Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Nat Commun. 2021 Feb 18;12(1):1122. doi: 10.1038/s41467-021-21458-z.
More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.
已有超过 240 个遗传风险位点与炎症性肠病（IBD）相关，但对于它们如何导致受累组织的疾病发展知之甚少。在这里，我们假设宿主遗传变异以炎症依赖的方式影响基因表达，并对 171 名 IBD 患者的 299 个来自炎症和非炎症黏膜的冷冻肠道活检组织进行了研究。进行了 RNA 测序，并使用全外显子测序和全基因组基因分型确定基因型。总共包含了 28746 个基因和 6894979 个 SNP。线性混合模型确定了 8881 个独立的肠道顺式表达数量性状基因座（cis-eQTLs）（FDR<0.05），并进行了交互分析，揭示了 190 个炎症依赖的肠道 cis-eQTLs（FDR<0.05），包括已知的 IBD 风险基因和编码免疫细胞受体和抗体的基因。炎症依赖的肠道 cis-eQTLs SNP（eSNP）主要与免疫细胞类型的流行率相互作用。炎症依赖的肠道 cis-eQTLs 揭示了炎症状态下的遗传易感性，这有助于确定参与炎症的细胞类型和炎症的潜在途径，这一知识可能指导未来的药物开发，并为 IBD 患者的精准医学提供个性化特征。
