Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci
Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci
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DOI：
10.1093/hmg/ddv161
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发表时间：
2015-08-01
影响因子：
3.5
通讯作者：
Boerwinkle, Eric
中科院分区：
文献类型：
--
作者：
Demerath, Ellen W.;Guan, Weihua;Boerwinkle, Eric
肥胖是慢性疾病病理生理的重要组成部分。识别与肥胖升高相关的表观遗传修饰，包括DNA甲基化变异，可能指向在许多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芯片阵列检测2097名非裔美国成年人白细胞DNA的DNA甲基化。采用混合效应回归模型检验甲基化β值与同期体重指数（BMI）和腰围（WC）以及BMI变化的相关性，并对批效应和潜在混杂因素进行调整。使用来自Framingham心脏研究中2377名白人成人的全血DNA和来自降脂药物和饮食网络遗传学研究中991名白人的CD4+ T细胞DNA进行复制，然后使用来自多组织人类表达资源队列中648名女性的脂肪组织DNA进行测试。76个BMI相关探针、164个wc相关探针和8个BMI变化相关探针在ARIC中通过了显著性阈值(P < 1 × 10(-7)；Bonferroni)，包括最近报道的HIF3A、CPT1A和ABCG1区域的探针。37个BMI探针和1个额外的WC探针实现了血液DNA复制。其中16个也在脂肪组织中复制，包括15个新的甲基化发现，涉及脂质代谢、免疫反应/细胞因子信号传导和其他不同途径的基因，包括LGALS3BP、KDM2B、PBX1和BBS2等。肥胖特征与许多CpG位点的DNA甲基化有关，尽管在组织类型、种族和分析方法上存在差异，但这种甲基化在研究中是重复的。
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 x 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.