Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Inflammatory Bowel Diseases Center, Humanitas Research Hospital, Milan, Italy.
Gastroenterology. 2020 Aug;159(2):549-561.e8. doi: 10.1053/j.gastro.2020.04.063. Epub 2020 May 1.
BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease.
DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells.
Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases.
In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.
胶原性结肠炎（CC）是一种炎症性肠病，其发病机制不明，涉及与 HLA 相关的免疫介导反应以及环境和遗传风险因素。我们对胶原性结肠炎患者队列进行了基于阵列的遗传关联研究，并研究了 CC 与克罗恩病（CD）、溃疡性结肠炎（UC）和乳糜泻之间的常见遗传基础。
使用 Illumina Immunochip 对 804 例 CC 福尔马林固定、石蜡包埋组织样本的 DNA 进行基因分型。CC 病例的匹配基因型数据由各自的联盟提供，包括 CD、UC 和乳糜泻病例。进行了发现关联研究，随后进行了独立队列的荟萃分析、多基因风险评分计算和跨表型分析。在造血细胞和肠细胞中评估了 CC 变体中调节表达数量性状基因座的富集。
三个 HLA 等位基因（HLA-B∗08:01、HLA-DRB1∗03:01 和 HLA-DQB1∗02:01）与祖先单倍型 8.1 相关，与 CC 风险增加显著相关。我们还发现 HLA-DRB1∗04:01 对 CC 风险有独立的保护作用。多基因风险评分量化了多个易感基因座的风险，与 CC 风险强烈相关。在各种细胞类型中，CC 易感性变体中检测到表达数量性状基因座的富集。跨表型分析确定了 CC 与其他免疫介导疾病之间复杂的多效性遗传模式。
在这项迄今为止最大的 CC 遗传研究中，对组织学证实的诊断进行了研究，我们强烈暗示了 HLA 基因座，并提出了疾病发病机制中的潜在非 HLA 机制。我们还检测到 CC、乳糜泻、CD 和 UC 之间存在共同的遗传风险，这支持了合并症的临床观察。
