Center for Crohn's and Colitis, Department of Gastroenterology, Kyung Hee University College of Medicine, Seoul, Republic of Korea.
Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea.
Clin Transl Gastroenterol. 2020 Jul;11(7):e00213. doi: 10.14309/ctg.0000000000000213.
The family history of inflammatory bowel disease (IBD) has been strongly associated with risk of developing IBD. This study aimed to identify the host genetic and gut microbial signatures in familial IBD.
Genetic analyses using genome-wide single nucleotide polymorphism genotyping and whole exome sequencing were performed to calculate weighted genetic risk scores from known IBD-associated common variants and to identify rare deleterious protein-altering variants specific to patients with familial IBD in 8 Korean families that each included more than 2 affected first-degree relatives (FDRs) and their unaffected FDR(s). In parallel, gut microbial community was analyzed by 16S rRNA sequencing of stools from the sample individuals.
The risk of familial IBD was not well explained by the genetic burden from common IBD-risk variants, suggesting the presence of family-shared genetic and environmental disease-risk factors. We identified 17 genes (AC113554.1, ACE, AKAP17A, AKAP9, ANK2, ASB16, ASIC3, DNPH1, DUS3L, FAM200A, FZD10, LAMA5, NUTM2F, PKN1, PRR26, WDR66, and ZC3H4) that each contained rare, potentially deleterious variants transmitted to the affected FDRs in multiple families. In addition, metagenomic analyses revealed significantly different diversity of gut microbiota and identified a number of differentially abundant taxa in affected FDRs, highlighting 22 novel familial disease-associated taxa with large abundance changes and the previously reported gut dysbiosis including low alpha diversity in IBD and 16 known IBD-specific taxa.
This study identified familial IBD-associated rare deleterious variants and gut microbial dysbiosis in familial IBD.
炎症性肠病（IBD）的家族史与发生 IBD 的风险密切相关。本研究旨在确定家族性 IBD 中的宿主遗传和肠道微生物特征。
使用全基因组单核苷酸多态性基因分型和外显子组测序进行遗传分析，以计算来自已知 IBD 相关常见变体的加权遗传风险评分，并确定 8 个韩国家族中每个家族中至少有 2 个受影响的一级亲属（FDR）及其未受影响的 FDR 的家族性 IBD 患者特有的罕见有害蛋白改变变体。同时，通过对样本个体粪便中的 16S rRNA 测序分析肠道微生物群落。
家族性 IBD 的风险不能很好地用常见 IBD 风险变体的遗传负担来解释，这表明存在家族共享的遗传和环境疾病风险因素。我们鉴定了 17 个基因（AC113554.1、ACE、AKAP17A、AKAP9、ANK2、ASB16、ASIC3、DNPH1、DUS3L、FAM200A、FZD10、LAMA5、NUTM2F、PKN1、PRR26、WDR66 和 ZC3H4），每个基因都包含传递给多个家族受影响 FDR 的罕见、潜在有害变体。此外，宏基因组分析显示肠道微生物群落的多样性存在显著差异，并鉴定出受影响 FDR 中大量丰度变化的大量差异丰度分类群，突出了 22 个新的与疾病相关的家族疾病相关分类群，其丰度变化较大，以及之前报道的 IBD 中包括 alpha 多样性低和 16 种已知的 IBD 特异性分类群的肠道失调。
本研究鉴定了家族性 IBD 相关的罕见有害变体和家族性 IBD 中的肠道微生物失调。
