PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality

IF 4.7 Q2 IMMUNOLOGY
Kalliopi Azariadis , Nikolaos K. Gatselis , Aggeliki Lyberopoulou , Pinelopi Arvaniti , Kalliopi Zachou , Stella Gabeta , George N. Dalekos
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Abstract

Background

Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).

Aim

Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH.

Method

Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).

Results

The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.

Conclusions

The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.

Abstract Image

自身免疫性肝炎中的 PNPLA3 I148 M 基因变异是诊断时疾病晚期、无肝硬化事件存活率和肝脏相关死亡率降低的特征
背景自身免疫性肝炎(AIH)是一种相对罕见的自身免疫性疾病,具有很强的遗传背景。我们的目的是研究 PNPLA3 I148 M 变体在 AIH 中的意义。方法评估了本中心随访的 200 名 AIH 患者,并以 100 名健康人作为对照。结果95/200(47.5%)名AIH患者存在I148 M变体,而47/100(47%)名健康对照者存在I148 M变体(P = 1.000)。基因型为 GG/CG 的患者在确诊时更有可能出现失代偿性肝硬化(GG/CG 6.3% vs. CC 1%,p = 0.039)。不同基因型的患者合并心血管代谢风险因素和并发 MASLD 的情况相似。37/186(19.9%)例患者出现单纯性脂肪变性,14/186(7.5%)例患者出现脂肪性肝炎,且肝活检结果与 PNPLA3 基因型无关。纤维化阶段和炎症等级与任何基因型均无相关性。治疗反应也与是否存在 I148 M 变异无关,尽管携带 GG/CG 基因型的患者需要更长的时间才能达到完全生化反应(p = 0.07)。在卡普兰-梅耶尔分析中,G 等位基因的同型性与治疗后患者无失代偿(p = 0.006)、无肝硬化事件(失代偿、肝移植、肝细胞癌;p = 0.001)、肝相关死亡或肝移植(p = 0.011)的生存率降低有关。结论无论是否存在 MASLD,AIH 患者中的 PNPLA3 I148 M 变异与诊断时晚期疾病风险增加、无肝硬化事件、肝相关死亡或肝移植的生存率降低有关。这标志着PNPLA3 I148 M变体作为一种新的AIH生物标记物的潜在作用,可用于识别疾病进展风险增加的患者。
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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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