Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH

Vinh Truong,Philip Wells,Claire Perret,David-Alexandre Trégouët,Michael Wilson,Siying Huang,Dylan Aïssi,Jessica Dennis,France Gagnon,Nora Zwingerman,Irfahan Kassam,Pierre-Emmanuel Morange,Mathieu Lemire

doi:10.1038/s41598-017-09552-z

Abstract

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10−6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.

Highlights

Triglycerides are pivotal players in lipid metabolism in health and disease
The two study populations differed in a few aspects: compared to the MARseille Thrombosis Association (MARTHA) study participants, who are all venous thromboembolism patients, only 11 participants in the F5L family study had a venous thromboembolism
The MARTHA study was mainly composed of females (77.5%), whereas the F5L family study had an equal proportion of males and females

Summary

Introduction

Triglycerides are pivotal players in lipid metabolism in health and disease. They are important sources of energy and transporters of dietary fat. Elevated blood triglyceride levels are associated with several chronic conditions. Elevated blood triglycerides, defined by fasting levels ≥150 mg/dL (1.7 mmol/L), is present in over 30% of the general adult US population[4]. Lifestyle interventions associated with decreased Body Mass Index (BMI) have shown to reduce blood triglycerides in some contexts (reviewed in4) but not all[8]. Understanding the molecular mechanisms underlying blood triglyceride variation is key to identifying new intervention targets. Epigenetic marks, such as DNA methylation, are molecular mechanisms that are heritable and reversible, and have been associated with a wide range of environmental stimuli and disease phenotypes[10]. This supports the use of DNA methylation profiles in blood as a means to elucidate clinically relevant mechanisms

Methods

Results

Conclusion