目的:中心性肥胖会增加对多种慢性疾病的易感性,从而对健康构成重大风险。表观遗传特征如DNA甲基化可能与特定的肥胖特征有关。这可以帮助我们了解遗传和环境因素如何相互作用以影响肥胖的发展。本研究旨在确定与中国北方汉族人群腰围(WC)相关的DNA甲基化位点,并阐明潜在的因果关系。
方法:从中国青岛双胞胎登记处选择59对WC不和谐单卵双胞胎(ΔWC>0)。采用广义估计方程模型估计WC上CpG位点的甲基化水平。甲基化和WC之间的因果关系是通过使用FimiliaL混淆(ICEFALCON)检查家庭混杂因素来评估的。此外,整个表观基因组分析的结果在验证阶段得到了证实.
结果:我们确定了26个CpG位点的差异甲基化达到假发现率(FDR)<0.05和22个差异甲基化区域(slk校正p<0.05)与WC密切相关。这些发现为26个基因提供了注释,值得注意的是MMP17、ITGA11、COL23A1、TFPI、A2ML1-AS1,MRGPRE,C2orf82和NINJ2。ICEFALCON分析表明,ITGA11和TFPI的DNA甲基化对WC具有因果效应,反之亦然(p<0.05)。随后的验证分析成功复制了26个鉴定位点中的10个(p<0.05)。
结论:我们的研究已经确定了中国北方汉族人群中特定的表观遗传变异与WC之间的关联。这些DNA甲基化特征可以为肥胖和WC的表观遗传调控提供新的见解,并暗示可能的生物学机制。
OBJECTIVE: Central obesity poses significant health risks because it increases susceptibility to multiple chronic diseases. Epigenetic features such as DNA methylation may be associated with specific obesity traits, which could help us understand how genetic and environmental factors interact to influence the development of obesity. This study aims to identify DNA methylation sites associated with the waist circumference (WC) in Northern Han Chinese population, and to elucidate potential causal relationships.
METHODS: A total of 59 pairs of WC discordant monozygotic twins (ΔWC >0) were selected from the Qingdao Twin Registry in
China. Generalized estimated equation model was employed to estimate the methylation levels of CpG sites on WC. Causal relationships between methylation and WC were assessed through the examination of family confounding factors using FAmiliaL CONfounding (ICE FALCON). Additionally, the findings of the epigenome-wide analysis were corroborated in the validation stage.
RESULTS: We identified 26 CpG sites with differential methylation reached false discovery rate (FDR) < 0.05 and 22 differentially methylated regions (slk-corrected p < 0.05) strongly linked to WC. These findings provided annotations for 26 genes, with notable emphasis on MMP17, ITGA11, COL23A1, TFPI, A2ML1-AS1, MRGPRE, C2orf82, and NINJ2. ICE FALCON analysis indicated the DNA methylation of ITGA11 and TFPI had a causal effect on WC and vice versa (p < 0.05). Subsequent validation analysis successfully replicated 10 (p < 0.05) out of the 26 identified sites.
CONCLUSIONS: Our research has ascertained an association between specific epigenetic variations and WC in the Northern Han Chinese population. These DNA methylation features can offer fresh insights into the epigenetic regulation of obesity and WC as well as hints to plausible biological mechanisms.