Table_3_Integration Analysis of m6A-SNPs and eQTLs Associated With Sepsis Reveals Platelet Degranulation and Staphylococcus aureus Infection are Mediated by m6A mRNA Methylation.xlsx

Sepsis is a major threat with high mortality rate for critically ill patients. Response to pathogen infection by the host immune system is a key biological process involved in the onset and development of sepsis. Heterogeneous host genome variation, especially single nucleotide polymorphisms (SNPs), has long been suggested to contribute to differences in disease progression. However, the function of SNPs located in non-coding regions remains to be elucidated. Recently, m6A mRNA modification levels were revealed to differ at SNPs. As m6A is a crucial regulator of gene expression, these SNPs might control genes by changing the m6A level on mRNA. To investigate the potential role of m6A SNPs in sepsis, we integrated m6A-SNP and expression quantitative trait loci (eQTLs) data. Analysis revealed 15,720 m6A-cis-eQTLs and 381 m6A-trans-eQTLs associated with sepsis. We identified 1321 genes as locations of m6A-cis-eQTLs. These were enriched in platelet degranulation and Staphylococcus aureus infection pathways, which are vital for the pathophysiological process of sepsis. We conclude that m6A modification of mRNA plays a very important role in sepsis, with m6A-cis-eQTLs potentially having the most effect on individual variation in sepsis progression.

脓毒症（Sepsis）是威胁危重症患者生命的高致死性重大疾病。宿主免疫系统对病原体感染的应答反应，是脓毒症发生与发展过程中的关键生物学过程。宿主基因组变异的异质性，尤其是单核苷酸多态性（single nucleotide polymorphisms, SNPs），长期以来被认为与疾病进展的个体差异密切相关。然而，位于非编码区域的SNPs的功能仍有待阐明。近期研究发现，SNPs位点处的m6A mRNA修饰水平存在差异。由于m6A是基因表达的关键调控因子，此类SNPs或可通过改变mRNA上的m6A修饰水平来调控基因表达。为探究m6A相关SNPs在脓毒症中的潜在作用，本研究整合了m6A-SNP与表达数量性状基因座（expression quantitative trait loci, eQTLs）数据。分析共鉴定出15720个与脓毒症相关的m6A顺式eQTL（m6A-cis-eQTLs）以及381个m6A反式eQTL（m6A-trans-eQTLs）。本研究共鉴定出1321个携带m6A顺式eQTL的基因。这些基因显著富集于血小板脱颗粒与金黄色葡萄球菌感染通路，而此类通路在脓毒症的病理生理过程中发挥重要作用。本研究最终得出结论：mRNA的m6A修饰在脓毒症的发生发展中发挥关键调控作用，其中m6A顺式eQTL或对脓毒症进展的个体差异影响最为显著。