, 255, 12.12.2016.

Research output: Contribution to journalArticle

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, SLR, Absher, DM, Binder, EB, Singleton, AB, Bandinelli, S, Peters, A, Waldenberger, M, Matullo, G, Schwartz, JD, Demerath, EW, Uitterlinden, AG, Meurs, JBJ, Franco, OH, Chen, YDI, 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 2016, 'DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases', Genome Biology, vol. 17, no. 1, 255. https://doi.org/10.1186/s13059-016-1119-5
Ligthart S, Marzi C, Aslibekyan S, Mendelson MM, Conneely KN, Tanaka T et al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. Genome Biology. 2016 Dec 12;17(1). 255. https://doi.org/10.1186/s13059-016-1119-5
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. ; Fiorito, Giovanni ; Wahl, Simone ; 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, André G. ; Meurs, Joyce B J ; Franco, Oscar H. ; Chen, Yii Der Ida ; Levy, Daniel ; Turner, Stephen T ; Deary, Ian J. ; Ressler, Kerry J. ; Dupuis, Josée ; Ferrucci, Luigi ; Ong, Ken K. ; Assimes, Themistocles L. ; Boerwinkle, Eric ; Koenig, Wolfgang ; Arnett, Donna K. ; Baccarelli, Andrea A. ; Benjamin, Emelia J. ; Dehghan, Abbas. / DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. In: Genome Biology. 2016 ; Vol. 17, No. 1.
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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.",
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TY - JOUR

T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

AU - Ligthart, Symen

AU - Marzi, Carola

AU - Aslibekyan, Stella

AU - Mendelson, Michael M.

AU - Conneely, Karen N.

AU - Tanaka, Toshiko

AU - Colicino, Elena

AU - Waite, Lindsay L.

AU - Joehanes, Roby

AU - Guan, Weihua

AU - Brody, Jennifer A.

AU - Elks, Cathy

AU - Marioni, Riccardo

AU - Jhun, Min A.

AU - Agha, Golareh

AU - Bressler, Jan

AU - Ward-Caviness, Cavin K.

AU - Chen, Brian H.

AU - Huan, Tianxiao

AU - Bakulski, Kelly

AU - Salfati, Elias L.

AU - Fiorito, Giovanni

AU - Wahl, Simone

AU - Schramm, Katharina

AU - Sha, Jin

AU - Hernandez, Dena G.

AU - Just, Allan C.

AU - Smith, Jennifer A.

AU - Sotoodehnia, Nona

AU - Pilling, Luke C.

AU - Pankow, James S.

AU - Tsao, Phil S.

AU - Liu, Chunyu

AU - Zhao, Wei

AU - Guarrera, Simonetta

AU - Michopoulos, Vasiliki J.

AU - Smith, Alicia K.

AU - Peters, Marjolein J.

AU - Melzer, David

AU - Vokonas, Pantel

AU - Fornage, Myriam

AU - Prokisch, Holger

AU - Bis, Joshua C.

AU - Chu, Audrey Y.

AU - Herder, Christian

AU - Grallert, Harald

AU - Yao, Chen

AU - Shah, Sonia

AU - McRae, Allan F.

AU - Lin, Honghuang

AU - Horvath, Steve

AU - Fallin, Daniele

AU - Hofman, Albert

AU - Wareham, Nicholas J.

AU - Wiggins, Kerri L.

AU - Feinberg, Andrew P.

AU - Starr, John M.

AU - Visscher, Peter M.

AU - Murabito, Joanne M.

AU - Kardia, Sharon L R

AU - Absher, Devin M.

AU - Binder, Elisabeth B.

AU - Singleton, Andrew B.

AU - Bandinelli, Stefania

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Matullo, Giuseppe

AU - Schwartz, Joel D.

AU - Demerath, Ellen W.

AU - Uitterlinden, André G.

AU - Meurs, Joyce B J

AU - Franco, Oscar H.

AU - Chen, Yii Der Ida

AU - Levy, Daniel

AU - Turner, Stephen T

AU - Deary, Ian J.

AU - Ressler, Kerry J.

AU - Dupuis, Josée

AU - Ferrucci, Luigi

AU - Ong, Ken K.

AU - Assimes, Themistocles L.

AU - Boerwinkle, Eric

AU - Koenig, Wolfgang

AU - Arnett, Donna K.

AU - Baccarelli, Andrea A.

AU - Benjamin, Emelia J.

AU - Dehghan, Abbas

PY - 2016/12/12

Y1 - 2016/12/12

N2 - 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.

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 × 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.

KW - Body mass index

KW - C-reactive protein

KW - Coronary heart disease

KW - Diabetes

KW - DNA methylation

KW - Epigenome-wide association study

KW - Inflammation

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U2 - 10.1186/s13059-016-1119-5

DO - 10.1186/s13059-016-1119-5

M3 - Article

C2 - 27955697

AN - SCOPUS:85003550816

VL - 17

JO - Genome Biology

JF - Genome Biology

SN - 1474-7596

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M1 - 255

ER -