patatin样磷脂酶结构域包含3(PNPLA3)rs738409,跨膜6超家族成员2(TM6SF2)rs58542926和膜结合的O-酰基转移酶结构域包含7(MBOAT7)rs641738的单核苷酸多态性(SNP)与丙型肝炎感染(HCV)患者的预后的关系尚不清楚。本研究旨在评估PNPLA3,TM6SF2和MBOAT7与基线纤维化阶段和直接抗病毒药物(DAAs)根除HCV后肝纤维化进展的关联。2015年6月至2020年6月在北京大学第一医院接受DAAs的171例患者被纳入回顾性队列。瞬时弹性成像用于确定基线时的肝脏硬度测量(LSM),治疗结束(EOT),治疗后24周(W24),以及最后一次随访(LFU)访问。我们使用QIAampBloodMiniKit(Qiagen)进行全血基因组DNA提取和聚合酶链反应,用于PNPLA3,TM6SF2和MBOAT7扩增目标基因。在多因素logistic回归分析中,PNPLA3rs738409SNP与基线纤维化分期相关,基线时晚期纤维化(≥F3)的校正比值比(OR)为2.52(95%置信区间[CI]=1.096-5.794,p=0.03).G和GG等位基因可预测晚期纤维化(OR=1.98,95%CI=1.021-4.196,p=0.015;OR=3.12,95%CI=1.572-6.536,p=0.005)。同样,基线时TM6SF2rs58542926的OR为2.608(95%CI=1.081~6.29,p=0.033).T和TT等位基因可预测晚期纤维化(OR=2.3,95%CI=1.005-5.98,p=0.007;OR=3.05,95%CI=1.32-6.87,p=0.001)。调整后,MBOAT7rs641738T+TT等位基因与基线纤维化分期无独立关联(95%CI=0.707-2.959,p=0.312).在EOT,纤维化改善和纤维化未改善组中有35例患者和136例患者,分别。Logistic回归分析显示,PNPLA3rs738409中G等位基因与纤维化进展相关(OR=2.47,95%CI=1.125~5.89,p=0.003)。GG等位基因可预测纤维化进展(OR=2.95,95%CI=1.35-6.35,p=0.005)。同样,对于纤维化进展,TM6SF2rs58542926中T和TT等位基因的OR分别为1.82和2.21(95%CI=1.006-5.373,p=0.045;95%CI=1.18-5.75,p=0.01).在W24访问中,我们发现PNPLA3rs738409中的G等位基因与纤维化进展之间存在关联(OR=2.218,95%CI=1.095-5.631,p=0.015).此外,GG等位基因也可预测纤维化进展(OR=2.558,95%CI=1.252-5.15,p=0.008)。同样,TM6SF2rs58542926中T等位基因和TT等位基因对纤维化进展的OR分别为2.056和2.652(95%CI=1.013-5.592,p=0.038;95%CI=1.25-5.956,p=0.015).对于额外的确认,我们利用Cox比例风险模型调查了纤维化进展.在多变量模型中,PNPLA3rs738409中的G和GG等位基因与进展为晚期纤维化的风险增加相关(风险比[HR]1.566,95%CI=1.02-2.575,p=0.017;HR2.109,95%CI=1.36-3.271,p=0.001)。此外,在多变量模型中,TM6SF2rs58542926中的T和TT等位基因与进展为晚期纤维化的风险增加相关(HR=1.322,95%CI=1.003-1.857,p=0.045;HR=1.855,95%CI=1.35-2.765,p=0.006)。相比之下,MBOAT7中的rs641738在单变量和多变量模型中没有显示出显著的趋势。rs738409的PNPLA3CG/GGSNP和rs58542926的TM6SF2CT/TTSNP与使用DAAs根除HCV后的基线纤维化阶段和纤维化进展相关。
The relationship of single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 with outcomes in patients with hepatitis C infection (HCV) is unclear. This
study aimed to evaluate the association of PNPLA3, TM6SF2, and MBOAT7 with the baseline fibrosis stage and progression of liver fibrosis after HCV eradication with direct antiviral agents (DAAs). A total of 171 patients who received the DAAs at the Peking University First Hospital between June 2015 and June 2020 were included in the retrospective cohort. Transient elastography was used to determine liver stiffness measurements (LSMs) at the baseline, the end of treatment (EOT), 24 weeks after treatment (W24), and the last follow-up (LFU) visit. We used the QIAamp Blood Mini Kit (Qiagen) for whole blood genomic DNA extraction and polymerase chain reaction for PNPLA3, TM6SF2, and MBOAT7 amplification of the target gene. The PNPLA3 rs738409 SNP was associated with the baseline fibrosis stage in multivariate