Guénard Frédéric, Tchernof André, Deshaies Yves, Biron Simon, Lescelleur Odette, Biertho Laurent, Marceau Simon, Pérusse Louis, Vohl Marie-Claude
Institute of Nutrition and Functional Foods (INAF), Québec, Canada; School of Nutrition, Laval University, Québec, Canada.
School of Nutrition, Laval University, Québec, Canada; Québec Heart and Lung Institute, Québec, Canada.
Transl Res. 2017 Jun;184:1-11.e2. doi: 10.1016/j.trsl.2017.01.002. Epub 2017 Feb 2.
A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)-binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels.
已有报道称基因对甲基化水平有影响，并且在各种组织中已鉴定出甲基化定量性状位点（meQTL）。基因和表观遗传因素在代谢综合征（MetS）发展中的作用也已得到关注。为了确定用于测试单核苷酸多态性（SNP）与MetS及其组分之间关联的候选基因，我们旨在评估基因变异对MetS不一致的严重肥胖男性中差异甲基化CpG位点的贡献。对31名MetS不一致的严重肥胖男性（16名患有MetS，15名未患有MetS）的内脏脂肪组织（VAT）进行了全基因组差异甲基化分析，确定了约17,800个可变CpG位点。为了识别与可变CpG位点甲基化水平相关的SNP（meQTL）而进行的全基因组关联研究揭示了2292个显著关联（P < 2.22×10），涉及2182个独特的meQTL，这些meQTL调节174个可变CpG位点的甲基化水平。在3021名肥胖个体的队列中，测试了两个破坏位于胶原蛋白编码COL11A2基因内的CpG位点的meQTL与MetS及其组分的关联。这些meQTL的罕见等位基因与空腹血糖水平相关。基于转录因子（TF）结合亲和力的预测，对这些meQTL进行的进一步分析表明其生物学影响是通过破坏TF结合位点介导的。当前研究在严重肥胖男性的VAT中鉴定出meQTL，并揭示了两个COL11A2 meQTL与空腹血糖水平的关联。
