Objective

Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.

Design

Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0–F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.

Results

703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3–4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.

Conclusion

In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.

中文翻译：

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PNPLA3、TM6SF2 和 HSD17B13 变体对经活检证实的非酒精性脂肪肝疾病严重程度的综合影响

客观的

已确定几种单核苷酸多态性对非酒精性脂肪肝（NAFLD）患者的疾病严重程度不利或具有保护作用。然而，目前尚不清楚是否将遗传风险因素单独或结合到 NAFLD 的风险分层算法中，实际上是否比临床风险因素提供了更多的益处。

设计

活检证实为 NAFLD 的患者对PNPLA3 - rs738409（次要等位基因：G）、TM6SF2 - rs58542926（次要等位基因：T）和HSD17B13 - rs72613567（次要等位基因：TA）变体进行基因分型。NAFLD 活动评分 (NAS) 和纤维化阶段 (F0-F4) 用于对所有肝活检样本进行分级和分期。该研究考虑了来自整个中欧七个中心的患者。

结果

纳入 703 名患者：NAS ≥ 5:173（24.6%）；纤维化：F3–4:81（11.5%）。PNPLA3 G/G 基因型与 NAS ≥ 5（aOR 2.23，p  = 0.007）和晚期纤维化（aOR-3.48，p  < 0.001）相关。TM6SF2 T/- 与晚期纤维化相关（aOR 1.99，p  = 0.023）。HSD17B13 TA/- 与 NAS ≥ 5 的较低概率相关（TA/T：aOR 0.65，p  = 0.041，TA/TA：aOR 0.40，p  = 0.033）。关于 NAS ≥ 5 的预测能力，众所周知的风险因素（年龄、性别、BMI、糖尿病和 ALT；基线模型）的 AUC 为 0.758，添加PNPLA3（AUC 0.766），HSB17B13(AUC 0.766) 和它们的组合 (AUC 0.775)，但不是TM6SF2 (AUC 0.762)，导致模型的诊断准确性更高。添加用于预测晚期纤维化的遗传标记（基线模型：年龄、性别、BMI、糖尿病：AUC 0.777）如果PNPLA3（AUC 0.789）和 TM6SF2（AUC 0.786）导致更高的 AUC ，但如果HSD17B13（ 0.777）则不会添加。

结论

在活检证实的 NAFLD 中，PNPLA3 G/-、TM6SF2 T/- 和HSD17B13 TA/- 携带与 NAFLD 的严重程度相关。将这些遗传风险因素纳入风险分层模型可能会提高其对 NAFLD 严重程度和/或肝活检晚期纤维化的预测准确性。