Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin USA.
TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin USA ; Human and Molecular Genetics Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, Wisconsin USA.
Clin Epigenetics. 2015 Feb 20;7(1):12. doi: 10.1186/s13148-015-0048-6. eCollection 2015.
The prevalence of chronic diseases such as cancer, type 2 diabetes, metabolic syndrome (MetS), and cardiovascular disease increases with age in all populations. Epigenetic features are hypothesized to play important roles in the pathophysiology of age-associated diseases, but a map of these markers is lacking. We searched for genome-wide age-associated methylation signatures in peripheral blood of individuals at high risks for MetS by profiling 485,000 CpG sites in 192 individuals of Northern European ancestry using the Illumina HM450 array. Subjects (ages 6-85 years) were part of seven extended families, and 73% of adults and 32% of children were overweight or obese.
We found 22,122 genome-wide significant age-associated CpG sites (P α=0.05 = 3.65 × 10(-7) after correction for multiple testing) of which 14,155 are positively associated with age while 7,967 are negatively associated. By applying a positional density-based clustering algorithm, we generated a map of epigenetic 'hot-spots' of age-associated genomic segments, which include 290 age-associated differentially methylated CpG clusters (aDMCs), of which 207 are positively associated with age. Gene/pathway enrichment analyses were performed on these clusters using FatiGO. Genes localized to both the positively (n = 241) and negatively (n = 16) age-associated clusters are significantly enriched in specific KEGG pathways and GO terms. The most significantly enriched pathways are the hedgehog signaling pathway (adjusted P = 3.96 × 10(-3)) and maturity-onset diabetes of the young (MODY) (adjusted P = 6.26 × 10(-3)) in the positive aDMCs and type I diabetes mellitus (adjusted P = 3.69 × 10(-7)) in the negative aDMCs. We also identified several epigenetic loci whose age-associated change rates differ between subjects diagnosed with MetS and those without.
We conclude that in a family cohort at high risk for MetS, age-associated epigenetic features enrich in biological pathways important for determining the fate of fat cells and for insulin production. We also observe that several genes known to be related to MetS show differential epigenetic response to age in individuals with and without MetS.
在所有人群中，癌症、2 型糖尿病、代谢综合征（MetS）和心血管疾病等慢性病的患病率随着年龄的增长而增加。表观遗传特征被认为在与年龄相关疾病的病理生理学中发挥着重要作用，但缺乏这些标记物的图谱。我们通过在 192 名北欧血统个体中使用 Illumina HM450 阵列对 485,000 个 CpG 位点进行分析，在患有 MetS 高风险的个体的外周血中搜索全基因组年龄相关的甲基化特征。受试者（年龄 6-85 岁）为七个扩展家族的一部分，73%的成年人和 32%的儿童超重或肥胖。
我们发现了 22,122 个全基因组显著的年龄相关 CpG 位点（Pα=0.05=3.65×10（-7），经多次测试校正后），其中 14,155 个与年龄呈正相关，7,967 个与年龄呈负相关。通过应用基于位置密度的聚类算法，我们生成了一个表观遗传“热点”的年龄相关基因组片段图谱，其中包括 290 个年龄相关的差异甲基化 CpG 簇（aDMCs），其中 207 个与年龄呈正相关。使用 FatiGO 对这些簇进行基因/途径富集分析。定位到正（n=241）和负（n=16）年龄相关簇的基因显著富集于特定的 KEGG 途径和 GO 术语。最显著富集的途径是 Hedgehog 信号通路（调整后的 P=3.96×10（-3））和年轻发病的成年型糖尿病（MODY）（调整后的 P=6.26×10（-3））在正 aDMCs 中，1 型糖尿病（调整后的 P=3.69×10（-7））在负 aDMCs 中。我们还发现了一些表观遗传基因座，其年龄相关的变化率在患有 MetS 和未患有 MetS 的受试者之间不同。
我们的结论是，在患有 MetS 高风险的家族队列中，与年龄相关的表观遗传特征在决定脂肪细胞命运和胰岛素产生的重要生物学途径中富集。我们还观察到，一些已知与 MetS 相关的基因在患有和不患有 MetS 的个体中对年龄的表观遗传反应不同。
