Ruofan Li, Kaiyan Su, Tianzhun Wu, Li Xu, Wenyu Song, Dandan Sun, Tao Zeng, Jinzhang Chen, Haibei Xin, Yuanfeng Li, Mengya Zang, Minggen Hu
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However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation.</p><p><strong>Results: </strong>In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10<sup>- 4</sup>) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels.</p><p><strong>Conclusions: </strong>Our study provides the most comprehensive ABC regulatory maps of the liver to date. 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引用次数: 0
摘要
非酒精性脂肪性肝病(NAFLD)是全球范围内最广泛的肝脏疾病,从非酒精性脂肪性肝病(NAFL)和脂肪性肝炎(NASH)到纤维化/肝硬化,并有可能发展为肝细胞癌(HCC)。全基因组关联研究(GWASs)已经确定了几种与NAFLD相关的单核苷酸多态性(snp)。然而,许多与NAFLD相关的GWAS信号位于非编码区,这给解释它们的功能注释带来了挑战。结果:本研究通过整合15个肝脏组织和细胞系的表观基因组数据,利用接触活性(ABC)模型构建肝脏增强基因图谱。我们构建了最全面的肝脏全基因组调控图谱,确定了543,486个增强子基因连接,包括267,857个增强子和16,872个靶基因。富集分析表明,ABC snp在活性染色质区域和活性染色质状态显著富集。通过结合ABC调控图谱和NAFLD GWAS数据,我们系统地确定了与NAFLD风险相关的ABC snp。通过功能注释,如途径富集和药物基因相互作用分析,我们确定了6个基因(GGT1、ACTG1、SPP1、EPHA2、PROZ和SHMT1)作为NAFLD候选基因,其中SHMT1先前有报道。在与候选基因相关的SNP中,ABC SNP rs2017869 (C等位基因的优势比[OR] = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4)的ABC评分最高。根据ABC图谱,rs2017869与GGT1有关,而针对该基因的几种药物,如碘甲状腺原氨酸,对NAFLD患者显示出潜在的益处。此外,我们发现另一个新基因EPHA2可能通过调节GGT水平在NAFLD中发挥关键作用。结论:我们的研究提供了迄今为止最全面的肝脏ABC调控图谱。该资源为识别调节变异和确定NAFLD等肝脏疾病的易感基因的优先级提供了有价值的参考。
Introduction: Non-alcoholic fatty liver disease (NAFLD) represents the most widespread liver disease globally, ranging from non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH) to fibrosis/cirrhosis, with potential progression to hepatocellular carcinoma (HCC). Genome-wide association studies (GWASs) have identified several single nucleotide polymorphisms (SNPs) associated with NAFLD. However, numerous GWAS signals associated with NAFLD locate in non-coding regions, posing a challenge for interpreting their functional annotation.
Results: In this study, we utilized the Activity-by-Contact (ABC) model to construct the enhancer-gene maps of liver by integrating epigenomic data from 15 liver tissues and cell lines. We constructed the most comprehensive genome-wide regulatory maps of the liver, identifying 543,486 enhancer-gene connections, including 267,857 enhancers and 16,872 target genes. Enrichment analyses revealed that the ABC SNPs are significantly enriched in active chromatin regions and active chromatin state. By combining the ABC regulatory maps and NAFLD GWAS data, we systematically identified ABC SNPs associated with NAFLD risk. Through the functional annotations, such as pathway enrichment and drug-gene interaction analyses, we identified 6 genes (GGT1, ACTG1, SPP1, EPHA2, PROZ and SHMT1) as candidate NAFLD genes, with SHMT1 previously reported. Among the SNPs connected to the candidate genes, the ABC SNP rs2017869 (odds ratio [OR] for the C allele = 1.10, 95% CI = 1.04-1.16, P = 5.97 × 10- 4) had the highest ABC score. According to the ABC maps, rs2017869 links to GGT1, and several drugs targeting this gene, such as liothyronine, showed potential benefits to patients with NAFLD. Furthermore, we identified that another novel gene, EPHA2, may play a crucial role in NAFLD by regulating the GGT levels.
Conclusions: Our study provides the most comprehensive ABC regulatory maps of the liver to date. This resource offers a valuable reference for identifying regulatory variants and prioritizing susceptibility genes of liver diseases, such as NAFLD.
期刊介绍:
BMC Genomics is an open access, peer-reviewed journal that considers articles on all aspects of genome-scale analysis, functional genomics, and proteomics.
BMC Genomics is part of the BMC series which publishes subject-specific journals focused on the needs of individual research communities across all areas of biology and medicine. We offer an efficient, fair and friendly peer review service, and are committed to publishing all sound science, provided that there is some advance in knowledge presented by the work.