logistic regression analysis adjusted for other factors, and the adjusted odds ratio (OR) for advanced fibrosis (≥F3) at baseline was 2.52 (95% confidence interval[CI] = 1.096-5.794, p = 0.03). The G and GG alleles were predictive of advanced fibrosis (OR = 1.98, 95% CI = 1.021-4.196, p = 0.015; OR = 3.12, 95% CI = 1.572-6.536, p = 0.005). Similarly, the OR of TM6SF2 rs58542926 at baseline was 2.608 (95% CI = 1.081-6.29, p = 0.033). T and TT alleles were predictive of advanced fibrosis (OR = 2.3, 95% CI = 1.005-5.98, p = 0.007; OR = 3.05, 95% CI = 1.32-6.87, p = 0.001). After adjustment, the MBOAT7 rs641738 T plus TT alleles were not independently associated with the baseline fibrosis stage (95% CI = 0.707-2.959, p = 0.312). At the EOT, there were 35 patients and 136 patients in the fibrosis improvement and fibrosis non-improvement group, respectively. Logistic regression analysis showed that the G allele in PNPLA3 rs738409 was associated with fibrosis progression (OR = 2.47, 95% CI = 1.125-5.89, p = 0.003). The GG alleles were predictive of fibrosis progression (OR = 2.95, 95% CI = 1.35-6.35, p = 0.005). Similarly, the ORs of the T and TT alleles in TM6SF2 rs58542926 for fibrosis progression were 1.82 and 2.21, respectively (95% CI = 1.006-5.373, p = 0.045; 95% CI = 1.18-5.75, p = 0.01). At the W24 visit, we found that there was an association between the G allele in PNPLA3 rs738409 and fibrosis progression (OR = 2.218, 95% CI = 1.095-5.631, p = 0.015). Moreover, GG alleles were also predictive for fibrosis progression (OR = 2.558, 95% CI = 1.252-5.15, p = 0.008). Similarly, the OR of T allele and TT alleles in TM6SF2 rs58542926 for fibrosis progression was 2.056 and 2.652 (95% CI = 1.013-5.592, p = 0.038; 95% CI = 1.25-5.956, p = 0.015). For additional affirmation, we surveyed fibrosis progression utilizing the Cox proportional hazards model. G and GG alleles in PNPLA3 rs738409 were associated with an increased risk of progression to advanced fibrosis in multivariate model (hazard ratio [HR]1.566, 95% CI = 1.02-2.575, p = 0.017; and HR2.109, 95% CI = 1.36-3.271, p = 0.001, respectively). Besides, T and TT alleles in TM6SF2 rs58542926 were associated with an increased risk of progression to advanced fibrosis in multivariate model (HR = 1.322, 95% CI = 1.003-1.857, p = 0.045; and HR = 1.855, 95% CI = 1.35-2.765, p = 0.006, respectively). In contrast, rs641738 in MBOAT7 did not show a significant trend in the univariate and multivariate models. The PNPLA3 CG/GG SNP at rs738409 and TM6SF2 CT/TT SNP at rs58542926 were associated with the baseline fibrosis stage and fibrosis progression after HCV eradication with DAAs.