ABSTRACT

Involvement of extracellular nicotinamide phosphoribosyltransferase (eNAMPT, i.e., visfatin or pre-B-cell colony-enhancing factor), a cancer metabokine, in chronically hepatitis C virus (HCV)-infected (CHC) patients with sustained virological responses (SVRs) remains elusive. This 8-year prospective cohort study evaluated eNAMPT profiles of 842 consecutive CHC patients, including 519 who had completed an anti-HCV therapy course and pre-therapy and 24-week post-therapy surveys. For 842 patients, pre-therapy associations were HCV RNA, homeostatic model assessment for insulin resistance (HOMA-IR) index, and body mass index with eNAMPT levels, and NAMPT-rs61330082 T allele with total cholesterol levels. NAMPT-rs10953502, NAMPT-rs2058539, and NAMPT-rs61330082 were in a linkage disequilibrium block, which was associated with total cholesterol levels. Compared to pre-therapy levels, at 24 weeks post-therapy, decreased eNAMPT and increased lipid levels were observed in SVR patients (n = 427). Among SVR patients, higher cumulative incidences of cardiovascular events occurred in those with a NAMPT-rs61330082 TT genotype than those with non-TT genotypes (28.2% vs. 8.4%, p < 0.001). NAMPT-rs61330082 TT genotype was independently associated with incident cardiovascular events (95% CI hazard ratio (HR): 1.88–10.37; HR: 4.415); no eNAMPT profiles were associated with incident malignancies. Of CHC patients, hepatic vascular endothelial cells and baseline peripheral leukocytes expressed higher eNAMPT levels than controls, and peripheral eNAMPT-positive leukocyte proportions decreased after SVR. During HCV infection, eNAMPT involvement in glucose metabolism was modulated by HCV RNA linked to lipid metabolism and NAMPT-associated SNPs. Hepatic endothelial cells and peripheral leukocytes potentially secrete eNAMPT. Caution is required for incident cardiovascular events in SVR patients with NAMPT-rs61330082 TT genotype.

摘要

细胞外烟酰胺磷酸核糖基转移酶（eNAMPT，即内脂素或前 B 细胞集落增强因子）（一种癌症代谢因子）在具有持续病毒学应答 (SVR) 的慢性丙型肝炎病毒 (HCV) 感染 (CHC) 患者中的参与仍然难以捉摸。这项为期 8 年的前瞻性队列研究评估了 842 名连续 CHC 患者的 eNAMPT 概况，其中包括 519 名已完成抗 HCV 治疗过程以及治疗前和 24 周治疗后调查的患者。对于 842 名患者，治疗前的关联包括 HCV RNA、胰岛素抵抗稳态模型评估 (HOMA-IR) 指数、体重指数与 eNAMPT 水平以及 NAMPT-rs61330082 T 等位基因与总胆固醇水平。NAMPT-rs10953502、NAMPT-rs2058539 和 NAMPT-rs61330082 处于连锁不平衡区块，与总胆固醇水平相关。与治疗前水平相比，治疗后 24 周，SVR 患者 (n = 427) 观察到 eNAMPT 降低和血脂水平升高。在 SVR 患者中，具有 NAMPT-rs61330082 TT 基因型的患者心血管事件的累积发生率高于非 TT 基因型的患者（28.2% vs. 8.4%，p < 0.001）。NAMPT-rs61330082 TT 基因型与心血管事件独立相关（95% CI 风险比 (HR)：1.88–10.37；HR：4.415）；没有 eNAMPT 谱与恶性肿瘤发生相关。在 CHC 患者中，肝血管内皮细胞和基线外周白细胞表达的 eNAMPT 水平高于对照组，且 SVR 后外周 eNAMPT 阳性白细胞比例下降。在 HCV 感染期间，eNAMPT 参与葡萄糖代谢受到与脂质代谢相关的 HCV RNA 和 NAMPT 相关 SNP 的调节。肝内皮细胞和外周白细胞可能分泌 eNAMPT。需要警惕携带 NAMPT-rs61330082 TT 基因型的 SVR 患者发生心血管事件。