Background & Aims

There are no biomarkers of nonalcoholic steatohepatitis (NASH) that are ready for routine clinical use. We investigated whether an analysis of PNPLA3 and TM6SF2 genotypes (rs738409 and rs58542926) can be used to identify patients with nonalcoholic fatty liver disease (NAFLD), with and without diabetes, who also have NASH.

Methods

We collected data from the Boramae registry in Korea on 453 patients with biopsy-proven NAFLD with sufficient clinical data for calculating scores. Patients enrolled from February 2014 through March 2016 were assigned to cohort 1 (n = 302; discovery cohort) and patients enrolled thereafter were assigned to cohort 2 (n = 151; validation cohort). DNA samples were obtained from all participants and analyzed for the PNPLA3 rs738409 C>G, TM6SF2 rs58542926 C>T, SREBF2 rs133291 C>T, MBOAT7-TMC4 rs641738 C>T, and HSD17B13 rs72613567 adenine insertion (A-INS) polymorphisms. We used multivariable logistic regression analyses with stepwise backward selection to build a model to determine patients’ risk for NASH (NASH PT) using the genotype and clinical data from cohort 1 and tested its accuracy in cohort 2. We used the receiver operating characteristic (ROC) curve to compare the diagnostic performances of the NASH PT and the NASH scoring systems.

Results

We developed a NASH PT scoring system based on PNPLA3 and TM6SF2 genotypes, diabetes status, insulin resistance, and levels of aspartate aminotransferase and high-sensitivity C-reactive protein. NASH PT scores identified patients with NASH with an area under the ROC (AUROC) of 0.859 (95% CI, 0.817–0.901) in cohort 1. In cohort 2, NASH PT scores identified patients with NASH with an AUROC of 0.787 (95% CI, 0.715–0.860), which was significantly higher than the AUROC of the NASH score (AUROC, 0.729; 95% CI, 0.647–0.812; P = .007). The AUROC of the NASH PT score for detecting NASH in patients with NAFLD with diabetes was 0.835 (95% CI, 0.776–0.895) and in patients without diabetes was 0.809 (95% CI, 0.757–0.861). The negative predictive value of the NASH PT score <–0.785 for NASH in patients with NAFLD with diabetes reached 0.905.

Conclusions

We developed a scoring system, based on polymorphisms in PNPLA3 and TM6SF2 and clinical factors that identifies patients with NAFLD, with or without diabetes, who have NASH, with an AUROC value of 0.787. This system might help clinicians better identify NAFLD patients at risk for NASH.

中文翻译：

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基于遗传和临床因素的评分系统的开发和验证，以确定亚洲非酒精性脂肪肝患者的脂肪性肝炎风险。

背景与目标

没有可供常规临床使用的非酒精性脂肪性肝炎 (NASH) 的生物标志物。我们调查了对PNPLA3和TM6SF2基因型（rs738409 和 rs58542926）的分析是否可用于识别非酒精性脂肪性肝病 (NAFLD) 患者，无论是否患有糖尿病，同时患有 NASH。

方法

我们从韩国 Boramae 登记处收集了 453 名经活检证实的 NAFLD 患者的数据，这些患者的临床数据足以计算评分。2014 年 2 月至 2016 年 3 月入组的患者被分配到队列 1（n = 302；发现队列），之后入组的患者被分配到队列 2（n = 151；验证队列）。从所有参与者获取 DNA 样本，并分析了PNPLA3 rs738409 C>G、TM6SF2 rs58542926 C>T、SREBF2 rs133291 C>T、MBOAT7-TMC4 rs641738 C>T 和HSD17B13rs72613567 腺嘌呤插入 (A-INS) 多态性。我们使用多变量逻辑回归分析和逐步向后选择来构建模型，使用来自队列 1 的基因型和临床数据确定患者的 NASH (NASH PT) 风险，并在队列 2 中测试其准确性。我们使用接收者操作特征 (ROC ) 曲线来比较 NASH PT 和 NASH 评分系统的诊断性能。

结果

我们开发了基于PNPLA3和TM6SF2基因型、糖尿病状态、胰岛素抵抗以及天冬氨酸转氨酶和高敏 C 反应蛋白水平的NASH PT 评分系统。NASH PT 评分确定了队列 1 中 ROC 下面积 (AUROC) 为 0.859 (95% CI, 0.817–0.901) 的 NASH 患者。在队列 2 中，NASH PT 评分确定了 AUROC 为 0.787 (95%) 的 NASH 患者CI，0.715–0.860），显着高于 NASH 评分的 AUROC（AUROC，0.729；95% CI，0.647–0.812；P = .007）。用于检测 NAFLD 合并糖尿病患者 NASH 的 NASH PT 评分的 AUROC 为 0.835（95% CI，0.776-0.895），无糖尿病患者的 AUROC 为 0.809（95% CI，0.757-0.861）。NASH PT 评分<–0.785 对 NAFLD 合并糖尿病患者 NASH 的阴性预测值达到 0.905。

结论

我们开发了一个基于PNPLA3和TM6SF2 中的多态性和临床因素的评分系统，该系统可识别患有或不患有糖尿病、患有 NASH 的 NAFLD 患者，其 AUROC 值为 0.787。该系统可能有助于临床医生更好地识别有 NASH 风险的 NAFLD 患者。