Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk.
Methylation quantitative trait locus analysis of chronic postsurgical pain uncovers epigenetic mediators of genetic risk.
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DOI：
10.2217/epi-2020-0424
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发表时间：
2021-04
期刊：
影响因子：
3.8
通讯作者：
V. Chidambaran;Xue Zhang;Valentina Pilipenko;Xiaoting Chen;Benjamin Wronowski;Kristie Geisler;Lisa J. Martin;A. Barski;M. Weirauch;H. Ji
中科院分区：
文献类型：
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作者：
V. Chidambaran;Xue Zhang;Valentina Pilipenko;Xiaoting Chen;Benjamin Wronowski;Kristie Geisler;Lisa J. Martin;A. Barski;M. Weirauch;H. Ji
背景：单核苷酸多态和DNA甲基化导致慢性术后疼痛(CPSP)的通路重叠，促使对CPSP相关甲基化数量性状基因座(MeQTL)进行初步研究。材料与方法：前瞻性招募接受脊柱融合术的儿童。对基因组和表观基因组范围的CPSP关联和DNA甲基化-单核苷酸多态关联/中介分析进行Logistic回归分析，以确定meQTL，然后进行功能基因组学分析。结果：CPSP组(n=20/58)和非CPSP组的疼痛程度不同。在2753个meQTL中，127个胞嘧啶-鸟嘌呤二核苷酸的DNA甲基化介导了470个meQTL与CPSP的关联(p<；0.05)。在PARK16基因座，CPSP风险meQTL与RAB7L1的DNA甲基化降低和PM20D1的DNA甲基化增加相关。相应的RAB7L1/PM20D1血液eQTL(GTEx)和组蛋白标记、转录因子结合位点和ATAC-seq峰的胞嘧啶-鸟嘌呤二核苷酸位点丰富表明转录因子结合发生了变化。结论：CPSP相关的meQTL提示表观遗传机制介导遗传风险。临床试验注册：NCT01839461，NCT01731873(ClinicalTrials.gov)。
Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).