Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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轻度至中度高甘油三酯血症的多基因性。

背景

轻中度高甘油三酯血症（HTG）患者被认为具有重度HTG患者中也存在的特定遗传易感性因素，但有关此问题的数据尚未见报道。

目的

这项研究的目的是表征轻度至中度HTG患者的遗传特征，并将其与重度HTG患者进行比较。

方法

使用我们的目标测序小组“ LipidSeq”对轻度至中度HTG患者的DNA进行了测序。对于每位患者，我们使用多基因风险评分评估1）破坏5个TG代谢基因的稀有变异体，以及2）16种常见单核苷酸多态性（SNP）的积累。然后将这些患者的基因谱与1000基因组计划的正常血脂对照组以及重度HTG患者进行比较。

结果

在134例轻至中度HTG患者中，9.0％携带杂合的稀有变异，26.9％携带常见SNP的过量积累。轻至中度HTG患者 携带罕见变异的可能性高2.38倍（95％CI [1.13-4.99]；P = .021），而3.26倍（95％CI [2.02-5.26]；P  <.0001 ）与1000个基因组计划相比，更有可能具有极端的多基因风险评分。此外，重度HTG患者 携带稀有变异的可能性为1.86倍（95％CI [0.98-3.51]；P = .032 ）和1.63倍（95％CI [1.07-2.48]；P  = .013）与轻至中度HTG患者相比，更可能具有极端的多基因风险评分。

结论

我们报道，考虑到罕见的变异破坏TG代谢基因或常见SNP的过量积累时，HTG表型严重性增加的患者中遗传决定因素的患病率增加。同样，这些发现证实，不管严重程度如何，HTG最普遍的遗传因素是多基因SNP积累。