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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.

Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. Three differentially methylated positions cg21607669 ( ), cg26382848 ( ) and cg10701000 ( ) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain ( ) at chromosome 6. We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.

The gut microbiota is recognized to have an important role in energy storage and the subsequent development of obesity. To date, bariatric surgery (indicated for severe obesity) represents the only treatment that enables substantial and sustained weight loss. Bariatric surgery is also a good model to study not only the pathophysiology of obesity and its related diseases but also the mechanisms involved in their improvement after weight reduction. Scarce data from humans and animal models have demonstrated that gut microbiota composition is modified after Roux-en-Y gastric bypass (RYGB), suggesting that weight reduction could affect gut microbiota composition. However, weight loss might not be the only factor responsible for those modifications. Indeed, bariatric surgery not only improves hormonal and inflammatory status, but also induces numerous changes in the digestive tract that might account for the observed modifications of microbiota ecology. In future bariatric surgery studies in humans or mice, these major surgery-induced modifications will need to be taken into account when analyzing the link between gut microbiota composition, obesity, its complications and their improvement after bariatric surgery. This Review outlines the potential mechanisms by which the major changes in the digestive tract after bariatric surgery can affect the gut microbiota.

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.