Cheng Guo, Chung Patrick Ho-Yu, Chan Edwin Kin-Wai, So Man-Ting, Sham Pak-Chung, Cherny Stacey S, Tam Paul Kwong-Hang, Garcia-Barceló Maria-Mercè
Department of Surgery, 1/F Hong Kong Jockey Club Building for Interdisciplinary Research, 5 Sassoon Road, Pokfulam, Hong Kong.
Department of Surgery, the Chinese University of Hong Kong, Hong Kong, SAR, China.
BMC Med Genomics. 2017 Apr 17;10(1):22. doi: 10.1186/s12920-017-0259-0.
Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance.
The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case-control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network.
Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers' immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway.
The study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics.
胆道闭锁（BA）较为罕见且遗传机制复杂，其发病机制尚不明确。该病病程多变，具有异质性，这给有效的疾病管理带来了阻碍。解读BA的表型差异是临床工作的重点，可通过基因型和表型的综合分析来实现。我们旨在探究BA的表型特征并明确其差异来源。
本研究为横断面观察性研究，并结合病例/对照关联分析。纳入181例III型非综合征性BA患者和431例对照进行病例对照关联检测，其中89例患者（47.19%为男性，出生于1981年6月15日至2007年9月17日）有详细的临床记录及病程随访（中位随访时间约17.2年）。通过全基因组基于基因的常见遗传变异（CV）和罕见拷贝数变异（CNV）关联检测来寻找BA相关基因，后者仅包括长度大于100kb且在BA患者中发现但在当地人群（N = 1381）或数据库（N = 11943）中未发现的CNV。在此，合并症定义为影响BA患者但与BA或BA治疗无已知关联的慢性疾病。我们研究了CNV的基因型-表型相关性、这些新变异与BA相关CV的关联性及其在BA候选基因网络中的作用。
89例患者中，41.57%患有合并症，包括自身免疫性过敏疾病（22.47%）。他们携带29个BA特有的CNV，其中3个CNV与携带者的免疫合并症相关，还有1个JAG1基因微缺失。BA-CNV交叉基因（N = 102）和CV标记基因（N = 103）均富含免疫炎症途径基因（FDR q < 0.20），且这两个基因集相互关联（置换p = 0.039）。代表CV和罕见CNV关联基因的分子网络呈核心/外周结构，免疫基因及其相关模块位于所有连接的连贯核心，表明其在BA发病机制途径中起主导作用。
本研究突出了患者复杂性现象作为一种新的BA表型特征，其由罕见CNV所支撑，这些罕见CNV在生物学上与CV汇聚到免疫炎症途径，推动了BA的发生以及临床上BA与免疫疾病的可能关联。
