PDF(Pubmed)
Abstract：
Inflammation underlies many conditions causing excess morbidity and mortality among people with HIV (PWH). A handful of single-trait epigenome-wide association studies (EWAS) have suggested that inflammation is associated with DNA methylation (DNAm) among PWH. Multi-trait EWAS may further improve statistical power and reveal pathways in common between different inflammatory markers. We conducted single-trait EWAS of three inflammatory markers (soluble CD14, D-dimers, and interleukin 6) in the Veteran Aging Cohort Study (n = 920). The study population was all male PWH with an average age of 51 years, and 82.3% self-reported as Black. We then applied two multi-trait EWAS methods-CPASSOC and OmniTest-to combine single-trait EWAS results. CPASSOC and OmniTest identified 189 and 157 inflammation-associated DNAm sites respectively, of which 112 overlapped. Among the identified sites, 56% were not significant in any single-trait EWAS. Top sites were mapped to inflammation-related genes including IFITM1, PARP9 and STAT1. These genes were significantly enriched in pathways such as \"type I interferon signaling\" and \"immune response to virus\". We demonstrate that multi-trait EWAS can improve the discovery of inflammation-associated DNAm sites, genes, and pathways. These DNAm sites suggest molecular mechanisms in response to inflammation associated with HIV and might hold the key to addressing persistent inflammation in PWH.
摘要：
炎症是许多导致HIV感染者（PWH）发病率和死亡率过高的疾病的基础。少数单性状表观基因组关联研究（EWAS）表明，炎症与PWH中的DNA甲基化（DNAm）有关。多性状EWAS可以进一步提高统计能力，并揭示不同炎症标志物之间的共同途径。我们对三种炎症标志物(可溶性CD14，D-二聚体，和白细胞介素6）在退伍军人衰老队列研究中（n=920）。研究人群均为男性PWH，平均年龄为51岁，82.3%的人自我报告为黑人。然后，我们应用了CPASSOC和OmniTest两种多性状EWAS方法来组合单性状EWAS结果。CPASSOC和OmniTest分别确定了189和157个与炎症相关的DNAm位点，其中112个重叠。在确定的地点中，56%的人在任何单性状EWAS中都不显著。顶级位点被定位到炎症相关基因，包括IFITM1，PARP9和STAT1。这些基因在“I型干扰素信号传导”和“对病毒的免疫应答”等途径中显著富集。我们证明了多性状EWAS可以改善炎症相关DNAm位点的发现，基因，和路径。这些DNAm位点提示了响应与HIV相关的炎症的分子机制，并且可能是解决PWH中持续炎症的关键。
