Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration (FDA) National Center for Toxicological Research, Jefferson, Arkansas, USA.
Division of Hepatology and Nutrition, Office of New Drugs, FDA Center for Drug Evaluation and Research, Silver Spring, Maryland, USA.
Clin Transl Gastroenterol. 2022 Jul 1;13(7):e00502. doi: 10.14309/ctg.0000000000000502. Epub 2022 Jun 2.
Indeterminate acute liver failure (IND-ALF) is a rare clinical syndrome with a high mortality rate. Lacking a known etiology makes rapid evaluation and treatment difficult, with liver transplantation often considered as the only therapeutic option. Our aim was to identify genetic variants from whole exome sequencing data that might be associated with IND-ALF clinical outcomes.
Bioinformatics analysis was performed on whole exome sequencing data for 22 patients with IND-ALF. A 2-tier approach was used to identify significant single-nucleotide polymorphisms (SNPs) associated with IND-ALF clinical outcomes. Tier 1 identified the SNPs with a higher relative risk in the IND-ALF population compared with those identified in control populations. Tier 2 determined the SNPs connected to transplant-free survival and associated with model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores.
Thirty-one SNPs were found associated with a higher relative risk in the IND-ALF population compared with those in controls, of which 11 belong to the human leukocyte antigen (HLA) class II genes but none for the class I. Further analysis showed that 5 SNPs: rs796202376, rs139189937, and rs113473719 of HLA-DRB5; rs9272712 of HLA-DQA1; and rs747397929 of IDO1 were associated with a higher probability of IND-ALF transplant-free survival. Using 3 selected SNPs, a model for the polygenic risk score was developed to predict IND-ALF prognoses, which are comparable with those by model for end-stage liver disease serum sodium and Acute Liver Failure Study Group prognostic scores.
Certain gene variants in HLA-DRB5, HLA-DQA1, and IDO1 were found associated with IND-ALF transplant-free survival. Once validated, these identified SNPs may help elucidate the mechanism of IND-ALF and assist in its diagnosis and management.
不明原因的急性肝衰竭（IND-ALF）是一种罕见的临床综合征，死亡率很高。由于缺乏已知的病因，快速评估和治疗变得困难，肝移植通常被认为是唯一的治疗选择。我们的目的是从全外显子组测序数据中识别可能与 IND-ALF 临床结局相关的遗传变异。
对 22 例 IND-ALF 患者的全外显子组测序数据进行生物信息学分析。采用两阶段方法来识别与 IND-ALF 临床结局相关的显著单核苷酸多态性（SNP）。第 1 阶段确定了与 IND-ALF 人群相比，在对照人群中具有更高相对风险的 SNP。第 2 阶段确定了与无移植存活率相关且与终末期肝病模型血清钠和急性肝衰竭研究组预后评分相关的 SNP。
在 IND-ALF 人群中发现 31 个 SNP 与对照人群相比具有更高的相对风险，其中 11 个属于人类白细胞抗原（HLA）Ⅱ类基因，但没有Ⅰ类基因。进一步分析表明，5 个 SNP：HLA-DRB5 的 rs796202376、rs139189937 和 rs113473719；HLA-DQA1 的 rs9272712；以及 IDO1 的 rs747397929 与 IND-ALF 无移植存活率较高有关。使用 3 个选定的 SNP，建立了多基因风险评分模型来预测 IND-ALF 预后，其与终末期肝病模型血清钠和急性肝衰竭研究组预后评分相当。
HLA-DRB5、HLA-DQA1 和 IDO1 中的某些基因变异与 IND-ALF 无移植存活率有关。一旦得到验证，这些鉴定的 SNP 可能有助于阐明 IND-ALF 的发病机制，并有助于其诊断和管理。
