含patatin样磷脂酶域3（rs738409C>G）基因多态性对慢性丙型肝炎纤维化进展和脂肪变的影响
只有20%的慢性丙型肝炎（CHC）患者会发展为肝硬化，并且纤维化进展存在高度的不可预测性。近期一项广泛基因组相关性研究表明在含patatin样磷脂酶域3（PNPLA3）基因上的一个基因突变（rs738409C>G）与脂肪变性有关，并且进一步论证该基因突变可影响非酒精性脂肪肝的纤维化严重程度。此项研究的目的就是评估这个基因多态性对肝脏组织损伤和CHC患者抗病毒治疗应答的影响。我们招募了537例来自3个欧洲中心（比利时布鲁塞尔n=229,德国汉诺威n=171,法国里昂n=137）白种CHC患者。集中检测了这些患者PNPLA3（rs738409C>G）的基因多态性。我们用横向和纵向两种方法研究了rs738409和PNPLA3区其它突变点对脂肪变和纤维化的影响。以前研究证明与纤维化进展有关的其它7个基因也纳入该研究中。最后，我们以干扰素λ3（IL28）[rs12979860C>T]突变作为参照和阳性对照，探索了rs738409对标准抗病毒治疗应答的影响。经过对年龄、性别、体重指数、酒精摄入和糖尿病调整后，rs738409突变的G等位纯合子携带者对脂肪变（OR=2.55,95%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）存在高危险。相反地，rs738409与抗HCV治疗失败并不独立相关（OR=1.07,95%CI 0.46-2.49，p=0.875），也不影响临床或生物变异。结论：具有PNPLA3（rs738409C>G）基因多态性的CHC患者易于发生脂肪变和纤维化进展。这个基因的多态性对CHC患者肝损伤可能是一个有价值的基因预测因子和潜在的治疗靶向。
吉林大学第一医院肝胆胰内科 陈林姣 摘译
本文首次发表于[Hepatology, 2011,54（1）：60-69]
Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression
and steatosis in chronic hepatitis C
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 PNPLA3 gene (rs738409 C>G) associated with steatosis, that was further demonstrated to influence severity of fibrosis in non-alcoholic fatty liver disease. Our aim was to study the impact of this polymorphism on histological liver damage and response to antiviral therapy in CHC. 537 Caucasian CHC patients were recruited from 3 European centers (Brussels, Belgium [n=229], Hannover, Germany [n=171] and Lyon, France [n=137]) and 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. Nine others variants previously associated with fibrosis progression were included. Finally, we explored the impact of rs738409 on response to standard antiviral therapy using the IL28B rs12979860 C>T variant both as a comparator and as a positive control. After adjustment for age, gender, 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. CONCLUSION: 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. (HEPATOLOGY 2011.).
