背景：编码I148M蛋白的PNPLA3基因多态性的纯合子影响慢性丙型肝炎患者（CHC）的脂肪变性和纤维发生。目的：对接受干扰素联合利巴韦林抗病毒治疗的CHC患者，根据病毒基因型和纤维化严重程度进行分组，其次，根据PNPLA3 148M/M基因型与白细胞介素-28B（IL28B）基因型对肝损害的相互作用进行分组，评价P148M/M基因型对其持续性病毒应答（SVR）和病毒动力学的影响。方法：在这项研究中，我们纳入了来自米兰和维也纳第三方参考检测中心的602例未经正规治疗的病人（60%基因型1性，30%高程度纤维化，33%IL28rs12979860 CC）。结果：在8%的患者中可检测到P148M/M基因型，虽然该基因型不影响所有病例的SVR（p=0.29），但是它与高程度纤维化基因1/4型（G1/4）患者的SVR（3/17,17%vs56/121,46%；p=0.034）和完全早期病毒学应答（4/17，23%vs68/121，56%；p=0.018）相关。经过对年龄、病毒载量、IL28B CC基因型、药物剂量和脂肪变性进行调整后，P148M/M基因型仍然是高程度纤维化G1/4型患者的SVR的预测因子（OR=0.23,95%CI 0.04-0.87）。在所有患者中P148M/M蛋白基因型与更高程度的纤维化相关（p=0.049），然而，IL28rs12979860 CC基因型只与非P148M/M基因型患者的高程度纤维化相关（p=0.017），且与年龄、体重指数{BMI}和丙氨酸氨基转移酶（ACT）水平无关。结论：除脂肪变之外，PNPLA3 P148M/M基因型与SVR和早期病毒动力学独立负相关，尽管只在难治性高纤维化的G1/4基因型患者中，但是对PNPLA3 P148M/M基因型的分组揭露了IL28B CC基因型和更严重肝纤维化的相关性。
吉林大学第一医院肝胆胰内科 陈林娇 摘译
本文首次发表于[Aliment Pharmacol Ther, 2012, 35(12):1434-1442]
本文首次发表于[Aliment Pharmacol Ther, 2012, 35(12):1434-1442]
Implications of PNPLA 3 polymorphism in chronic hepatitis C patients
receiving peginterferon plus ribavirin
receiving peginterferon plus ribavirin
Abstract
BACKGROUND:
Homozygosity for the PNPLA3 p.I148M polymorphism influences steatosis and fibrogenesis in chronic hepatitis C (CHC).
AIM:
To evaluate the effect of p.148M/M on sustained virological response (SVR) and viral kinetics in patients who underwent antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype and fibrosis severity, and secondarily, the interaction with interleukin-28B ( IL28B ) genotype on liver damage.
METHODS:
In this observational study, we considered 602 treatment-naïve consecutive patients from tertiary referral centres in Milan and Vienna [61% genotype 1 (G1), 30% advanced fibrosis, 33% IL28B rs12979860 CC].
RESULTS:
The p.148M/M genotype, detected in 8% of patients, did not influence SVR in the overall series (P = 0.29), but it was associated with SVR (3/17, 17% vs. 56/121, 46%; P = 0.034) and complete early viral response (4/17, 23% vs. 68/121, 56%; P = 0.018) in G1/4 patients with advanced fibrosis. After adjustment for age, viral load, IL28B CC genotype, treatment dose, and steatosis, p.148M/M remained a predictor of SVR in G1/4 patients with advanced fibrosis (OR 0.23, 95% CI 0.04-0.87). The p.148M/M genotype was associated with more advanced fibrosis in the overall series (P = 0.049), whereas the rs12979860 IL28B CC genotype only in patients negative for p.148M/M (P = 0.017), independently of age, BMI and alanine transaminase levels (OR 1.51, 95% CI 1.01-2.27).
CONCLUSIONS:
PNPLA3 p.148M/M genotype was negatively associated with SVR and early viral kinetics independently of steatosis, albeit only in difficult-to-cure G1/4 patients with advanced fibrosis, whereas stratification for the p.148M/M PNPLA3 genotype unmasked an association between IL28B CC genotype and more severe liver fibrosis.
