DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.
DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.
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DOI：
10.1186/s13059-016-1119-5
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发表时间：
2016-12-12
期刊：
影响因子：
12.3
通讯作者：
Dehghan A
中科院分区：
文献类型：
--
作者：
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;WHI-EMPC Investigators;Fiorito G;CHARGE epigenetics of Coronary Heart Disease;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
慢性低度炎症反映了复杂疾病发病机制中涉及的亚临床免疫应答。识别DNA甲基化与慢性低度炎症相关的遗传位点可能揭示炎症的新途径或治疗靶点。我们对大量欧洲人群（n = 8863）和非裔美国人（n = 4111）的跨种族复制中血清C反应蛋白（CRP）的表观全基因组关联研究（EWAS）进行了荟萃分析，CRP是低度炎症的敏感标志物。我们发现，在欧洲血统的发现组中，218个CpG位点的差异甲基化与CRP相关（P < 1.15 × 10-7），在非裔美国人中复制了58个CpG位点（45个独特位点）（P < 2.29 × 10-4）。为了进一步描述这些发现的分子和临床相关性，我们研究了与基因表达、基因序列变异和临床结局的相关性。9个（16%）CpG位点的DNA甲基化与全血基因顺式表达相关（P < 8.47 × 10-5），10个（17%）CpG位点与附近的遗传变异相关（P < 2.50 × 10-3），51个（88%）CpG位点还与至少一种相关的心脏代谢实体相关（P < 9.58 × 10-5）。重复CpG位点的加性加权评分可解释年龄校正和性别校正CRP的高达6%的个体间变异（R2），与已知CRP相关遗传变异无关。我们已经完成了慢性低度炎症的EWAS，并确定了许多潜在炎症的新遗传位点，这些位点可能作为开发新型炎症治疗干预措施的靶点。本文的在线版本（doi：10.1186/s13059-016-1119-5）包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
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影响因子：
30.8
作者：
Westra, Harm-Jan;Peters, Marjolein J.;Esko, Tonu;Yaghootkar, Hanieh;Schurmann, Claudia;Kettunen, Johannes;Christiansen, Mark W.;Fairfax, Benjamin P.;Schramm, Katharina;Powell, Joseph E.;Zhernakova, Alexandra;Zhernakova, Daria V.;Veldink, Jan H.;Van den Berg, Leonard H.;Karjalainen, Juha;Withoff, Sebo;Uitterlinden, Andre G.;Hofman, Albert;Rivadeneira, Fernando;'t Hoen, Peter A. C.;Reinmaa, Eva;Fischer, Krista;Nelis, Mari;Milani, Lili;Melzer, David;Ferrucci, Luigi;Singleton, Andrew B.;Hernandez, Dena G.;Nalls, Michael A.;Homuth, Georg;Nauck, Matthias;Radke, Doerte;Voelker, Uwe;Perola, Markus;Salomaa, Veikko;Brody, Jennifer;Suchy-Dicey, Astrid;Gharib, Sina A.;Enquobahrie, Daniel A.;Lumley, Thomas;Montgomery, Grant W.;Makino, Seiko;Prokisch, Holger;Herder, Christian;Roden, Michael;Grallert, Harald;Meitinger, Thomas;Strauch, Konstantin;Li, Yang;Jansen, Ritsert C.;Visscher, Peter M.;Knight, Julian C.;Psaty, Bruce M.;Ripatti, Samuli;Teumer, Alexander;Frayling, Timothy M.;Metspalu, Andres;van Meurs, Joyce B. J.;Franke, Lude
通讯作者：
Franke, Lude
影响因子：
37.8
作者：
Dehghan A;Dupuis J;Barbalic M;Bis JC;Eiriksdottir G;Lu C;Pellikka N;Wallaschofski H;Kettunen J;Henneman P;Baumert J;Strachan DP;Fuchsberger C;Vitart V;Wilson JF;Paré G;Naitza S;Rudock ME;Surakka I;de Geus EJ;Alizadeh BZ;Guralnik J;Shuldiner A;Tanaka T;Zee RY;Schnabel RB;Nambi V;Kavousi M;Ripatti S;Nauck M;Smith NL;Smith AV;Sundvall J;Scheet P;Liu Y;Ruokonen A;Rose LM;Larson MG;Hoogeveen RC;Freimer NB;Teumer A;Tracy RP;Launer LJ;Buring JE;Yamamoto JF;Folsom AR;Sijbrands EJ;Pankow J;Elliott P;Keaney JF;Sun W;Sarin AP;Fontes JD;Badola S;Astor BC;Hofman A;Pouta A;Werdan K;Greiser KH;Kuss O;Meyer zu Schwabedissen HE;Thiery J;Jamshidi Y;Nolte IM;Soranzo N;Spector TD;Völzke H;Parker AN;Aspelund T;Bates D;Young L;Tsui K;Siscovick DS;Guo X;Rotter JI;Uda M;Schlessinger D;Rudan I;Hicks AA;Penninx BW;Thorand B;Gieger C;Coresh J;Willemsen G;Harris TB;Uitterlinden AG;Järvelin MR;Rice K;Radke D;Salomaa V;Willems van Dijk K;Boerwinkle E;Vasan RS;Ferrucci L;Gibson QD;Bandinelli S;Snieder H;Boomsma DI;Xiao X;Campbell H;Hayward C;Pramstaller PP;van Duijn CM;Peltonen L;Psaty BM;Gudnason V;Ridker PM;Homuth G;Koenig W;Ballantyne CM;Witteman JC;Benjamin EJ;Perola M;Chasman DI
通讯作者：
Chasman DI
影响因子：
168.9
作者：
Dick, Katherine J.;Nelson, Christopher P.;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.
DOI：
10.1161/circgenetics.108.829747
发表时间：
2009-02
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Psaty BM;O'Donnell CJ;Gudnason V;Lunetta KL;Folsom AR;Rotter JI;Uitterlinden AG;Harris TB;Witteman JC;Boerwinkle E;CHARGE Consortium
通讯作者：
CHARGE Consortium
DOI：
10.1093/bioinformatics/btq340
发表时间：
2010-09-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Willer CJ;Li Y;Abecasis GR
通讯作者：
Abecasis GR