Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
J Hepatol. 2015 Mar;62(3):512-8. doi: 10.1016/j.jhep.2014.10.011. Epub 2014 Oct 20.
BACKGROUND & AIMS: Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis.
The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis.
Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03).
The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.
载脂蛋白样磷脂酶域包含 3 号（PNPLA3）的遗传变异体和糖尿病与慢性丙型肝炎（CHC）感染患者的肝脏疾病严重程度相关。我们旨在探讨其在确定丙型肝炎病毒（HCV）相关肝纤维化中的相互作用。
在 1077 例经活检证实的 CHC 患者中验证了 PNPLA3 基因多态性 rs738409。分析了其他临床变量，包括糖尿病状态，以确定与桥接纤维化相关的因素。
进展性肝纤维化患者 GG 基因型（14.5%比 10.4%，p=0.06 在隐性模型中）和 GG/GC 基因型携带率（64.0%比 56.8%，p=0.03 在显性模型中）更高。逐步逻辑回归分析显示，预测进展性肝纤维化的因素包括年龄（比值比[OR]：1.02，95%置信区间[CI]：1.008-1.037，p=0.002）、糖尿病（OR：1.81，CI：1.236-2.653，p=0.002）、甲胎蛋白（OR：1.006，CI：1.001-1.01，p=0.01）、血小板计数（OR：1.009，CI：1.006-1.012，p<0.001）和 PNPLA3 rs738409 CG/GG 基因型（OR：1.34，CI：1.006-1.785，p=0.046）。当根据糖尿病状态对患者进行分组时，PNPLA3 基因变异仅在糖尿病患者中与进展性肝纤维化相关，而在非糖尿病患者中则无相关性。在糖尿病患者中，使用隐性模型（OR：4.53，CI：1.356-15.106，p=0.014）或显性模型（OR：2.20，CI：1.026-4.734，p=0.04），PNPLA3 基因是桥接纤维化的最重要预测因子。与非糖尿病患者相比，具有糖尿病/ GG 基因型的患者更可能发生进展性肝纤维化（OR：8.79，CI：2.889-26.719，p<0.001），其次是具有糖尿病/非-GG 基因型的患者（OR：1.55，CI：1.048-2.286，p=0.03）。
PNPLA3 基因变异在 HCV 相关进展性肝纤维化中的作用在糖尿病患者中增强。这种强烈的遗传-环境相互作用导致 CHC 患者发生严重肝脏疾病的风险增加。
