Background: Both Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) play a key role on dyslipidaemia. We aim to evaluate whether NPC1L1 and HMGCR genetic variants are associated with susceptibility of premature triple-vessel disease (PTVD).

Methods: Four single-nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, and rs2073547) of NPC1L1; and three SNPs (rs12916, rs2303151, and rs4629571) of HMGCR were genotyped in 872 PTVD patients (males ≤ 50 years old and females ≤ 60 years old), and 401 healthy controls.

Results: After adjusting for age and sex, rs12916 of HMGCR was associated with the risk of PTVD in dominance model [odds ratio (OR) = 1.68, 95% confidence intervals (CI): 1.29–2.18, P < 0.001], recessive model (OR = 1.43, 95% CI: 1.08–1.90, P = 0.013) and codominant model (OR = 1.38, 95% CI: 1.17–1.63, P < 0.001); meanwhile, rs4720470 of NPC1L1 was related to increased risk of PTVD in recessive model (OR = 1.74, 95% CI: 1.14–2.74, P = 0.013). Patients who carried both variant rs4720470 and rs12916 also had the risk of PTVD (P < 0.001); however, there were no correlation between these SNPs and the SNYTAX score (all P > 0.05).

Conclusions: This is the first report that rs4720470 is a novel polymorphism of the NPC1L1 gene associated with PTVD, and rs12916 of HMGCR gene appears to be a strong genetic marker of PTVD. Our study may improve the early warning, therapeutic strategies and drug development of PTVD.

背景：Niemann-Pick C1 样 1 (NPC1L1) 和 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR) 在血脂异常中起关键作用。我们旨在评估 NPC1L1 和 HMGCR 基因变异是否与早发三支血管疾病 (PTVD) 的易感性相关。

方法：NPC1L1 的四个单核苷酸多态性 (SNP) (rs11763759、rs4720470、rs2072183 和 rs2073547)；在 872 名 PTVD 患者（男性≤50 岁，女性≤60 岁）和 401 名健康对照者中对 HMGCR 的三个 SNP（rs12916、rs2303151 和 rs4629571）进行了基因分型。

结果：在调整年龄和性别后，HMGCR 的 rs12916 与优势模型中的 PTVD 风险相关 [优势比 (OR) = 1.68, 95% 置信区间 (CI): 1.29–2.18,磷< 0.001]，隐性模型（OR = 1.43，95% CI：1.08–1.90，磷= 0.013) 和共显性模型 (OR = 1.38, 95% CI: 1.17–1.63,磷< 0.001); 同时，NPC1L1 的 rs4720470 与隐性模型中 PTVD 风险增加有关（OR = 1.74, 95% CI: 1.14–2.74,磷= 0.013)。同时携带变异 rs4720470 和 rs12916 的患者也有 PTVD 的风险（磷< 0.001); 然而，这些 SNP 与 SNYTAX 评分之间没有相关性（所有磷> 0.05)。

结论：这是首次报道rs4720470是与PTVD相关的NPC1L1基因的新多态性，HMGCR基因的rs12916似乎是PTVD的强遗传标记。我们的研究可能会改善 PTVD 的早期预警、治疗策略和药物开发。