背景:PNPLA3-rs738409-G,TM6SF2-rs58542926-T,和HSD17B13-rs6834314-A多态性与肝硬化有关,肝失代偿,和HCC。然而,在已经患有肝硬化的人中,它们是否仍然与HCC和代偿失调相关尚不清楚,这限制了遗传学在风险分层中的临床应用,因为HCC在没有肝硬化的情况下并不常见。我们旨在描述PNPLA3,TM6SF2和HSD17B13基因型对肝脏失代偿的影响,HCC,基线代偿性肝硬化患者的肝脏相关死亡率或肝移植。
方法:我们对密歇根基因组学计划中接受基因分型的患者进行了单中心回顾性研究。主要预测因子是PNPLA3,TM6SF2和HSD17B13基因型。主要结果是肝脏失代偿,HCC,或肝脏相关的死亡率/移植。我们对我们的队列进行了竞争风险Fine-Gray分析。
结果:我们确定了732例基线代偿性肝硬化患者。随访期间,50%的患者出现代偿失调,13%发展为肝癌,24%接受了肝移植,27%的人死亡。PNPLA3-rs738409-G基因型与HCC事件风险相关:调整的亚风险比2.42(1.40-4.17),对于PNPLA3-rs738409-GG,p=0.0015PNPLA3-rs738409-CC基因型。PNPLA3-rs738409-GG携带者的肝癌5年累积发病率高于PNPLA3-rs738409-CC/-CG携带者:15.6%(9.0%-24.0%)7.4%(5.2%-10.0%),p<0.001。PNPLA3基因型与失代偿或肝脏相关死亡率或肝移植的综合结局无关。TM6SF2和HSD17B13基因型与失代偿或HCC无关。
结论:PNPLA3-rs738409-G等位基因与基线代偿性肝硬化患者的HCC风险增加相关。患有肝硬化和PNPLA3-rs738409-GG基因型的人可能需要更密集的HCC监测。
BACKGROUND: The PNPLA3-rs738409-G, TM6SF2-rs58542926-T, and HSD17B13-rs6834314-A polymorphisms have been associated with cirrhosis, hepatic decompensation, and HCC. However, whether they remain associated with HCC and decompensation in people who already have cirrhosis remains unclear, which limits the clinical utility of genetics in risk stratification as HCC is uncommon in the absence of cirrhosis. We aimed to characterize the effects of PNPLA3, TM6SF2, and HSD17B13 genotype on hepatic decompensation, HCC, and liver-related mortality or liver transplant in patients with baseline compensated cirrhosis.
METHODS: We conducted a single-center retrospective study of patients in the Michigan Genomics Initiative who underwent genotyping. The primary predictors were PNPLA3, TM6SF2, and HSD17B13 genotypes. Primary outcomes were either hepatic decompensation, HCC, or liver-related mortality/transplant. We conducted competing risk Fine-Gray analyses on our cohort.
RESULTS: We identified 732 patients with baseline compensated cirrhosis. During follow-up, 50% of patients developed decompensation, 13% developed HCC, 24% underwent liver transplant, and 27% died. PNPLA3-rs738409-G genotype was associated with risk of incident HCC: adjusted subhazard hazard ratio 2.42 (1.40-4.17), p=0.0015 for PNPLA3-rs738409-GG vs. PNPLA3-rs738409-CC genotype. The 5-year cumulative incidence of HCC was higher in PNPLA3-rs738409-GG carriers than PNPLA3-rs738409-CC/-CG carriers: 15.6% (9.0%-24.0%) vs. 7.4% (5.2%-10.0%), p<0.001. PNPLA3 genotype was not associated with decompensation or the combined outcome of liver-related mortality or liver transplant. TM6SF2 and HSD17B13 genotypes were not associated with decompensation or HCC.
CONCLUSIONS: The PNPLA3-rs738409-G allele is associated with an increased risk of HCC among patients with baseline compensated cirrhosis. People with cirrhosis and PNPLA3-rs738409-GG genotype may warrant more intensive HCC surveillance.