Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Erasme Hospital, Brussels, Belgium.
Hepatology. 2011 Jul;54(1):60-9. doi: 10.1002/hep.24350.
Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence severity of fibrosis in nonalcoholic fatty liver disease. The aim of this study was to assess the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. We recruited 537 Caucasian CHC patients from three European centers (Brussels, Belgium [n = 229]; Hannover, Germany [n = 171]; Lyon, France [n = 137]); these patients were centrally genotyped for the PNPLA3 (rs738409 C>G) polymorphism. We studied the influence of rs738409 and other variants in the PNPLA3 region on steatosis and fibrosis assessed both in a cross-sectional and longitudinal manner. Seven other variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the interferon lambda 3 (IL28B) [rs12979860 C>T] variant both as a comparator and as a positive control. After adjustment for age, sex, body mass index, alcohol consumption, and diabetes, rs738409 mutant G allele homozygote carriers remained at higher risk for steatosis (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.08-6.03, P = 0.034), fibrosis (OR 3.13, 95% CI 1.50-6.51, P = 0.002), and fibrosis progression (OR 2.64, 95% CI 1.22-5.67, P = 0.013). Conversely, rs738409 was not independently associated with treatment failure (OR 1.07, 95% CI 0.46-2.49, P = 0.875) and did not influence clinical or biological variables.
The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in CHC. This polymorphism may represent a valuable genetic predictor and a potential therapeutic target in CHC liver damage.
只有 20%的慢性丙型肝炎（CHC）患者会发展为肝硬化，纤维化进展仍然高度不可预测。最近的全基因组关联研究发现了 patatin-样磷脂酶-3（PNPLA3）基因（rs738409 C>G）中的一个遗传变异与脂肪变性有关，进一步证明该变异与非酒精性脂肪性肝病的纤维化严重程度有关。本研究旨在评估该多态性对 CHC 患者肝组织损伤和抗病毒治疗反应的影响。我们从三个欧洲中心（比利时布鲁塞尔[229 例]；德国汉诺威[171 例]；法国里昂[137 例]）招募了 537 例白人 CHC 患者；这些患者的 patatin-样磷脂酶-3（rs738409 C>G）多态性进行了中心基因分型。我们研究了 rs738409 以及 PNPLA3 区域内其他与脂肪变性和纤维化相关的变异对脂肪变性和纤维化的影响，这些影响分别以横断面和纵向方式进行评估。还包括了另外 7 个先前与纤维化进展相关的变体。最后，我们使用干扰素 lambda 3（IL28B）[rs12979860 C>T]变体作为比较和阳性对照，探讨了 rs738409 对标准抗病毒治疗反应的影响。在调整年龄、性别、体重指数、饮酒和糖尿病后，rs738409 突变 G 等位基因纯合子携带者仍处于更高的脂肪变性风险（比值比[OR]2.55，95%置信区间[CI]1.08-6.03，P = 0.034）、纤维化（OR 3.13，95%CI 1.50-6.51，P = 0.002）和纤维化进展（OR 2.64，95%CI 1.22-5.67，P = 0.013）。相反，rs738409 与治疗失败（OR 1.07，95%CI 0.46-2.49，P = 0.875）无关，也不影响临床或生物学变量。
PNPLA3（rs738409 C>G）多态性有利于 CHC 中的脂肪变性和纤维化进展。该多态性可能是 CHC 肝损伤的一个有价值的遗传预测因子和潜在的治疗靶点。
