Demerath Ellen W, Guan Weihua, Grove Megan L, Aslibekyan Stella, Mendelson Michael, Zhou Yi-Hui, Hedman Åsa K, Sandling Johanna K, Li Li-An, Irvin Marguerite R, Zhi Degui, Deloukas Panos, Liang Liming, Liu Chunyu, Bressler Jan, Spector Tim D, North Kari, Li Yun, Absher Devin M, Levy Daniel, Arnett Donna K, Fornage Myriam, Pankow James S, Boerwinkle Eric
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA,
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA.
Hum Mol Genet. 2015 Aug 1;24(15):4464-79. doi: 10.1093/hmg/ddv161. Epub 2015 May 1.
Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
肥胖是慢性疾病病理生理学的一个重要组成部分。识别与肥胖程度升高相关的表观遗传修饰，包括DNA甲基化变异，可能会指向在多种情况下失调的基因组途径。在社区动脉粥样硬化风险（ARIC）研究中，使用Illumina 450K Bead Chip芯片阵列检测了2097名非裔美国成年人白细胞DNA中的DNA甲基化。采用混合效应回归模型来测试甲基化β值与同时期体重指数（BMI）、腰围（WC）以及BMI变化之间的关联，并对批次效应和潜在混杂因素进行了调整。随后，在弗雷明汉心脏研究中使用2377名白人成年人的全血DNA以及在降脂药物和饮食网络研究遗传学中使用991名白人的CD4 + T细胞DNA进行了重复验证，之后又在多组织人类表达资源队列中使用648名女性的脂肪组织DNA进行了测试。在ARIC研究中，76个与BMI相关的探针、164个与WC相关的探针和8个与BMI变化相关的探针达到了显著性阈值（P < 1×10(-7)；Bonferroni法），包括最近报道的HIF3A、CPT1A和ABCG1区域中的探针。使用血液DNA对37个BMI探针和另外1个WC探针进行了重复验证。其中16个在脂肪组织中也得到了重复验证，包括在参与脂质代谢、免疫反应/细胞因子信号传导和其他多种途径的基因附近发现的15个新的甲基化结果，这些基因包括LGALS3BP、KDM2B、PBX1和BBS2等。尽管组织类型、种族和分析方法存在差异，但肥胖特征与众多CpG位点的DNA甲基化相关，这些位点在不同研究中均可重复出现。
