Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
J Clin Lipidol. 2020 Jan-Feb;14(1):28-34.e2. doi: 10.1016/j.jacl.2020.01.003. Epub 2020 Jan 14.
Patients with mild-to-moderate hypertriglyceridemia (HTG) are thought to share specific genetic susceptibility factors that are also present in patients with severe HTG, but no data have been reported on this issue.
The objective of this study was to characterize genetic profiles of patients with mild-to-moderate HTG and compare them to patients with severe HTG.
DNA from patients with mild-to-moderate HTG was sequenced using our targeted sequencing panel, "LipidSeq". For each patient, we assessed 1) rare variants disrupting five TG metabolism genes and 2) the accumulation of 16 common single-nucleotide polymorphisms (SNPs) using a polygenic risk score. The genetic profiles for these patients were then compared with normolipidemic controls from the 1000 Genomes Project and with patients with severe HTG.
Across 134 patients with mild-to-moderate HTG, 9.0% carried heterozygous rare variants and 26.9% had an excess accumulation of common SNPs. Patients with mild-to-moderate HTG were 2.38 times (95% CI [1.13-4.99]; P = .021) more likely to carry a rare variant and 3.26 times (95% CI [2.02-5.26]; P < .0001) more likely to have an extreme polygenic risk score compared with the 1000 Genomes Project. In addition, patients with severe HTG were 1.86 times (95% CI [0.98-3.51]; P = .032) more likely to carry a rare variant and 1.63 times (95% CI [1.07-2.48]; P = .013) more likely to have an extreme polygenic risk score than patients with mild-to-moderate HTG.
We report an increased prevalence of genetic determinants in patients with an increased severity of the HTG phenotype when considering either rare variants disrupting TG metabolism genes or an excess accumulation of common SNPs. As well, the findings confirm that the most prevalent genetic contributor to HTG, regardless of severity, is polygenic SNP accumulation.
患有轻中度高甘油三酯血症（HTG）的患者被认为具有相同的特定遗传易感性因素，这些因素也存在于患有重度 HTG 的患者中，但尚未有关于此问题的报道。
本研究的目的是描述轻中度 HTG 患者的遗传特征，并将其与重度 HTG 患者进行比较。
使用我们的靶向测序panel“LipidSeq”对轻中度 HTG 患者的 DNA 进行测序。对于每位患者，我们评估了 1）破坏五个 TG 代谢基因的罕见变异，以及 2）使用多基因风险评分累积的 16 个常见单核苷酸多态性（SNP）。然后，将这些患者的遗传特征与 1000 基因组计划中的正常脂质对照组以及重度 HTG 患者进行比较。
在 134 名轻中度 HTG 患者中，9.0％的患者携带杂合罕见变异，26.9％的患者具有常见 SNP 的过度累积。与 1000 基因组计划相比，轻中度 HTG 患者携带罕见变异的可能性高 2.38 倍（95％CI [1.13-4.99]；P=0.021），携带极端多基因风险评分的可能性高 3.26 倍（95％CI [2.02-5.26]；P<0.0001）。此外，与轻中度 HTG 患者相比，重度 HTG 患者携带罕见变异的可能性高 1.86 倍（95％CI [0.98-3.51]；P=0.032），携带极端多基因风险评分的可能性高 1.63 倍（95％CI [1.07-2.48]；P=0.013）。
我们报告了在考虑 TG 代谢基因破坏的罕见变异或常见 SNP 过度累积时，HTG 表型严重程度增加的患者中遗传决定因素的发生率增加。此外，研究结果证实，无论 HTG 的严重程度如何，最常见的遗传贡献者都是多基因 SNP 累积。
