Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

中文翻译：

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遗传关联分析确定与原发性硬化性胆管炎疾病进展相关的变异

目的 原发性硬化性胆管炎 (PSC) 是一种遗传复杂的炎症性胆管疾病，病因不明，通常导致肝移植或死亡。关于遗传对 PSC 的严重程度和进展的贡献知之甚少。本研究的目的是确定与 PSC 疾病进展和并发症发展相关的遗传变异。设计 我们在 3402 名 PSC 患者的大型队列中收集了标准化的 PSC 亚表型。在进行质量控制后，我们将所有患者的 130 422 个单核苷酸多态性（使用 Illumina 免疫芯片获得）与其疾病亚表型相结合。使用逻辑回归和 Cox 比例风险模型，我们确定了与二元和事件发生时间 PSC 亚表型相关的遗传变异。结果 我们确定遗传变异 rs853974 与无肝移植存活相关（p=6.07×10-9）。Kaplan-Meier 生存分析显示 rs853974 纯合 AA 等位基因携带者的无移植生存率为 50.9%（95% CI 41.5% 至 59.5%），而 GG 携带者 10 年的无移植生存率为 72.8%（95% CI 69.6% 至 75.7%） PSC 诊断后。对于该区域的候选基因 RSPO3，我们展示了在关键的肝脏驻留效应细胞中的表达，例如人和鼠胆管细胞以及人肝星状细胞。结论 我们提出了一个大型国际 PSC 队列，并报告了与 PSC 疾病进展相关的基因位点。对于无肝移植生存，我们确定了一个全基因组的重要信号，并证明了候选基因 RSPO3 在关键的肝脏驻留效应细胞中的表达。