慢性低度炎症的DNA甲基化特征与复杂疾病相关。
DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.
作者信息
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, van 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
机构信息
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherber, Germany.
出版信息
Genome Biol. 2016 Dec 12;17(1):255. doi: 10.1186/s13059-016-1119-5.
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) in the discovery panel of European ancestry and replicated (P < 2.29 × 10) 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), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10). 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.
背景
慢性低度炎症反映了一种参与复杂疾病发病机制的亚临床免疫反应。识别DNA甲基化与慢性低度炎症相关的基因位点可能揭示炎症的新途径或治疗靶点。
结果
我们对欧洲裔大样本群体（n = 8863）中血清C反应蛋白（CRP，一种低度炎症的敏感标志物）的全基因组关联研究（EWAS）进行了荟萃分析，并在非裔美国人（n = 4111）中进行了跨种族复制。我们发现218个CpG位点的差异甲基化与欧洲血统发现队列中的CRP相关（P < 1.15×10），并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）。为了进一步表征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关联。九个（16%）CpG位点的DNA甲基化与顺式全血基因表达相关（P < 8.47×10），十个（17%）CpG位点与附近的基因变异相关（P < 2.50×10），51个（88%）也与至少一种相关的心脏代谢实体相关（P < 9.58×10）。复制的CpG位点的加性加权评分在年龄和性别调整后的CRP个体间变异中占比高达6%（R2），独立于已知的CRP相关基因变异。
结论
我们完成了慢性低度炎症的EWAS，并确定了许多炎症潜在的新基因位点，这些位点可能成为开发新型炎症治疗干预措施的靶点。
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