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

被引：212

作者：

Ligthart, Symen ^{[1
]}

Marzi, Carola ^{[2
,3
]}

Aslibekyan, Stella ^{[4
]}

Mendelson, Michael M. ^{[5
,6
,7
]}

Conneely, Karen N. ^{[8
]}

Tanaka, Toshiko ^{[9
]}

Colicino, Elena ^{[10
]}

Waite, Lindsay L. ^{[11
]}

Joehanes, Roby ^{[12
]}

Guan, Weihua ^{[13
]}

Brody, Jennifer A. ^{[14
]}

Elks, Cathy ^{[15
]}

Marioni, Riccardo ^{[16
,17
,18
]}

Jhun, Min A. ^{[19
]}

Agha, Golareh ^{[10
]}

Bressler, Jan ^{[20
]}

Ward-Caviness, Cavin K. ^{[21
]}

Chen, Brian H. ^{[22
]}

Huan, Tianxiao ^{[7
]}

Bakulski, Kelly ^{[23
]}

Salfati, Elias L. ^{[24
]}

Wahl, Simon ^{[2
,3
]}

Schramm, Katharina ^{[27
,28
]}

Sha, Jin ^{[4
]}

Hernandez, Dena G. ^{[29
]}

Just, Allan C. ^{[10
]}

Smith, Jennifer A. ^{[19
]}

Sotoodehnia, Nona ^{[14
]}

Pilling, Luke C. ^{[30
]}

Pankow, James S. ^{[31
]}

Tsao, Phil S. ^{[32
,33
]}

Liu, Chunyu ^{[7
,34
]}

Zhao, Wei ^{[19
]}

Guarrera, Simonetta ^{[25
,26
]}

Michopoulos, Vasiliki J. ^{[35
]}

Smith, Alicia K. ^{[35
]}

Peters, Marjolein J. ^{[36
]}

Melzer, David ^{[30
]}

Vokonas, Pantel ^{[37
,38
,39
]}

Fornage, Myriam ^{[20
]}

Prokisch, Holger ^{[27
,28
]}

Bis, Joshua C. ^{[14
]}

Chu, Audrey Y. ^{[7
]}

Herder, Christian ^{[40
,41
]}

Grallert, Harald ^{[2
,3
]}

Yao, Chen ^{[7
]}

Shah, Sonia ^{[18
,42
]}

McRae, Allan F. ^{[18
,42
]}

Lin, Honghuang ^{[34
]}

Horvath, Steve ^{[43
]}

机构：

[1] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[2] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherber, Germany

[3] German Ctr Diabet Res DZD eV, Munich, Germany

[4] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA

[5] Boston Univ, Sch Med, Boston, MA 02215 USA

[6] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA

[7] NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA

[8] Emory Univ, Dept Human Genet, Sch Med, Atlanta, GA 30322 USA

[9] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA

[10] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[11] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[12] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA

[13] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA

[14] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA

[15] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[16] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[17] Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[18] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[19] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA

[20] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA

[21] Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, Neuherber, Germany

[22] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA

[23] Johns Hopkins Univ, Ctr Epigenet, Sch Med, Baltimore, MD USA

[24] Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA

[25] Human Genet Fdn, Turin, Italy

[26] Univ Turin, Dept Med Sci, Turin, Italy

[27] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Human Genet, Neuherberg, Germany

[28] Tech Univ Munich, Inst Human Genet, Munich, Germany

[29] NIA, Lab Neurogenet, Bethesda, MD 20892 USA

[30] Univ Exeter, Epidemiol & Publ Hlth, Sch Med, Exeter, Devon, England

[31] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA

[32] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA

[33] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA

[34] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA

[35] Emory Univ, Dept Psychiat & Behav Sci, Sch Med, Atlanta, GA 30322 USA

[36] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[37] VA Boston Healthcare Syst, Boston, MA USA

[38] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA

[39] Boston Univ, Sch Med, Boston, MA 02215 USA

[40] Univ Dusseldorf, Leibniz Ctr Diabet Res Heinrich Heine, Inst Clin Diabetol, German Diabet Ctr, Dusseldorf, Germany

[41] German Ctr Diabet Res DZD eV, Munich, Germany

[42] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia

[43] Univ Calif Los Angeles, Dept Human Genet, Gonda Res Ctr, David Geffen Sch Med, Los Angeles, CA USA

[44] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[45] Max Planck Inst Psychiat, Munich, Germany

[46] ASF, Geriatr Unit, Florence, Italy

[47] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth & Epidemiol, Boston, MA USA

[48] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA

[49] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA

[50] McLean Hosp, Div Depress & Anxiety Disorders, Belmont, MA 02178 USA

来源：

GENOME BIOLOGY | 2016年 / 17卷

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease; WIDE ASSOCIATION; ATHEROSCLEROSIS;

D O I：

10.1186/s13059-016-1119-5

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

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